Query: disulfide bond

title: A Bioinspired Disulfide/Dithiol Redox Switch in a Rhenium Complex as Proton, H Atom, and Hydride Transfer Reagent.
abstract: The transfer of multiple electrons and protons is of crucial importance in many reactions relevant in biology and chemistry. Natural redox active cofactors are capable of storing and releasing electrons and protons under relatively mild conditions and thus serve as blueprints for synthetic proton coupled electron transfer (PCET) reagents. Inspired by the prominence of the 2e /2H+ disulfide/dithiol couple in biology, we investigate herein the diverse PCET reactivity of a Re complex equipped with a bipyridine ligand featuring a unique SH* S moiety in the backbone. The disulfide bond in fac [Re(S Sbpy)(CO)3Cl] (1, S Sbpy [1,2]dithiino[4,3 b:5,6 b']dipyridine) undergoes two successive reductions at equal potentials of 1.16 V vs Fc+|0 at room temperature forming [Re(S2bpy)(CO)3Cl]2 (12 S2bpy [2,2' bipyridine] 3,3' bis(thiolate) 12 has two adjacent thiolate functions at the bpy periphery, which can be protonated forming the S H* S unit, 1H The disulfide/dithiol switch exhibits a rich PCET reactivity and can release a proton (DGdegH+ 34 kcal mol 1, pKa 24.7) an H atom (DGdegH* 59 kcal mol 1) or a hydride ion (DGdegH 60 kcal mol 1) as demonstrated in the reactivity with various organic test substrates.

title: Extended Hydrogen Bond Networks for Effective Proton Coupled Electron Transfer (PCET) Reactions: The Unexpected Role of Thiophenol and Its Acidic Channel in Photocatalytic Hydroamidations.
abstract: Preorganization and aggregation in photoredox catalysis can significantly affect reactivities or selectivities but are often neglected in synthetic and mechanistic studies, since the averaging effect of flexible ensembles can effectively hide the key activation signatures. In addition, aggregation effects are often overlooked due to highly diluted samples used in many UV studies. One prominent example is Knowles's acceleration effect of thiophenol in proton coupled electron transfer mediated hydroamidations, for which mainly radical properties were discussed. Here, cooperative reactivity enhancements of thiophenol/disulfide mixtures reveal the importance of H bond networks. For the first time an in depth NMR spectroscopic aggregation and H bond analysis of donor and acceptor combined with MD simulations was performed revealing that thiophenol acts also as an acid. The formed phosphate H+ phosphate dimers provide an extended H bond network with amides allowing a productive regeneration of the photocatalyst to become effective. The radical and acidic properties of PhSH were substituted by Ph2S2 and phosphoric acid. This provides a handle for optimization of radical and ionic channels and yields accelerations up to 1 order of magnitude under synthetic conditions. Reaction profiles with different light intensities unveil photogenerated amidyl radical reservoirs lasting over minutes, substantiating the positive effect of the H bond network prior to radical cyclization. We expect the presented concepts of effective activation via H bond networks and the reactivity improvement via the separation of ionic and radical channels to be generally applicable in photoredox catalysis. In addition, this study shows that control of aggregates and ensembles will be a key to future photocatalysis.

title: An Unusual "OR" Gate for Allosteric Regulation of Mammalian Transglutaminase 2 in the Extracellular Matrix.
abstract: Transglutaminase 2 (TG2) is a highly expressed mammalian enzyme whose biological function is unclear, although its catalytic activity in the small intestine appears necessary for celiac disease (CeD) pathogenesis. While TG2 activity is reversibly regulated by multiple allosteric mechanisms, their roles under fluctuating physiological conditions are not well understood. Here, we demonstrate that extracellular TG2 activity is competitively controlled by the mutually exclusive binding of a high affinity Ca2+ ion or the formation of a strained disulfide bond. Binding of Ca2+ at the high affinity site does not activate TG2 per se, but it protects against oxidative enzyme deactivation while preserving the ability of Ca2+ ions to occupy weaker binding sites capable of allosteric TG2 activation. In contrast, disulfide bond formation competitively occludes the high affinity Ca2+ site while resulting in complete TG2 inactivation. Because both outcomes are comparably favorable under typical extracellular conditions, subtle changes in the availability of redox catalysts or promoters in the extracellular matrix can dramatically alter steady state TG2 activity. Thus, TG2 harbors a molecular "OR" gate that determines its catalytic fate upon export from cells.

title: Regulating the Anticancer Efficacy of Sgc8 Combretastatin A4 Conjugates: A Case of Recognizing the Significance of Linker Chemistry for the Design of Aptamer Based Targeted Drug Delivery Strategies.
abstract: The unique merits of aptamers, including specificity, high binding affinity, easy cell internalization, and rapid tissue accumulation abilities, have led aptamer drug conjugates to evolve into one of the most attractive strategies for targeted drug delivery purposes. Nevertheless, the critical role of linkers in regulating anticancer efficacy of these conjugates, especially those engineered by automated modular synthesis techniques, has been rarely explored. In this work, we utilized Sgc8c aptamer and combretastatin A4 to develop three conjugates with either a phosphodiester bond linker, a disulfide bond linker, or a carbamate linker to study their payload release mechanisms and the influence on anticancer efficacy. These investigations allowed us to identify the unique activation pathway of the phosphodiester bond linker that is activated by both nucleophilic attack of glutathione and degradation caused by phosphodiesterase, which is highly associated with the higher cytotoxicity of the conjugate. Importantly, the understanding of the chemistry of phosphodiester bond linker activation allowed us to further design another XQ 2d CA4 conjugate that can induce pancreatic cancer cells apoptosis in a more efficient manner.

title: Mechanism of Pyrroloquinoline Quinone Dependent Hydride Transfer Chemistry from Spectroscopic and High Resolution X ray Structural Studies of the Methanol Dehydrogenase from Methylococcus capsulatus (Bath)
abstract: The active site of methanol dehydrogenase (MDH) contains a rare disulfide bridge between adjacent cysteine residues. As a vicinal disulfide, the structure is highly strained, suggesting it might work together with the pyrroloquinoline quinone (PQQ) prosthetic group and the Ca2+ ion in the catalytic turnover during methanol (CH3OH) oxidation. We purify MDH from Methylococcus capsulatus (Bath) with the disulfide bridge broken into two thiols. Spectroscopic and high resolution X ray crystallographic studies of this form of MDH indicate that the disulfide bridge is redox active. We observe an internal redox process within the holo MDH that produces a disulfide radical anion concomitant with a companion PQQ radical, as evidenced by an optical absorption at 408 nm and a magnetically dipolar coupled biradical in the EPR spectrum. These observations are corroborated by electron density changes between the two cysteine sulfurs of the disulfide bridge as well as between the bound Ca2+ ion and the O5 C5 bond of the PQQ in the high resolution X ray structure. On the basis of these findings, we propose a mechanism for the controlled redistribution of the two electrons during hydride transfer from the CH3OH in the alcohol oxidation without formation of the reduced PQQ ethenediol, a biradical mechanism that allows for possible recovery of the hydride for transfer to an external NAD+ oxidant in the regeneration of the PQQ cofactor for multiple catalytic turnovers. In support of this mechanism, a steady state level of the disulfide radical anion is observed during turnover of the MDH in the presence of CH3OH and NAD+

title: Nickel Sulfonate Mode of Substrate Binding for Forward and Reverse Reactions of Methyl SCoM Reductase Suggest a Radical Mechanism Involving Long Range Electron Transfer.
abstract: Methyl coenzyme M reductase (MCR) catalyzes both the synthesis and the anaerobic oxidation of methane (AOM) Its catalytic site contains Ni at the core of cofactor F430. The Ni ion, in its low valent Ni(I) state, lights the fuse leading to homolysis of the C S bond of methyl coenzyme M (methyl SCoM) to generate a methyl radical, which abstracts a hydrogen atom from coenzyme B (HSCoB) to generate methane and the mixed disulfide CoMSSCoB. Direct reversal of this reaction activates methane to initiate anaerobic methane oxidation. On the basis of the crystal structures, which reveal a Ni thiol interaction between Ni(II) MCR and inhibitor CoMSH, a Ni(I) thioether complex with substrate methyl SCoM has been transposed to canonical MCR mechanisms. Similarly, a Ni(I) disulfide with CoMSSCoB is proposed for the reverse reaction. However, this Ni(I) sulfur interaction poses a conundrum for the proposed hydrogen atom abstraction reaction because the >6 A distance between the thiol group of SCoB and the thiol of SCoM observed in the structures appears to be too long for such a reaction. The spectroscopic, kinetic, structural, and computational studies described here establish that both methyl SCoM and CoMSSCoB bind to the active Ni(I) state of MCR through their sulfonate groups, forming a hexacoordinate Ni(I) N/O complex, not Ni(I) S. These studies rule out direct Ni(I) sulfur interactions in both substrate bound states. As a solution to the mechanistic conundrum, we propose that both the forward and the reverse MCR reactions emanate through long range electron transfer from the Ni(I) sulfonate complexes with methyl SCoM and CoMSSCoB, respectively.

title: Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif.
abstract: Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to mM concentrations) they must also be able to resist non specific triggering by the ca. 50 mM background of non catalytic cellular monothiols. However, no such selective reduction sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.

title: Highly Z Selective Double Bond Transposition in Simple Alkenes and Allylarenes through a Spin Accelerated Allyl Mechanism.
abstract: Double bond transposition in alkenes (isomerization) offers opportunities for the synthesis of bioactive molecules, but requires high selectivity to avoid mixtures of products. Generation of Z alkenes, which are present in many natural products and pharmaceuticals, is particularly challenging because it is usually less thermodynamically favorable than generation of the E isomers. We report a b dialdiminate supported, high spin cobalt(I) complex that can convert terminal alkenes, including previously recalcitrant allylbenzenes, to Z 2 alkenes with unprecedentedly high regioselectivity and stereoselectivity. Deuterium labeling studies indicate that the catalyst operates through a p allyl mechanism, which is different from the alkyl mechanism that is followed by other Z selective catalysts. Computations indicate that the triplet cobalt(I) alkene complex undergoes a spin state change from the resting state triplet to a singlet in the lowest energy C H activation transition state, which leads to the Z product. This suggests that this change in spin state enables the catalyst to differentiate the stereodefining barriers in this system, and more generally that spin state changes may offer a route toward novel stereocontrol methods for first row transition metals.

title: Single Molecule Activation and Quantification of Mechanically Triggered Palladium Carbene Bond Dissociation.
abstract: Metal complexed N heterocyclic carbene (NHC) mechanophores are latent reactants and catalysts for a range of mechanically driven chemical responses, but mechanochemical scission of the metal NHC bond has not been experimentally characterized. Here we report the single molecule force spectroscopy of ligand dissociation from a pincer NHC pyridine NHC Pd(II) complex. The force coupled rate constant for ligand dissociation reaches 50 s 1 at forces of approximately 930 pN. Experimental and computational observations support a dissociative, rather than associative, mechanism of ligand displacement, with rate limiting scission of the Pd NHC bond followed by rapid dissociation of the pyridine moiety from Pd.

title: Weak yet Decisive: Molecular Halogen Bond and Competing Weak Interactions of Iodobenzene and Quinuclidine.
abstract: The halogen bonded adduct between the commonly used constituents quinuclidine and iodobenzene is based on a single weak nitrogen iodine contact, and the isolation of this adduct was initially unexpected. Iodobenzene does not contain any electron withdrawing group and therefore represents an unconventional halogen bond donor. Based on excellent diffraction data of high resolution, an electron density study was successfully accomplished and confirmed one of the longest N**I molecular halogen bonds with a distance of 2.9301(4) A. The topological analysis identified the XB as a directional but weak s hole interaction and revealed secondary contacts between peripheral regions of opposite charge. These additional contacts and their competition with a nitrogen based interaction were confirmed by NOESY experiments in solution. Integration enabled us to determine the relative NOE ratios and provided insight regarding the existing interactions.