Patent Description:
Photodynamic therapy (PDT) is one of the most promising techniques being explored for use in a variety of medical applications [<NUM>], [<NUM>] and particularly is a well-recognized treatment for the destruction of tumors [<NUM>]. Photodynamic therapy uses light and a photosensitizer (a dye) to achieve its desired medical effect. A large number of naturally occurring and synthetic dyes have been evaluated as potential photosensitizers for photodynamic therapy. Perhaps the most widely studied photosensitizers are the tetrapyrrolic macrocyclic compounds. Among them, especially porphyrins and chlorins have been tested for their PDT efficacy. Porphyrins are macrocyclic compounds with bridges of one carbon atom joining pyrroles to form a characteristic tetrapyrrole ring structure. There are many different classes of porphyrin derivatives including those containing dihydro-pyrrole units. Chlorins, as referred to in the present invention, are porphyrin derivatives containing one dihydro-pyrrole unit whereas bacteriochlorins are characterized by two dihydro-pyrrole units (in general in chlorins one double bond of the aromatic system in β-position is absent and in bacteriochlorins two opposite double bonds are absent compared to the porphyrin). As examples of tetrapyrrolic macrocyclic compounds used as photosensitizers, <CIT> discloses glyco-substituted dihydroxy-chlorins for antibacterial PDT, <CIT> provides β,β'-dihydroxy meso-substituted chlorins as photosensitizers, and <CIT> discloses tetrapyrrole compounds containing a fluorinated substituent where the compound is a chlorin or a bacteriochlorin for PDT diagnostic and therapeutic application.

There are several properties that an effective photosensitizer should accomplish. Among them, a desirable characteristic in order to efficiently destroy deep target tissues is a strong absorption at long wavelength. Many current photosensitizers are not efficient enough as they have low absorption in the red region of the spectrum. Chlorins have the advantage that they possess an intense absorption in the red and near-infrared region of the electromagnetic spectrum. As light of longer wavelength penetrates deeper into the tissue, it is thus possible to treat e.g. more expanded tumors, if the PDT is employed for tumor therapy. Chlorins possessing potential for PDT can either be derived from natural sources or from total synthesis. Another issue for PDT is the non-specific accumulation of the photosensitizer in undesired tissues (e.g. the skin) which leads to - in the case of skin accumulation - prolonged photosensitivity of the patient which is unpleasant for the patient and can lead to severe burns and scarring.

Thus, there is a need to enhance the effectiveness of prior art biologically active compounds used as photosensitizers in order to successfully perform a wide range of light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases. Moreover, it is necessary to provide novel methods of preparation and improved photosensitizer formulations more potent than those available up to date.

Photosensitzers for anti-tumor PDT are highly lipophilic compounds with a low or no water solubility [<NUM>]. So, for the administration of photosensitizers suitable pharmaceutical formulations are needed. In this respect, International Publication N° <CIT> discloses suitable photosensitizer formulations based on poly-lactic-co-glycolic-acid (PLGA) whereas International Publication N° <CIT> discloses formulations based on human serum albumin (HSA) nanoparticles. International Publication N° <CIT> discloses suitable liposomal formulations for the photosensitizers that are subject of the present invention. Possible oral formulations for such photosensitizers are described in International Publication N° <CIT> and in International Publication N° <CIT>.

Nanoparticle formulations of photosensitizers for tumor treatment can benefit from the EPR effect (enhanced permeability and retention effect) of malign tissue where particles of a certain size can more easily leave the blood stream due to the specific structure of tumor tissue and where they are retained for longer periods due to the underdeveloped lymphatic system [<NUM>], [<NUM>]. In the art, a number of methods are described to connect photosensitizer molecules to macromolecular or nanoparticle carriers [<NUM>]. One example for possible carrier systems are polymers. <CIT> discloses polymers as carrier systems for pharmaceuticals. However, specifically for photosensitizers there is a need to release the photosensitizer molecule from the nanoparticle or the macromolecular carrier, given that the close proximity of the photosensitizer molecules to the carrier system changes their photophysical behavior and may lead to a suppression of the desired action, i.e. the generation of reactive oxygen species (ROS) on illumination.

It is the aim of the present invention to provide biologically active compounds that can be used as photosensitizers for a wide range of applications including light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases.

It is an objective of the present invention to use the chemically stable porphyrin and chlorin derivatives for various medical applications such as photodynamic therapy.

It is yet an objective of the present invention to provide A<NUM>B-tetrakis-meso-substituted porphyrin and chlorin structures that can be used in the photodynamic therapy of tumors and other hyperproliferative diseases, dermatological disorders, viral or bacterial infections, opthamological disorders or urological disorders.

It is yet another object of the present invention to provide unsymmetrically tetrakis-meso-substituted porphyrin and chlorin structures that can be used for the fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis and similar inflammatory diseases.

It is yet another objective of the present invention to provide pharmaceutically acceptable formulations for the biologically active compounds of the present invention such as liposomal formulation, physical encapsulation or covalent attachment to nanoparticles to be injected, avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.

It is yet another objective of the present invention to provide conjugates of porphyrin and chlorin photosensitizers attached to highly water-soluble polymers such as hyperbranched polyglycerol (hPG) to ensure a sufficient water-solubility of these conjugates.

It is yet another objective of the present invention to provide an A<NUM>B-porphyrin or chlorin for the specific linkage to different carrier systems via various functional groups (amine, hydroxyl, maleimide, cyclooctyne, alkyne, alkene).

It is yet another objective of the present invention to provide a porphyrin or chlorin, which is linked to a carrier system. The linkage possesses one or more cleavable moieties which releases the active compound under defined conditions. This allows the controlled release at the side of action for the active compound in biological systems.

It is yet another objective of the present invention to provide a porphyrin or chlorin, which is linked to a carrier system with a functional targeting group. This allows the active targeting at the side of action, which increases the phototoxicity.

It is another object of the present invention to provide highly amphiphilic compounds to be used in the PDT-treatment of tumors, dermatological disorders, viral or bacterial infections, opthamological disorders or urological disorders.

The invention is set out be the in the appendant set of claims. Below methods are disclosed to obtain biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders. An embodiment of the disclosed methods consists of a method to synthesize an A<NUM>B-porphyrin with defined meso-substituents and then converting the B-position to a functional group which allows the connection of this porphyrin system. In another embodiment the substituent at the B-position consists of a cleavable linker, which allows the controlled release at the site of action. Another embodiment is to provide amphiphilic compounds with a higher membrane affinity and increased PDT-efficacy. Another embodiment consists of formulate the desired A<NUM>B-porphyrin onto a polymeric nanoparticle formulation to be injected avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.

The above and other objects, features and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings.

The present disclosure provides biologically active compounds that can be used as photosensitizers for a wide range of light irradiation treatments such as photodynamic therapy of cancer, hyperproliferative diseases, dermatological disorders, viral or bacterial infectious diseases, ophthalmological disorders and/or urological disorders. The alternative photosensitizers provided herein have the advantage that they are easily produced and characterized. Moreover, as the present disclosure provides methods to tailor amphiphilic compounds for desired PDT applications, target tissue selectivity is increased and thus PDT efficacy.

The biologically active compounds of the present disclosure that can be used for different medical indications, particularly PDT, are A<NUM>B-tetrakis-meso-substituted porphyrin structures which are loaded onto polymeric nanoparticles. Additionally, the novel compounds extend their applications as they can be used for fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis and similar inflammatory diseases.

In order to obtain the photosensitizers the present disclosure uses the chemically stable porphyrin and chlorin derivatives according to formulae shown in <FIG> and provides methods of preparation to obtain meso substituted porphyrins, more particularly the A<NUM>B-tetrakis-meso-substituted porphyrin loaded on polymeric nanoparticles structures that can be used in the photodynamic therapy.

An embodiment of the present disclosure consists of a method to synthesize an A<NUM>B-porphyrin or chlorin with defined of meso-substituents. The B substituent contains the functionality (maleimide, cyclooctyne, alkyne, alkene, amine or hydroxyl) for linking it to the carrier system and the cleavable moiety (e.g. an acetal or disulfide containing linker; an example of a porphyrin of the A<NUM>B type is illustrated in <FIG>, where e.g. A is the polar substituent and B the cleavable linker with the functional group) and then linking this porphyrin or chlorin to a polymeric carrier system e.g. by copper-catalyzed click or copper-free click reaction.

In yet another embodiment of the present disclosure an A<NUM>B-porphyrin or chlorin is synthesized and connected via a cleavable disulfide moiety to the polymeric carrier system.

In yet another embodiment of the present disclosure an A<NUM>B-porphyrin or chlorin is synthesized and connected via a cleavable acetal moiety to the polymeric carrier system.

In a specifically preferred embodiment of the present disclosure a porphyrin or chlorin of the A<NUM>B-type is synthesized, having <NUM>-hydroxyphenyl as substituent A and pentafluorophenyl residue as substituent B. Then this porphyrin is modified via a nucleophilic aromatic substitution with cystamine. To obtain the cyclooctyne functionality the porphyrin or chlorin is then reacted with (<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate. The final porphyrin can be linked via a copper-free click-reaction to hPG-azide.

In another specifically preferred embodiment of the present disclosure a porphyrin or chlorin of the A<NUM>B-type is synthesized, having <NUM>-hydroxyphenyl as substituent A and pentafluorophenyl residue as substituent B. Then this porphyrin is modified via a nucleophilic aromatic substitution with cystamine. To obtain the alkyne functionality the porphyrin or chlorin is then reacted with propiolic acid, and e.g. DCC and HOBt hydrate. The final porphyrin or chlorin can be linked to a polymer carrying azide groups (hPG-azide) via copper-catalyzed click-reaction.

In a specifically preferred embodiment of the present disclosure a porphyrin or chlorin of the A<NUM>B-type is synthesized, having <NUM>-hydroxyphenyl as substituent A and pentafluorophenyl residue as substituent B. Then this porphyrin is modified via a nucleophilic aromatic substitution with diaminohexane. To obtain the cyclooctyne functionality the porphyrin is then reacted with (<NUM>R,<NUM>S,<NUM>r)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate. The final porphyrin or chlorin is linked via a copper-free click-reaction to a polymer (hPG) involving azide groups in connection with acetal groups thereby achieving the synthesis of a cleavable conjugate.

In a specifically preferred embodiment of the present disclosure a porphyrin or chlorin of the A<NUM>B-type is synthesized, having <NUM>-hydroxyphenyl as substituent A and pentafluorophenyl residue as substituent B. Then this porphyrin or chlorin is modified via a nucleophilic aromatic substitution with cystamine. To obtain the cyclooctyne functionality the porphyrin or chlorin is then reacted with (<NUM>R,<NUM>S,<NUM>r)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate. The final porphyrin or chlorin is linked via copper-free click-reaction to a polymer (hPG) involving azide groups in connection with acetal groups, thereby achieving the synthesis of a cleavable conjugate. The specific advantage of this conjugate is that it can be cleaved under reductive (cystamine linker) as well as acidic (acetal linker) conditions.

In yet another specifically preferred embodiment of the present disclosure conjugates are prepared in which photosensitizers are attached to a polymer (hPG) and in which in addition glyco-substituents are also attached to this polymer, which render these glyco-photosensitizer-polymer conjugates especially suitable for a use in antibacterial photodynamic therapy. In this case the photosensitizers may directly be attached to the polymer or may be attached to the polymer via a cleavable linker. Adjusting the amount of glyco-substitution can be used to enhance the phototoxic effect of the conjugates against bacteria (see examples <NUM>. <NUM>-<NUM>.

Acceptable starting materials for the synthesis of the porphyrins or chlorins which are the part of the subject of the present disclosure are pyrrole and aldehydes. More specifically, pyrrole and two aldehydes, two aromatic aldehydes are employed for the synthesis of the A<NUM>B-substituted porphyrins which are the basis of the synthesis of the corresponding cleavable porphyrin or chlorin polymer conjugates. Pyrrole and aldehydes are subjected to a condensation reaction. Suitable methods for this condensation have long been known in the art [<NUM>]. For the synthesis of chlorins from porphyrins methods are known in the art e.g. [<NUM>], [<NUM>].

The synthesis of porphyrins that can be linked to polymers via linkers is exemplified with examples <NUM>-<NUM> and examples <NUM>-<NUM>. The synthesis of porphyrins bearing specifically disulfide or acetal as the cleavable linker is exemplified with examples <NUM>-<NUM> and <NUM>-<NUM>. The use of such cleavable porphyrins or chlorins as substrates for the linkage to hyperbranched polyglycerol (hPG) is a key feature of the present invention as it gives access to controlled release at the side of action for the active compound in biological systems. This is illustrated with examples <NUM>-<NUM>. The linkage of porphyrins to hyperbranched polyglycerol (hPG) via other linkers is exemplified with examples <NUM>-<NUM>.

Linkages of porphyrins to polymeric carrier systems that are known in the art [<NUM>] use covalent bonds which are not cleavable like the conjugates of the present disclosure. The use of non-cleavable connections between the photosensitizer molecules and the polymer is not favorable because they can quench each other (reduction of phototoxicity). It is a specific advantage of the conjugates of the present disclosure that they can be prepared in diverse molecular weights and sizes which i. allows to fine-tune the properties of the conjugates in such a way that they enrich at the side of action via the EPR effect, which is limited to a specific nanoparticle size-range to achieve intra-tumoral accumulation [<NUM>]. To achieve the desired nanoparticle size-range the polymer-porphyrin or polymer-chlorin conjugates may also be prepared making use of specific polymerization techniques (e.g. nanogel precipitation).

Examples <NUM>-<NUM> illustrate the cleavability of the linkers, and examples <NUM>-<NUM> illustrate the phototoxic effect in cell culture and in bacteria.

PDT is accomplished by first incorporating the derivatives into a pharmaceutically acceptable application vehicle (which maybe e.g. an ethanolic or water-based solution of the conjugates or the porphyrin or chlorin derivatives but also a combination with other nanoparticles or a liposomal formulation) for delivery of the derivatives or conjugates to a specific treatment site. After administering the derivatives or conjugates in the vehicle to a treatment area, sufficient time is allowed so that the porphyrin and chlorin derivatives preferentially accumulate in the diseased tissue. Lastly, the treatment area is irradiated with light of a proper wavelength and sufficient power to activate the porphyrin or chlorin derivatives to induce necrosis or apoptosis in the cells of said diseased tissue. Thus, one of the main advantages is that convenient pharmaceutical formulations can be created for the biologically active compounds of the present invention such as the linkage to polymeric nanoparticles to be injected avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems. Due to their amphiphilic nature, the chemically stable porphyrin and chlorin derivatives of the present disclosure can be prepared in various pharmaceutically acceptable and active preparations for different administration methods, e.g. injections. In a specifically preferred embodiment such amphiphilic compounds are loaded onto polymeric nanoparticles (examples <NUM>-<NUM> and <NUM>-<NUM>). This polymeric nanoparticle formulation can then be injected avoiding undesirable effects such as precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.

The following examples are presented to provide those of ordinary skill in the art with a full and illustrative disclosure and description of how to make the porphyrin derivatives of the invention and are not intended to limit the scope of what the inventor regards as the invention. Though examples are shown for porphyrins it is clear that the methods employed (e.g. the nucleophilic functionalization to the linkers and the connection to the polymer carriers) are also applicable to other porphyrinoids e.g. corroles or BODIPYs. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature etc.), but some experimental errors and deviations should be accounted for. Also, best measures have been taken to name the compounds with their systematic IUPAC name, nevertheless the basic reference are the given structural formulas based on the experimental spectroscopic data.

L-Ascorbic acid sodium salt (<NUM>%); dimethyl sulfoxide (DMSO) (≥ <NUM>%) extra dry over molecular sieves; dimethylformamide (DMF) (<NUM>%) extra dry over molecular sieves; nitromethane (≥ <NUM>%) for analysis; sodium methoxide, <NUM> solution in methanol; tetrahydrofuran (<NUM>%) extra dry over molecular sieve, stabilized; triethyl amine pure (<NUM>%) and trimethyl orthoformate (<NUM>%) were purchased from Acros Organics. Cystamine hydrochloride (≥ <NUM>%); <NUM>,<NUM>-dicyclohexylcarbodiimide (DCC) (<NUM>%); <NUM>-hydroxybenzotriazole hydrate (HOBt hydrate); <NUM>-maleimidopropionic acid N-hydroxysuccinimide ester (<NUM>%); methanol (≥ <NUM>%); propargylamine (<NUM>%); propiolic acid (<NUM>%) and triethylamine (≥ <NUM>%) were purchased from Sigma Aldrich. Dichloromethane (DCM) (≥ <NUM>%) was purchased from Fisher Chemical. Sodium acetate x <NUM><NUM>O for analysis (<NUM>%); sodium dihydrogen phosphate (<NUM>%) pure and zinc acetate x <NUM><NUM>O for analysis (<NUM>%) were purchased from Grassing. Ammonia solution (≥ <NUM>%) pure; dimethyl sulfoxide ROTIDRY® (≤ <NUM> ppm H<NUM>O) (≥ <NUM>%); sodium chloride (≥ <NUM>%) p. , ACS, ISO; sodium hydroxide (≥ <NUM>%) and sodium sulfate (≥ <NUM>%) were purchased from Roth. <NUM>-Hydroxybenzaldehyde (≥ <NUM>%) for synthesis and sodium hydrogen phosphate (≥ <NUM>%) for analysis were purchased from Merck. Indium(III) trifluoromethane sulfonate (<NUM>%) was purchased from ABCR. Tetrahydrofuran (THF) (≥ <NUM>%) for HPLC was purchased from VWR. <NUM>,<NUM>-Diaminohexane (≥ <NUM>%) was purchased from Alfa Aesar. All these chemicals were used without further purification. Acetone-D<NUM> (<NUM>%); chloroform-D<NUM> (<NUM>%) stab. with silver; deuterium oxide (<NUM>%), methyl alcohol-D<NUM> (<NUM>%) and tetrahydrofuran-Ds (<NUM>%) were purchased from Deutero GmbH. <NUM>-(Allyloxy)-<NUM>-(dimethoxymethyl)benzene [<NUM>], <NUM>-(oxiran-<NUM>-ylmethoxy)benzaldehyde[<NUM>], (<NUM>R,<NUM>S,<NUM>r)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate exo + (1R,<NUM>,<NUM>)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate endo ([<NUM>]; [<NUM>]); hPG-acetal-azide ([<NUM>]; [<NUM>]); Propargylated-mannose protected + hPG-mannose-azide[<NUM>]; hPG-azide[<NUM>]; <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-pentafluorophenylporphyrin + <NUM>,<NUM>,<NUM>-tris(<NUM>-acetoxyphenyl)-<NUM>-pentafluorophenylporphyrin [<NUM>] and <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(<NUM>,<NUM>-dihydroxypropoxy)tetrafluorophenyl]porphyrin[<NUM>] were prepared according to the literature or with slight modifications. All solvents were dry or distilled before using.

Thin-layer chromatography (TLC): TLC analysis was performed on Merck silica gel <NUM> F<NUM> precoated aluminium sheets with fluorescence indicator F<NUM>. In addition, detection of the intrinsic tetrapyrrole fluorescence was performed by UV light at <NUM>.

Column chromatography: The preparative purification of mixtures by column chromatography was conducted on Silica gel, pore size <NUM> A°, <NUM>-<NUM> particle size, high purity contains <NUM>% Ca from Fluka or MN Silica Gel <NUM>, <NUM>-<NUM>/<NUM>-<NUM> mesh, American Society for Testing (ASTM) for column chromatography from Machery-Nagel. The different eluents and the brand of the silica gel used in the synthesis are given in the individual procedures.

Dialysis: Dialysis (dialysis tubing benzoylated, avg. flat width <NUM> (<NUM> in. ), Sigma Aldrich) was performed in a <NUM> or <NUM> beaker and the solvents were changed <NUM> times over a period of <NUM> hours. The used solvents are described in synthesis.

NMR spectroscopy: <NUM>H, <NUM>C and <NUM>F spectra were recorded on Bruker BioSpin™ AC250 (<NUM>H NMR: <NUM>), JEOL™ ECX <NUM> (<NUM>H NMR: <NUM>, <NUM>F NMR: <NUM>), JEOL™ ECP <NUM> (<NUM>H NMR: <NUM>, <NUM>C NMR: <NUM>, <NUM>F NMR: <NUM>) and Bruker BioSpin AVANCE700 (<NUM>H NMR: <NUM>, <NUM>C NMR: <NUM>) instruments. As deuterated solvents CDCl<NUM>, [D6]Acetone, D<NUM>O, CD<NUM>OD and [D8]THF were used. Chemical shifts δ are given in ppm relative to tetramethylsilane (TMS) as an internal standard or relative to the resonance of the solvent (<NUM>H NMR: chloroform: δ = <NUM> ppm, acetone: δ = <NUM> ppm, deuterium oxide: δ = <NUM> ppm, methanol: δ = <NUM> ppm + <NUM> ppm and THF δ = <NUM> ppm + <NUM> ppm, <NUM>C NMR: chloroform: δ = <NUM> ppm, acetone: δ = <NUM> ppm + <NUM> ppm, methanol: δ = <NUM> ppm and THF δ = <NUM> ppm + <NUM> ppm). All spectra were recorded at RT. Abbreviations for the signals: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), p (pentet), h (heptet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet) and td (triplet of doublet).

MS spectrometry: Electrospray ionization (ESI) mass spectra were measured on an Agilent <NUM> ESI-TOF from Agilent Technologies.

UV/Vis Spectroscopy: The UV/Vis measurements were performed on a Specord S300 spectrometer from Analytik Jena at RT. The used solvents are given in the individual procedure.

Melting point (m. ) measurements: The m. measurements were performed on a Thermovar m. microscope from Reichert.

In a sample tube with magnetic stirrer <NUM>-hydroxybenzaldehyde (<NUM>%, <NUM>, <NUM>µmol), trimethyl orthoformate (<NUM>%, <NUM>µl, <NUM>µmol) and indium(III) trifluoromethane sulfonate (<NUM>%, <NUM>, <NUM>µmol) were mixed and stirred neat for <NUM>. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(<NUM>,<NUM>-dihydroxypropoxy)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was added and the mixture was stirred for another <NUM>. The reaction was quenched with triethyl amine (<NUM>%, <NUM>µl, <NUM> mmol). The reaction mixture was diluted with <NUM> ethyl acetate and washed three times with <NUM> phosphate buffer (<NUM>, pH <NUM>). The organic layer was dried over Na<NUM>SO<NUM> and the solvent was evaporated in vacuum. The crude product was purified by column chromatography (n-hexane/acetone <NUM>:<NUM>, Fluka) to obtain (±)-<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(<NUM>-hydroxyphenyl)-<NUM>,<NUM>-dioxolan-<NUM>-yl)-methoxy)tetrafluorophenyl]porphyrin <NUM> (<NUM>, <NUM>µmol, <NUM>% yield).

<NUM>H NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>-<NUM> (bm, <NUM>, β + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM> (bs, <NUM>, acetal-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM>, <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM>, <NUM> (s, <NUM>, acetal-H), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), -<NUM> (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>+ ([M+H]+): <NUM> found: <NUM>.

In a sample tube with magnetic stirrer <NUM>-(oxiran-<NUM>-ylmethoxy)benzaldehyde (<NUM>, <NUM>µmol), trimethyl orthoformate (<NUM>%, <NUM>µl, <NUM>µmol) and indium(III) trifluoromethane sulfonate (<NUM>%, <NUM>, <NUM>µmol) were mixed and stirred neat for <NUM>. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(<NUM>,<NUM>-dihydroxypropoxy)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) and <NUM> drops of DCM were added and the mixture was stirred for another <NUM>. The reaction was quenched with triethyl amine (<NUM>%, <NUM>µl, <NUM>µmol). The reaction mixture was diluted with <NUM> ethyl acetate and washed three times with <NUM> phosphate buffer (<NUM>, pH <NUM>). The organic layer was dried over Na<NUM>SO<NUM> and the solvent was evaporated in vacuum. The crude product was purified by column chromatography (n-hexane/acetone <NUM>:<NUM>, Fluka) followed by a second column chromatography (n-hexane/acetone <NUM>:<NUM>, Fluka) to obtain (±)-<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(<NUM>-(oxiran-<NUM>-ylmethoxy)phenyl)-<NUM>,<NUM>-dioxolan-<NUM>-yl)methoxy)-tetrafluorophenyl]porphyrin <NUM> (<NUM>, <NUM>µmol, <NUM>% yield).

<NUM>H NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>-<NUM> (bm, <NUM>, β + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>, <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>, <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM>, <NUM> (s, <NUM>, acetal-H), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), -<NUM>-(-<NUM>) (m, <NUM>, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, m-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>+ ([M+ H]+): <NUM> found: <NUM>.

In a <NUM> flask with magnetic stirrer <NUM>-(allyloxy)-<NUM>-(dimethoxymethyl)benzene (<NUM>, <NUM>µmol), <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(<NUM>,<NUM>-dihydroxypropoxy)tetrafluoro-phenyl]porphyrin (<NUM>, <NUM>µmol) and indium(III) trifluoromethane sulfonate (<NUM>%, <NUM>, <NUM>µmol) were dissolved in <NUM> of nitromethane. After <NUM> <NUM> of dry THF was added and the reaction mixture was stirred for another <NUM>. <NUM>-(Allyloxy)-<NUM>-(dimethoxymethyl)benzene (<NUM>, <NUM> mmol) and indium(III) trifluoromethane sulfonate (<NUM>%, <NUM>, <NUM>µmol) were added. After <NUM> d the reaction was completed. The reaction mixture was diluted with <NUM> MeOH/triethyl amine (<NUM>:<NUM>) and filtered over silica gel. The product was recrystallized from DCM/(MeOH/H<NUM>O <NUM>:<NUM> + NH<NUM> (pH <NUM>)) to obtain (±)-<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(<NUM>-(allyloxy)phenyl)-<NUM>,<NUM>-dioxolan-<NUM>-yl)methoxy)tetrafluorophenyl]porphyrin <NUM> (<NUM>, <NUM>µmol, <NUM>% yield).

<NUM>H NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>-<NUM> (bm, <NUM>, β + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>, <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>, <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>, acetal-<NUM>,<NUM>-Ar), <NUM>, <NUM> (s, <NUM>, acetal-H), <NUM>-<NUM>, <NUM>-<NUM> (m, <NUM>, CH=CH<NUM>), <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> (m, <NUM>, CH=CH<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>J(H,H)=<NUM>, <NUM>, CH<NUM>CH=), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>CH=), <NUM>-<NUM> (m, <NUM>), -<NUM>-(-<NUM>) (m, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, m-ArF). : <NUM>-<NUM>. HRMS (ESI): calc. for C<NUM>H<NUM>iF<NUM>N<NUM>O<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (acetone): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer sodium hydroxide (<NUM>%, <NUM>, <NUM> mmol) was dissolved in <NUM> of H<NUM>O. To the stirring solution cystamine dihydrochloride (<NUM>%, <NUM>, <NUM> mmol) was added. After <NUM> stirring the aqueous solution was extracted four times with <NUM> of DCM. Afterwards the organic layer was dried over Na<NUM>SO<NUM>. The product was evaporated to dryness and the remaining residue was dissolved in <NUM> of DMSO (Roth). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-pentafluorophenylporphyrin (<NUM>, <NUM>µmol) was added. The solution was stirred at <NUM> for <NUM> in the microwave oven (<NUM> W). The crude product was diluted with <NUM> of ethyl acetate and washed once with <NUM> of saturated NaCl-solution and twice with H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM>. The crude product was evaporated to dryness and the remaining residue was purified by column chromatography (DCM/methanol <NUM>:<NUM>, Fluka) and recrystallization from DCM to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl)amino) tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield) as a purple solid.

<NUM>H NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>-<NUM> (m, <NUM>, β + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (bs, <NUM>, NH), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, NHCH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>NH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, SCH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, SCH<NUM>), -<NUM> (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D8]THF, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM><NUM><NUM>S<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (ethanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-pentafluorophenylporphyrin (<NUM>, <NUM>µmol) was dissolved in <NUM> of dry DMSO (Acros). To the stirring solution <NUM>,<NUM>-diaminohexane (<NUM>%, <NUM>, <NUM> mmol) was added. The solution was stirred at <NUM> for <NUM>. The crude product was diluted with <NUM> of ethyl acetate and washed twice with <NUM> of saturated NaCl-solution and twice with <NUM> H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM>. The crude product was evaporated to dryness and the remaining residue was purified by column chromatography (DCM/methanol <NUM>:<NUM>, Fluka) and recrystallization from DCM to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-aminohexylamino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield) as a purple solid.

<NUM>H NMR (CD<NUM>OD, <NUM>): δ (ppm) = <NUM> (bs, <NUM>, β), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, NHCH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, NHCH<NUM>), <NUM> (p, <NUM>J(H,H) = <NUM>, <NUM>, NHCH<NUM>CH<NUM>), <NUM>-<NUM> (m, <NUM>, NHCH<NUM>CH<NUM> + NHCH<NUM>CH<NUM>CH<NUM>). <NUM>C NMR (CD<NUM>OD, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (CD<NUM>OD, <NUM>): δ (ppm) = -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, m-ArF); -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, oArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>+ ([M+ H]+): <NUM>,<NUM>; found: <NUM>,<NUM>. UV/Vis (MeOH): λmax (ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer under argon <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was dissolved in <NUM> of anhydrous DMF. <NUM>-(Maleimido)propionic acid N-hydroxysuccinimide ester (<NUM>%, <NUM>, <NUM>µmol) was added and the solution was stirred for <NUM> at RT. The reaction mixture was diluted with <NUM> ethyl acetate and washed four times with <NUM> H<NUM>O. The organic layer was dried over Na<NUM>SO<NUM> and the solvent was evaporated in vacuum. The crude product was purified by column chromatography (DCM/MeOH <NUM>:<NUM>, Fluka). The product was recrystallized from n-hexane to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-((<NUM>-maleimidyl)propanamido)ethyl)-disulfanyl)ethyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield).

<NUM>H NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>-<NUM> (bm, <NUM>, β), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, NHCO), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (s, <NUM>, HC=CH), <NUM> (bs, <NUM>, ArF-NH), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>), <NUM>-<NUM> (m, <NUM>, CH<NUM>N), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>NHCO), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>CH<NUM>S), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, SCH<NUM>CH<NUM>NHCO), <NUM>-<NUM> (m, <NUM>, COCH<NUM>), -<NUM> (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D8]THF, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (methanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> two-necked flask with magnetic stirrer under argon (<NUM>R,<NUM>S,<NUM>r)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate exo (<NUM>, <NUM>µmol) was dissolved in <NUM> of anhydrous DMF. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl) amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) and triethyl amine (<NUM>%, <NUM>µl, <NUM>µmol) were added and the solution was stirred for <NUM> at RT. The reaction mixture was diluted with <NUM> ethyl acetate and washed four times with <NUM> H<NUM>O. The organic layer was dried over Na<NUM>SO<NUM> and the solvent was evaporated in vacuum. The crude product was purified by column chromatography (DCM/MeOH <NUM>:<NUM>, Fluka). The product was recrystallized from n-hexane to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)-carbonyl)amino)ethyl)disulfanyl)ethyl) amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield).

<NUM>H NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>-<NUM> (m, <NUM>, β), <NUM>-<NUM> (s, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, C(O)NH), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NH), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, OCH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, C(O)NHCH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArL-NHCH<NUM>CH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, C(O)NHCH<NUM>CH<NUM>), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM>,<NUM> (p, <NUM>, <NUM>J(H,H) = <NUM>, <NUM>-Bicyclo), -<NUM> (s, <NUM>, inner core NH). <NUM>C NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D8]THF, <NUM>): δ (ppm) = -<NUM> (t, <NUM>J(F,F) = <NUM>, 2F, m-ArF), -<NUM> (s, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (methanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> two-necked flask with magnetic stirrer under argon (<NUM>R,<NUM>S,<NUM>s)-Bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-methyl (<NUM>-nitrophenyl) carbonate endo (<NUM>, <NUM>µmol) was dissolved in <NUM> of anhydrous DMF. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-aminoethyl)disulfanyl) ethyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) and triethyl amine (<NUM>%, <NUM>µl, <NUM>µmol) were added and the solution was stirred for <NUM> at RT. The reaction mixture was diluted with <NUM> ethyl acetate and washed four times with <NUM> H<NUM>O. The organic layer was dried over Na<NUM>SO<NUM> and the solvent was evaporated in vacuum. The crude product was purified by column chromatography (DCM/MeOH <NUM>:<NUM>, Fluka). The product was recrystallized from n-hexane to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)-carbonyl)amino)ethyl)disulfanyl)ethyl) amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield).

HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S<NUM>- ([M- H]-): <NUM> found: <NUM>.

In a <NUM> flask with magnetic stirrer DCC (<NUM>%, <NUM>, <NUM>µmol), propiolic acid (<NUM>%, <NUM>µl, <NUM>µmol) and HOBt hydrate (<NUM>, <NUM>µmol) were dissolved in <NUM> of THF and stirred for <NUM> at RT. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-(<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl amino))phenyl]porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred for <NUM> at RT. The crude product was dissolved in <NUM> of ethyl acetate and washed three times with <NUM> of H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM> and the solution was evaporated to dryness. The crude product was purified by column chromatography (DCM/methanol <NUM>:<NUM>, Machery-Nagel) and recrystallization from DCM/n-hexane to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-(<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl propiolamido))phenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield) as a purple solid.

<NUM>H NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM> (bs, <NUM>, <NUM>,<NUM>-β), <NUM> (bs, <NUM>, <NUM>,<NUM>-β), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>,<NUM>-β + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM> (bs, <NUM>, NHC(O)), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NH), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>NHC(O)), <NUM> (s, <NUM>, C≡CH), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>CH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>CH<NUM>NHC(O)), -<NUM> (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ (ppm) = -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, m-ArF), -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, oArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (ethanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-(<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl-propiolamido))phenyl]porphyrin (<NUM>, <NUM>µmol) was dissolved in <NUM> of methanol. A point of a spatula of sodium acetate and zinc acetate dihydrate (<NUM>, <NUM>µmol) was added to the stirred solution. The solution was stirred for <NUM> at RT. The crude product was dissolved in <NUM> of ethyl acetate and washed three times with <NUM> of H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM> and the solution was evaporated to dryness. The crude product was purified by recrystallization from DCM/n-hexane to obtain f <NUM>,<NUM>,<NUM>-tris-(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-(<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl propiol-amido))phenyl]porphyrinato}-zinc(II) (<NUM>, <NUM>µmol, <NUM>% yield) as a pink solid.

<NUM>H NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-β), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-β), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-β), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-β), <NUM> (bs, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM> (bs, <NUM>, NHC(O)), <NUM> (s, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>CH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>NHC(O)), <NUM> (s, <NUM>, C≡CH), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArL-NHCH<NUM>CH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, CH<NUM>CH<NUM>NHC(O)). <NUM>C NMR ([D6]Acetone, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ (ppm) = -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, m-ArF), -<NUM>-(-<NUM>) (m, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S<NUM>Zn+ ([M]+): <NUM> found: <NUM>. UV/Vis (ethanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer hPG<NUM>-acetal-azide with <NUM>% azide groups (<NUM>, <NUM>µmol, <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros) basified with <NUM>% v/v NEt<NUM>. <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-((<NUM>R,<NUM>S,<NUM>s,Z)-bicyclo[<NUM>. <NUM>]non-<NUM>-in-<NUM>-yl)methylcarbonyl)hexylamino)phenyl]-porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM> d. The crude product was purified by dialysis in acetone/H<NUM>O (<NUM>:<NUM>) + <NUM>% v/v NEt<NUM> for <NUM> d to obtain the purple product (<NUM>-(<NUM>-methoxy-<NUM>-(<NUM>-((5aS,<NUM>R,6aR)-<NUM>-((((<NUM>-((<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)porphyrin-<NUM>-yl)phenyl)amino)hexyl)carbamoyl)oxy)methyl)-<NUM>,5a,<NUM>,6a,<NUM>,<NUM>-hexahydrocyclopropa[<NUM>,<NUM>]cycloocta[<NUM>,<NUM>-d][<NUM>,<NUM>,<NUM>]triazol-<NUM>(<NUM>H)-yl)propoxy)phenyl)-<NUM>,<NUM>-dioxolan-<NUM>-yl)-hPG<NUM> with <NUM> porphyrin groups (<NUM>, <NUM>µmol, <NUM>µmol porphyrin groups, quant. yield, <NUM>% conversion).

<NUM>H NMR ([D8]THF/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>-<NUM> (m, β), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, Ar), <NUM>-<NUM> (m, acetal-H), <NUM>-<NUM> (m, hPG-backbone + CH<NUM>), <NUM>-<NUM> (m, CH<NUM>), <NUM>-<NUM> (m, CH<NUM>, CH), -<NUM> (s, pyrrole-NH). <NUM>C NMR ([D8]THF/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

In a <NUM> two-necked flask with magnetic stirrer hPG<NUM>-acetal-azide with <NUM> azide groups (<NUM>, <NUM>µmol, <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-((<NUM>R,<NUM>S,<NUM>s,Z)-bicyclo[<NUM>. <NUM>]non-<NUM>-in-<NUM>-yl)methylcarbonyl)hexylamino)phenyl]-porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM>. The crude product was purified by dialysis in THF + <NUM>. 05wt% aqueous ammonia for <NUM> d to obtain the purple product ((5aR,<NUM>S,6aS)-<NUM>-(<NUM>-(<NUM>-(<NUM>-ethyl-<NUM>,<NUM>-dioxolan-<NUM>-yl)phenoxy)propyl)-<NUM>,<NUM>,<NUM>,5a,<NUM>,6a,<NUM>,<NUM>-octahydrocyclopropa-[<NUM>,<NUM>]-cycloocta-[<NUM>,<NUM>-d]-[<NUM>,<NUM>,<NUM>]triazol-<NUM>-yl)methyl-(<NUM>-((<NUM>,<NUM>,<NUM>,<NUM>-tetrafluor-<NUM>-(<NUM>,<NUM>,<NUM>-tris-(<NUM>-hydroxyphenyl)porphyrin-<NUM>-yl)phenyl)-amino)-hexyl)carbamat-hPG<NUM>,<NUM> with <NUM> porphyrin groups (<NUM>, <NUM>µmol, <NUM>µmol porphyrin groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>-<NUM> (m, β), <NUM>-<NUM> (m, Ar), <NUM> (bs, Ar), <NUM> (bs, Ar + triazole-H), <NUM> (bs, Ar), <NUM> (bs, Ar), <NUM>-<NUM> (m, acetal-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin), <NUM> (bs, porphyrin), <NUM>-<NUM> (m, porphyrin), <NUM>-<NUM> (m, porphyrin), <NUM>-<NUM> (m, porphyrin). <NUM>C NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>,<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D8]THF, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (s, m-Ar-F); -<NUM>-(-<NUM>) (m, o-Ar-F).

In a <NUM> two-necked flask with magnetic stirrer hPG<NUM>-acetal-azide with <NUM> azide groups (<NUM>, <NUM> nmol, <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>,<NUM>,<NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)ethyl)disulfanyl)ethyl)amino)tetrafluorophenyl]-porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM>. The crude product was purified by dialysis in THF + <NUM>. 05wt% aqueous ammonia for <NUM> d to obtain the purple product ((5aR,<NUM>S,6aS)-<NUM>-(<NUM>-(<NUM>-(<NUM>-Ethyl-<NUM>,<NUM>-dioxolan-<NUM>-yl)phenoxy)propyl)-<NUM>,<NUM>,<NUM>,5a,<NUM>,6a,<NUM>,<NUM>-octahydrocyclopropa-[<NUM>,<NUM>]-cycloocta-[<NUM>,<NUM>-d]-[<NUM>,<NUM>,<NUM>]-triazol-<NUM>-yl)-methyl-((<NUM>-((<NUM>,<NUM>,<NUM>,<NUM>-tetrafluor-<NUM>-(<NUM>,<NUM>,<NUM>-tris-(<NUM>-hydroxyphenyl)porphyrin-<NUM>-yl)phenyl)-amino)disulfanyl)ethylamino)carbamat-hPG<NUM>,<NUM> with <NUM> porphyrin groups (<NUM>, <NUM> nmol, <NUM>µmol porphyrin groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>-<NUM> (m, β), <NUM>-<NUM> (m, Ar), <NUM> (bs, Ar), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, Ar), <NUM>-<NUM> (m, acetal-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin), <NUM>-<NUM> (m, porphyrin), <NUM>-<NUM> (m, porphyrin) <NUM>-<NUM> (m, porphyrin), <NUM>-<NUM> (m, porphyrin), -<NUM> (m, pyrrole-NH). <NUM>C NMR ([D8]THF, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D8]THF, <NUM>): δ (ppm) = -<NUM>-(-<NUM>) (m, m-Ar-F), -<NUM>-(-<NUM>) (m, o-Ar-F).

In a <NUM> flask with magnetic stirrer hPG<NUM>-azide with <NUM>% azide groups (<NUM>, <NUM>µmol, <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>,<NUM>,<NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)-carbonyl)amino)ethyl)disulfanyl)ethyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM>. The crude product was purified by dialysis in acetone/H<NUM>O (<NUM>:<NUM>) for <NUM> d to obtain the purple product <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>,<NUM>,<NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)-carbonyl)amino)ethyl)disulfanyl)ethyl)amino)tetrafluorophenyl)porphyrin-hPG<NUM>-azide with <NUM>% porphyrin and <NUM>% azide groups (<NUM>, <NUM>µmol, <NUM>µmol porphyrin and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR ([D6]Acetone /D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM> (bs, β), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, meso-NH), <NUM>-<NUM> (m, hPG-backbone + cystamine-CH<NUM>), <NUM>-<NUM> (m, cystamine-CH<NUM> + cyclooctyne-CH<NUM>), <NUM>-<NUM> (m, cyclooctyne-CH), -<NUM> (s, pyrrole-NH). <NUM>C NMR ([D6]Acetone /D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (porphyrin); <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (hPG); <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (porphyrin).

In a <NUM> flask with magnetic stirrer hPG<NUM>-mannose-azide with <NUM>% mannose and <NUM>% azide groups (<NUM>, <NUM> nmol, <NUM>µmol mannose and <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>,<NUM>,<NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)ethyl)disulfanyl)-ethyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM> d. The crude product was purified by dialysis in acetone for <NUM> d to obtain the purple product <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>r)-bicyclo[<NUM>,<NUM>,<NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)ethyl)disulfanyl)ethyl)amino)tetra-fluorophenyl)porphyrin-hPG<NUM>-mannose-azide with <NUM>% porphyrin, <NUM>% mannose and <NUM>% azide groups (<NUM>, <NUM> nmol, <NUM>µmol porphyrin, <NUM>µmol mannose and <NUM>µmol azide groups, quant. yield, <NUM>% conversion).

<NUM>H NMR ([D6]Acetone/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM> (bs, β), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, Man: H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, -OCH<NUM>; hPG backbone; cystamine-CH<NUM> + cyclooctyne-CH<NUM>). <NUM>C NMR ([D6]Acetone/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

In a <NUM> flask with magnetic stirrer hPG<NUM>-azide with <NUM>% azide groups (<NUM>, <NUM>µmol, <NUM>µmol azide groups) was dissolved in <NUM> of DMSO (Roth). {<NUM>,<NUM>,<NUM>-Tris-(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-(N-(<NUM>-((<NUM>-aminoethyl)disulfanyl)ethyl propiol-amido))phenyl]porphyrinato}-zinc(II) (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in <NUM>µl H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) were added and the solution was stirred at RT for <NUM> d. The crude product was purified by dialysis in acetone/H<NUM>O (<NUM>:<NUM>) for <NUM> d to obtain the purple honey-like product f <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-N-((<NUM>-((<NUM>-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl-carboxamido)ethyl)disulfanyl)ethyl)aminophenyl)]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrin zinc(II) complex and <NUM>% azide groups (<NUM>, <NUM>µmol, <NUM>µmol porphyrin and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR (D<NUM>O, <NUM>): δ (ppm) = <NUM>-<NUM> (m, β), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, hPG backbone + cystamine-CH<NUM>), <NUM> (CH<NUM>-hPG starter unit), <NUM> (CH<NUM>-hPG starter unit). <NUM>C NMR (D<NUM>O, <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (porphyrin); <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (hPG). UV/Vis (acetone/H<NUM>O <NUM>:<NUM>): λmax = <NUM>, <NUM>, <NUM>.

In a <NUM> flask with magnetic stirrer <NUM>,<NUM>,<NUM>-tris(<NUM>-acetoxyphenyl)-<NUM>-pentafluorophenylporphyrin (<NUM>, <NUM>µmol) was dissolved in <NUM> dry DMSO (Roth) under argon. Propargylamine (<NUM>%, <NUM>µl, <NUM>, <NUM> mmol) was added and the solution was stirred at <NUM> for <NUM>. The crude product was diluted with <NUM> of ethyl acetate and washed three times with <NUM> H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM>. The crude product was evaporated to dryness and the remaining residue was purified by column chromatography (DCM/acetone <NUM>:<NUM>, Machery-Nagel) and recrystallization from DCM/n-hexane to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield) as a purple solid.

<NUM>H NMR ([D6]Acetone, <NUM>): δ = <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-β), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-β), <NUM> (bs, <NUM>, <NUM>,<NUM>,<NUM>,<NUM>-β), <NUM> (s, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>-meso-<NUM>-Ar + <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NH), <NUM>-<NUM> (m, <NUM>, CH<NUM>), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, C≡CH), -<NUM> ppm (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> ppm. <NUM>F NMR ([D6]Acetone, <NUM>): δ = -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, mArF), -<NUM> ppm (d, <NUM>J(F,F) = <NUM>, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>+ ([M+ H]+): <NUM> found: <NUM>. UV/Vis (ethanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was dissolved in <NUM> of methanol. A point of a spatula of sodium acetate and zinc acetate dihydrate (<NUM>, <NUM> mmol) were added to the stirring solution. The solution was stirred for <NUM> at RT. The crude product was diluted with <NUM> ethyl acetate and washed three times with <NUM> of H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM> and the solution was evaporated to dryness. The crude product was purified by recrystallization from DCM/n-hexane to obtain {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluoro-phenyl]porphyrinato}-zinc(II) (<NUM>, <NUM>µmol, <NUM>% yield) as a pink solid.

<NUM>H NMR ([D6]Acetone, <NUM>): δ = <NUM> (s, <NUM>, <NUM>,<NUM>,<NUM>,<NUM>-β), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>,<NUM>-β), <NUM> (bs, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>,<NUM>-Ar), <NUM> (t, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>; 4J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>; <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM>-<NUM> (m, <NUM>, ArF-NH), <NUM>-<NUM> (m, <NUM>, CH<NUM>), <NUM> ppm (t, <NUM>J(H,H) = <NUM>, <NUM>, C≡CH). <NUM>C NMR ([D6]Acetone, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> ppm. <NUM>F NMR ([D6]Acetone, <NUM>): δ = -<NUM> (d, <NUM>J(F,F) = <NUM>, 2F, m-ArF), -<NUM> ppm (d, <NUM>J(F,F) = <NUM>, 2F, o-ArF). HRMS (ESI): calc. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>Zn+ ([M]+): <NUM> found: <NUM>. UV/Vis (ethanol): λmax(ε) = <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer (<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-ylmethyl (<NUM>-nitrophenyl) carbonate endo (<NUM>, <NUM>µmol) was dissolved in <NUM> of anhydrous DMF under argon. To the stirring solution <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-amino-hexylamino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) and NEt<NUM> (<NUM>%, <NUM>µl, <NUM>, <NUM>µmol) were added. The solution was stirred for <NUM> at RT. The crude product was diluted with <NUM> of ethyl acetate and washed four times with <NUM> of H<NUM>O. Afterwards the organic layer was dried over Na<NUM>SO<NUM>. The crude product was evaporated to dryness and the remaining residue was purified by column chromatography (DCM/methanol <NUM>:<NUM>, Fluka) to obtain <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)hexyl)amino)tetra-fluorophenyl]porphyrin (<NUM>, <NUM>µmol, <NUM>% yield) as a purple solid.

<NUM>H NMR ([D6]Acetone, <NUM>): δ = <NUM> (bs, <NUM>, <NUM>,<NUM>-β), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-β), <NUM> (bs, <NUM>, <NUM>,<NUM>,<NUM>,<NUM>-β), <NUM> (s, <NUM>, <NUM>,<NUM>,<NUM>-meso-<NUM>-Ar-OH), <NUM> (bs, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar + <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-meso-<NUM>-Ar), <NUM> (dd, <NUM>J(H,H) = <NUM>, 4J(H,H) = <NUM>, <NUM>, <NUM>,<NUM>-meso-<NUM>-Ar), <NUM> (bs, <NUM>, C(O)NH), <NUM> (bs, <NUM>, ArF-NH), <NUM> (d, <NUM>J(H,H) = <NUM>, <NUM>, OCH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, ArF-NHCH<NUM>), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, C(O)NHCH<NUM>), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-Bicyclo), <NUM> (q, <NUM>J(H,H) = <NUM>, <NUM>, ArL-NHCH<NUM>CH<NUM>), <NUM>-<NUM> (m, <NUM>, C(O)NHCH<NUM>CH<NUM>CH<NUM>CH<NUM> + <NUM>,<NUM>-Bicyclo), <NUM> (p, <NUM>J(H,H) = <NUM>, <NUM>, <NUM>-Bicyclo), <NUM>-<NUM> (m, <NUM>, <NUM>,<NUM>-Bicyclo), -<NUM> (s, <NUM>, pyrrole-NH). <NUM>C NMR ([D6]Acetone, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR ([D6]Acetone, <NUM>): δ = -<NUM>-(-<NUM>) (m, 2F, m-ArF), -<NUM> ppm (d, <NUM>J(F,F) = <NUM>, 2F, o-ArF). UV/Vis (acetone): λmax (ε) = <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM><NUM>), <NUM> (<NUM><NUM>).

In a <NUM> flask with magnetic stirrer hPG-azide was dissolved in <NUM> of DMSO (Acros). {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluorophenyl]porphy-rinato}-zinc(II), L-ascorbic acid sodium salt in H<NUM>O and copper(II) sulfate hydrate in H<NUM>O were added and the solution was stirred at RT for <NUM> d. Afterwards the reaction mixture was heated to <NUM> for <NUM>. The crude product was purified by dialysis for <NUM> d to obtain the purple product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)-tetrafluorophenyl]porphyrinato}-zinc(II)-hPG-azide.

In a <NUM> flask with magnetic stirrer {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG-azide was dissolved in <NUM> of DMSO (Acros). Propargylated-mannose protected, L-ascorbic acid sodium salt in H<NUM>O and copper(II) sulfate hydrate in H<NUM>O were added and the solution was stirred at RT for <NUM> d. Afterwards the reaction mixture was heated to <NUM> for <NUM>. The crude product was purified by dialysis for <NUM> d to obtain the purple product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG-mannose protected.

In a <NUM> two-necked flask with magnetic stirrer {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG-mannose protected was dissolved in <NUM> of anhydrous DMF and <NUM> of dry MeOH under argon. NaOMe in MeOH was added and the solution was stirred at RT for <NUM> d. H<NUM>O was added and the solution was stirred for <NUM>. The crude product was purified by dialysis for <NUM> d to obtain the purple product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG-mannose.

According to the general synthesis procedure: hPG<NUM>-azide with <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol azide groups), {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluorophenyl]porphyrinato}-zinc(II) (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol), were used. The crude product was purified by dialysis (acetone/H<NUM>O (<NUM>:<NUM>)) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrins and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR ([D6]Acetone/D<NUM>O <NUM>:<NUM>, <NUM>): δ = <NUM>-<NUM> (bs, β), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM>).

According to the general synthesis procedure: hPG<NUM>-azide with <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol azide groups), {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(prop-<NUM>-yn-<NUM>-ylamino))tetrafluorophenyl]porphyrinato}-zinc(II) (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol), were used. The crude product was purified by dialysis (acetone/H<NUM>O (<NUM>:<NUM>)) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrins and <NUM>% azides (<NUM>, <NUM> nmol, <NUM>µmol porphyrin and <NUM>µmol azide groups, <NUM>% yield, quant. conversion).

<NUM>H NMR ([D6]Acetone, <NUM>): δ = <NUM>-<NUM> (bs, β + OH), <NUM>-<NUM> (m, Ar + triazole-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM>).

According to the general synthesis procedure: {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrins and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin and <NUM>µmol azide groups), propargylated-mannose protected (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol), were used. The crude product was purified by dialysis (acetone/H<NUM>O (<NUM>:<NUM>)) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose protected with <NUM>% porphyrins, <NUM>% mannose protected and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin, <NUM>µmol mannose protected and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR ([D6]Acetone, <NUM>): δ = <NUM>-<NUM> (bs, β + OH), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, Man: H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM> + Man), <NUM>-<NUM> (m, OAc). <NUM>C NMR ([D6]Acetone, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

According to the general synthesis procedure: {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrins and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin and <NUM>µmol azide groups), propargylated-mannose protected (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol), were used. The crude product was purified by dialysis (acetone/H<NUM>O (<NUM>:<NUM>)) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>. <NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose protected with <NUM>% porphyrins, <NUM>% mannose protected and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin, <NUM>µmol mannose protected and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

According to the general synthesis procedure: {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-azide with <NUM>% porphyrins and <NUM>% azides (<NUM>, <NUM> nmol, <NUM>µmol porphyrin and <NUM>µmol azide groups), propargylated-mannose protected (<NUM>, <NUM>µmol), L-ascorbic acid sodium salt (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol) and copper(II) sulfate hydrate (<NUM>µl, <NUM> in H<NUM>O, <NUM>µmol), were used. The crude product was purified by dialysis (acetone/H<NUM>O (<NUM>:<NUM>)) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose protected with <NUM>% porphyrins, <NUM>% mannose protected and <NUM>% azides (<NUM>, <NUM> nmol, <NUM>µmol porphyrin, <NUM>µmol mannose protected and <NUM>µmol azide groups, <NUM>% yield, <NUM>% conversion).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ = <NUM>-<NUM> (bs, β + OH), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, Man: H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM> + Man), <NUM>-<NUM> (m, OAc). <NUM>C NMR (CDCl<NUM>, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

According to the general synthesis procedure: {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose with <NUM>% porphyrins, <NUM>% mannose protected and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin, <NUM>µmol mannose protected and <NUM>µmol azide groups) and NaOMe (<NUM>, <NUM> in MeOH, <NUM>µmol) were used. The crude product was purified by dialysis (H<NUM>O) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose with <NUM>% porphyrins, <NUM>% mannose and <NUM>% azides (<NUM>, <NUM>µmol, <NUM>µmol porphyrin, <NUM>µmol mannose and <NUM>µmol azide groups, <NUM>% yield, quant. conversion).

<NUM>H NMR (D<NUM>O, <NUM>): δ = <NUM>-<NUM> (bs, β), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM> + Man). <NUM>C NMR (D<NUM>O, <NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

According to the general synthesis procedure: {<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose protected with <NUM>% porphyrins, <NUM>% mannose protected and <NUM>% azides (<NUM>, <NUM> nmol, <NUM>µmol porphyrin, <NUM>µmol mannose protected and <NUM>µmol azide groups) and NaOMe (<NUM>µl, <NUM> in MeOH, <NUM>µmol) were used. The crude product was purified by dialysis (H<NUM>O) to obtain the product {<NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-(N-(<NUM>H-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl))amino)tetrafluorophenyl]porphyrinato}-zinc(II)-hPG<NUM>-mannose with <NUM>% porphyrins, <NUM>% mannose and <NUM>% azides (<NUM>, <NUM> nmol, <NUM>µmol porphyrin, <NUM>µmol mannose and <NUM>µmol azide groups, <NUM>% yield, quant. conversion).

<NUM>H NMR ([D6]DMSO, <NUM>): δ = <NUM>-<NUM> (bs, β + OH), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, hPG-backbone + porphyrin-CH<NUM> + Man).

In a <NUM> flask with magnetic stirrer hPG<NUM>-mannose-azide with <NUM>% mannose and <NUM>% azide groups (<NUM>, <NUM> nmol, <NUM>µmol mannose and <NUM>µmol azide groups) was dissolved in <NUM> of dry DMSO (Acros). <NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)hexyl)amino)tetrafluorophenyl]porphyrin (<NUM>, <NUM>µmol) was added and the solution was stirred at RT for <NUM> d. The crude product was purified by dialysis in acetone for <NUM> d to obtain the purple product <NUM>,<NUM>,<NUM>-tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>-((<NUM>-(((((<NUM>R,<NUM>S,<NUM>s)-bicyclo[<NUM>. <NUM>]non-<NUM>-yn-<NUM>-yl)methoxy)carbonyl)amino)hexyl)amino)tetrafluorophenyl]porphyrin-hPG<NUM>-mannose-azide with <NUM>% porphyrin, <NUM>% mannose and <NUM>% azide groups (<NUM>, <NUM> nmol, <NUM>µmol porphyrin, <NUM>µmol mannose and <NUM>µmol azide groups, quant. yield, <NUM>% conversion).

<NUM>H NMR ([D8]THF/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>-<NUM> (bs, β), <NUM>-<NUM> (m, Ar + porphyrin/Man-triazole-H), <NUM>-<NUM> (m, Man: H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, H-<NUM>, - OCH<NUM>; hPG backbone; porphyrin-CH<NUM> + cyclooctyne-CH<NUM>), <NUM>-<NUM> (porphyrin-CH<NUM> + cyclooctyne-CH<NUM>). <NUM>C NMR ([D8]THF/D<NUM>O (<NUM>:<NUM>), <NUM>): δ (ppm) = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Compound <NUM> ({<NUM>,<NUM>,<NUM>-Tris(<NUM>-hydroxyphenyl)-<NUM>-[<NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-N-((<NUM>-((<NUM>-(<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl-carboxamido)ethyl)-disulfanyl)ethyl)aminophenyl)]porphyrinato}-zinc(II)-hPG19. <NUM>-azide with <NUM>% porphyrin zinc(II) complex and <NUM>% azide groups) (point of a spatula) was dissolved in methanol/H<NUM>O (<NUM>) in presence of DTT (<NUM> mmolL-<NUM>). The solution was heated to <NUM>. Fluorescence spectra were measured after <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>.

Compound <NUM> (point of a spatula) was dissolved in methanol (<NUM>). DTT (<NUM>) was added and the solution was heated to <NUM> for <NUM>. A TLC in methanol was performed.

Compound <NUM> (point of a spatula) was dissolved in H<NUM>O (<NUM>). DTT (<NUM>) was added and the solution was kept for <NUM> at RT. A SEC in H<NUM>O was performed.

Compound <NUM> (<NUM>) was dissolved in methanol/H<NUM>O (<NUM>, <NUM>:<NUM>). After the sample was been degassed with argon, it was filled into a dialysis tube. The sample was dialyzed in a beaker with DTT (<NUM> mmolL-<NUM>) in methanol/H<NUM>O (<NUM>, <NUM>:<NUM>) for <NUM>. Compound <NUM> (<NUM>) was dissolved in methanol/H<NUM>O (<NUM>, <NUM>:<NUM>) and filled into a dialysis tube. The sample was dialyzed in a beaker with methanol/H<NUM>O (<NUM>, <NUM>:<NUM>) for <NUM>. During the dialysis outside the tube fluorescence spectra were measured after <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>.

The photosensitzing activity was determined in the following cell lines:.

The cell lines were grown in DMEM (PAA Laboratories GmbH) supplemented with <NUM> % heat-inactivated fetal calf serum (FCS, PAA Laboratories GmbH), <NUM> % penicillin (<NUM> IU) and streptomycin (<NUM> µg/ml, PAA Laboratories GmbH). Cells were kept as a monolayer culture in a humidified incubator (<NUM> % CO<NUM> in air at <NUM>).

A photosensitizer stock solution was prepared in DMSO and was kept in the dark at <NUM>. Further dilution was performed in DMEM medium without phenol red supplemented with <NUM> % FCS to reach a final photosensitizer concentration of <NUM> or <NUM> µM, respectively.

<NUM> · <NUM><NUM> cells/ml were seeded in micro plates (<NUM> · <NUM><NUM> cells/well). Cells were incubated with fresh medium (DMEM without phenol red) containing <NUM> % FCS with <NUM> or <NUM> µM of the photosensitizer for <NUM> before light exposure. Before photosensitization, cells were washed, cell culture medium was exchanged with DMEM without phenol red and <NUM> % FCS, then irridiated at room temperature with a <NUM> diode laser (Ceralas PDT <NUM>, biolitec AG) or with a white light source at a fixed fluence rate of <NUM> mW/cm<NUM> (<NUM> J/cm<NUM>). Following irradiation, cells were incubated in a humidified incubator (<NUM> % CO<NUM> in air at <NUM>) for <NUM> until cell viability assay.

The cell viability was assessed by the XTT assay. <NUM> XTT (sodium <NUM>'-[phenylaminocarbonyl)-<NUM>,<NUM>-tetrazolium]-bis(<NUM>-methoxy-<NUM>-nitro)benzene sulfonic acid, Applichem GmbH) is dissolved in <NUM> PBS-Buffer (without Ca<NUM>+ and Mg<NUM>) and sterile filtered. Solution was stored in the dark at -<NUM> until use. A sterile solution containing PMS (N-methyl dibenzopyrazine methyl sulfate, Applichem GmbH) was needed as an activation reagent for the XTT. <NUM> PMS was dissolved in <NUM> PBS-Buffer. The XTT reagent solution was thawed in a <NUM> water bath and the activation solution (PMS) was added immediately prior to use. To prepare a reaction solution sufficient for one micro plate (<NUM> wells), <NUM> activation solution (PMS) was given to <NUM> XTT reagent. The medium in the micro plate was exchanged with RPMI without phenol red and <NUM> % FCS (<NUM> µl) prior adding <NUM> µl XTT reaction solution per well. The micro plate was incubated for <NUM>-<NUM> hours at <NUM> and <NUM> % CO<NUM> until an orange dye is to be formed. The micro plate has been shaken gently to evenly distribute the dye in the wells.

The absorbance of the samples was measured with a spectrophotometer (Infinite <NUM>, Tecan Group Ltd. ) at a wavelength of <NUM>. In order to measure reference absorbance (to measure non-specific readings) a wavelength of <NUM>-<NUM> was used. The examples illustrate the photodynamic activity ("DT" means dark toxicity and "Laser" means photo toxicity).

<FIG> shows the cell toxicity test of conjugate MS153/BLC <NUM> after <NUM> incubation and irradiation with a <NUM> laser at <NUM> J/cm<NUM>.

<FIG> shows the cell toxicity test of conjugate MS154/BLC <NUM> after <NUM> incubation and irradiation with a <NUM> laser at <NUM> J/cm<NUM>.

<FIG> shows the cell toxicity test of conjugate MS109a/BLC <NUM> after <NUM> incubation and irradiation with white light source.

The organisms studied were two members of the microflora wounds; Staphylococcus aureus DSM <NUM>, Gram-positive; and Pseudomonas aeruginosa DSM <NUM>, Gram-negative.

Cultures cells are suspended in sterile phosphate-buffered saline (PBS) or sterile PBS supplemented with <NUM>% sterile horse blood serum. The final OD (Optical Density) at <NUM>, <NUM> in all cases was <NUM>. The bacterial suspensions are placed into sterile black well plates with clear bottoms. Concentrations of photosensitizer used in the study were as follows: <NUM>, <NUM> and <NUM>.

After an incubation time period of <NUM> minutes, the samples are exposed to laser light of <NUM>, power set <NUM> W, and irradiation time of <NUM>. With the irradiation time, the resulting energy fluency is of about <NUM> J/cm<NUM>. Control plates contained no photosensitizer and are not exposed to laser light. The control samples for dark toxicity are only exposed to photosensitizer without any illumination.

After irradiation, the samples are removed and suspended again in the culture media. The numbers of colony-forming units (CFU/ml) are enumerated after an adequate incubation time period.

<FIG> shows the antibacterial phototoxicity testing of conjugate MS154/BLC <NUM>.

<FIG> shows the antibacterial phototoxicity testing of conjugate MS153/BLC <NUM>.

<FIG> shows the antibacterial phototoxicity testing of conjugate MS168/BLC <NUM>.

<FIG> shows the antibacterial phototoxicity testing of conjugate MS <NUM> /BLC <NUM>.

<FIG> shows the antibacterial phototoxicity testing of conjugate MS152/BLC <NUM>.

Claim 1:
A tetrapyrrolic compound of the formulas <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
wherein:
A and B are selected from the group consisting of:
<CHM>
R<NUM> is -O-, -NH- or -S-;
R<NUM> is a substituted or unsubstituted alkyl group or fluoroalkyl group consisting of <NUM>-<NUM> carbon atoms;
M is Zn, Cu, Fe, Co, or Pd forming a metallated tetrapyrrole or void forming a metal-free tetrapyrrole;
CL is a cleavable linker comprising a disulfide, acetal, ester or imine;
L is a functional group comprising maleimide, cyclooctyne, alkyne, alkene, amine, carboxylic acid, hydroxyl, thiol, azide or acid chloride or a targeting group comprising carbohydrates (e.g. mannose, mannose-<NUM>-phosphate, galactose), antibodies (e.g. IgG, IgA, IgM, IgD, IgE antibodies), proteins (e.g. transferrin), oligopeptides (e.g. cyclic and acyclic RGD-containing oligopeptides), oligonucleotides (e.g. aptamers) or vitamins (e.g. folate);
P is a polymeric structure selected from the group consisting of hyperbranched polyglycerol (hPG), poly-ε-caprolactone (PCL), polylactic acid (PLA), polybutyl cyanoacrylate (PBCA), polyhexyl cyanoacrylate (PHCA), polystyrene (PS) and poly(methyl methacrylate) (PMMA);
R<NUM> is a substituent either in the meta- or para- position of the phenyl ring selected from the group consisting of -OH, -COOH, -NH<NUM>, - COOX, -NHX, -OX, -NH-Y-COOH, and -CO-Y-NH<NUM>, wherein X is a polyethyleneglycol-residue with (CH<NUM>CH<NUM>O)nCH<NUM> with n=<NUM>-<NUM> or a carbohydrate moiety; and Y is peptides or oligopeptides wherein n=<NUM>-<NUM>.