bluuebunny/crossref_metadata_2025 huggingface dataset:
Monofunctional and Interstrand DNA Adducts of Platinum(II)Complexes
Authors: Brabec Viktor , Boudny Vladimír
Published: March 2007

The effects produced in DNA by monofunctional or
interstrand adducts of platinum(II) complexes have been
summarized. The monofunctional adducts destabilize DNA in a
sequence‐dependent manner via conformational distortions,
which may have a denaturational character. It has been
suggested that this conformational alteration facilitates in
DNA the formation of the bidentate DNA adducts, whose
formation is associated with a permanent or transient local
denaturation. In addition, DNA interstrand cross‐linking by
cis‐diamminedichloroplatinum(II) and its trans isomer
produce in DNA lesions that have quite different
characteristics. It has been suggested that these
differences may have relevance to the distinct antitumor
efficacy of the two platinum isomers.
Lanthanide Chelates as a Tool in Nucleic Acid Chemistry
Authors: Mukkala Veli-Matti , Takalo Harri , Liitti Päivi , Kankare Jouko , Kuusela Satu , Lönnberg Harri
Published: March 2007

The potentiality of lanthanide chelates as photoluminescent markers and cleaving agents
of nucleic acids is discussed, the main emphasis being on the chelates derived from aromatic
nitrogen bases.
Transition and Group IIB Metal Complexes With “Active Aldehyde” Derivatives of Thiamine
Authors: Louloudi Maria , Hadjiliadis Nick , Laussac Jean Pierre , Bau Robert
Published: March 2007

The Zn2+, Cd2+, Hg2+, Co2+ and Ni2+ ions produce zwitterionic type
complexes with the ligands (L), 2‐(α‐hydroxy‐benzyl)thiamine=HBT and 2‐(α‐hydroxy‐cyclohexyl‐methyl)thiamine = HCMT, of the type MLCl3. The ligands
are in the S conformation, the metals are bound to N1, of the pyrimidine moiety
of thiamine and the complexes have a trigonally distorted tetrahedral structure,
as the crystal structure of the complex Zn(HCMT)Cl3 (orthorombic, a=14.4 b=14.1
c=17.4 β=105.6O V=3392A3 R=13.8%), the one and two dimensional  1H nmr
spectra of the Zn2+, Cd2+ and Hg2+ complexes and the electronic spectra of the
Co2+ and Ni2+ complexes show. A brief review of the previous techniques
(structure of the Hg(HBT)Cl3 complex, IR‐Raman spectra,  13C nmr in solution
and solid state etc) used to characterize these complexes, is also given here and
the proper conclusions drawn.
Interactions Between Zinc and Thymulin
Authors: Dardenne Mireille , Pleau Jean-Marie
Published: March 2007

Thymulin (formerly called "Facteur Thymique Sérique or FTS) is a metallopeptidic hormone
selectively produced by thymic epithelial cells (TEC) and known to induce intra and extra‐thymic T
cell differentiation. It was initially isolated from porcine serum and shown to be present in calf thymus
extract. Its amino‐acid sequence was determined (<Glu‐Ala‐Lys‐Ser‐Gln‐Gly‐Gly‐Ser‐Asn). It is a
nonapeptide whose biological activity is dependent on the presence of zinc, in an equimolecular
ratio. The metallopeptide thus formed bears a specific tridimensional conformation detected by
nuclear magnetic resonance studies, and that yielded a new monoclonal antibody‐defined epitope.
The presence of zinc and metallothionein has been demonstrated within TEC which produce the
peptide, suggesting that the molecule is secreted in its active zinc‐containing form. The
zinc/thymulin relationship, was further studied using various models of mild zinc deficiency in
experimental animals and in humans. Serum thymulin activity was decreased as a result of zinc
deficiency, and was corrected by in vivo and in vitro zinc supplementation, suggesting that this
parameter could be a sensitive indicator of zinc deficiency. When considered together with the
parallel variations seen in T‐cell subpopulations and lymphokine production, these observations
could provide a possible explanation of the role of zinc on T cell functions.
Multinuclear Metal Nucleobase Complexes
Authors: Schreiber A. , Rauter H. , Krumm M. , Menzer S. , Hillgeris E. C. , Lippert B.
Published: March 2007

Of all properties of metal nucleobase complexes, formation of multinuclear species appears to be
an outstanding feature. After a brief introduction into well known polymeric metal nucleobase
complexes, three aspects recently Studied in our laboratory will be dealt with in more detail: (i) Heteronuclear
complexes derived from trans‐ (1‐MeC=1‐methylcytosine).
They form, e. g. with Pd(II) or Hg(II), upon single deprotonation of the exocyclic amino group of
each 1‐MeC ligand, compounds of type trans‐, displaying Pt‐M bond
formation. (ii) Cyclic nucleobase complexes derived from cis‐a2Pt(II). A cyclic compound of composition
(UH=monoanion of unsubstituted uracil) is presented and the
analogy with organic calix‐[4]‐arenes is pointed out. (iii) Cyclic nucleobase complexes from trans‐a2Pt(II). Possible ways for the preparation of macrocyclic nucleobase complexes containing trans‐a2Pt(II) linkages are outlined and precursors and intermediates are presented.
Antitumor Organometallics. IV. The Mutagenic Potential of SomeDiphenylantimony(III) Dithiophosphorus Derivatives
Authors: Socaciu Carmen , Pasca Ioan , Silvestru Cristian , Bara Adela , Haiduc Ionel
Published: March 2007

Two diphenylantimony(III) derivatives of dithiophosphorus ligands, i.e. Ph2SbS2PPh2 and
Ph2SbS2P(OPr‐i) 2, which were previously found to exhibit antitumor properties, have been now
investigated for potential mutagenic effects in healthy and Ehrlich ascites tumor‐bearing mice. Two
short‐term tests, i.e. the micronucleus test and the cytogenetic analysis, were used as end‐points
for mutagenicity. The results are consistent with a mutagenic potential for both organoantimony(III)
compounds tested, the effect being higher for the phosphorodithioato derivative.
The Hypolipidemic Activity of Metal Complexes of AmineCarboxyboranes in Rodents
Authors: Hall Iris H. , Spielvogel Bernard F. , Sood Anup , Morse Karan W. , Norwood Verrill M. , Wong Oi. T.
Published: March 2007

The metal complexes of amine‐carboxyborane including copper, chromium, zinc, calcium amd cobalt were
effective hypolipidemic agents lowering both serum cholesterol and triglyceride levels significantly in mice at
8 mg/kg/day, I.P. after 16 days. The agents reduced acetyl CoA synthetase, ATP‐dependent citrate lyase, acyl
CoA cholesterol acyl transferase, ‐glycerol‐3‐phosphate acyl transferase activities of rat liver and small
intestinal mucosa after 14 days treatment. The neutral cholesterol ester hydrolase activity was elevated by the
agents in both tissues. The metal complexes altered lipid levels in the bile of rats after treatment as well as
the bile acid composition after 14 days administration, orally. The agents blocked enterohepatic absorption of
cholesterol from rat isolated intestinal loops.
Myochrysine Solution Structure and Reactivity
Authors: Elder R. C. , Jones William B. , Zhao Zheng , Dorsey John G. , Tepperman Katherine
Published: March 2007

We have determined the framework structure of Myochrysine (disodium gold(I)thiomalate) in the
solid state and extremely concentrated aqueous solution, previously. It consists of an open chain polymer
with linear gold coordination to two thiolates from the thiomalic acid moieties which bridge between pairs
of gold atoms providing an Au‐S‐Au angle of 95°. The question remained: was this structure relevant to
the dilute solutions of drugs administered and the still lower concentrations of gold found in the bodies of
patients (typically 1 ppm Au in blood and urine or 5 μM in Au). We have provided an answer to that
question using extended X‐ray absorption spectroscopy (EXAFS) and capillary zone electrophoresis
(CZE). EXAFS studies confirm that the polymeric structure with two sulfur atoms per gold atom persists
from molar concentrations down to millimolar concentrations. CZE is able to separate and detect
Myochrysine at millimolar levels. More importantly, at micromolar levels Myochrysine solutions exhibit
identical CZE behavior to that measured at millimolar levels. Thus, aqueous solutions of the drug remain
oligomeric at concentrations commensurate with those found in patient blood and urine.

The reactivity of Myochrysine with cyanide, a species especially prevalent in smoking patients,
was explored using CZE. Cyanide freely replaces thiomalic acid to form and thiomalic acid via
a mixed ligand intermediate. The overall apparent equilibrium constant (Kapp) for the reaction is 6×10-4M-1.
Further reaction of with a large excess of L, where L is cysteine, N‐acetylcysteine, or
glutathione, shows that these amino acids readily replace cyanide to form . These species are thus
potential metabolites and could possibly be active forms of gold in vivo. That all of these species are readily
separated and quantified using CZE demonstrates that capillary electrophoresis is an accessible and
powerful tool to add to those used for the study of gold‐based antiarthritis drugs.
Transport of the Dicyanogold(I) Anion
Authors: Tepperman Katherine , Zhang Yafei , Roy Pamela W. , Floyd Roger , Zhao Zheng , Dorsey John G. , Elder R. C.
Published: March 2007

We have shown that dicyanogold(I), is a common metabolite found in blood and
urine samples of patients treated with different gold based drugs. Some patients have high levels
of gold within their red blood cells (RBCs). Size exclusion and C18 reversed phase
chromatography show that the majority of the gold in RBC lysates is bound to protein, but small
molecules such as dicyanogold(I) and gold‐glutathione complexes are also present. Dicyanogold
incubation with red blood cells in vitro leads to a rapid and complete uptake of gold. This uptake
is unaffected by DIDS, an inhibitor of the anion channel, but is blocked by the addition of external
cyanide. Dicyanogold is also readily taken up by H9 cells, a continuous CD4+ cell line. This
uptake is significantly inhibited by N‐ethylmaleimide, suggesting a requirement for sulfhydryl
groups. Dicyanogold inhibits the replication of the AIDS virus, HIV, in a cell culture model.
Antitumour Organometallics. III. In Vivo Activity ofDiphenylantimony(III) and Diorganotin(IV) DithiophosphorusDerivatives Against P388 Leukemia
Authors: Keppler Bernhard K. , Silvestru Cristian , Haiduc Ionel
Published: March 2007

Diphenylantimony(III) and diorganotin(IV) derivatives of dithiophosphorus ligands, i.e. (R′ = Ph, OPr‐i) and
(R = n‐Bu, Ph, R′ = Ph; R = Ph, R′ = OPr‐i),
have been screened against P388 leukemia in mice. All the compounds showed marginal activity
towards this tumor system, some of them increasing the life span of the animals with more than
20%. The best results were obtained with (di‐iso‐propylphosphorodithioato)diphenylantimony(III)
which exhibited a T/C value of 136%, at a dose of 5 mg/kg, administered on days 1,2 and 3 after
tumor transplantation.
Chelating Agents and the Regulation of Metal Ions
Authors: Bulman Robert A.
Published: March 2007

Up to about the early 1980s it was perhaps still possible to summarize in a review of a moderate
length the development of the medicinal applications of chelation chemistry and the exploitation of
such chemistry in regulating the metal ion concentrations in the body. However, in the last few years
there has a great surge in the development of chelation chemistry and its usage in medicine and
related areas of life sciences research. It is no longer the case that such a review primarily
concentrates upon the use of chelating agents in removing toxic metals from the body but it must
now cover the use of chelating agents in the imaging procedures nuclear medicine and magnetic
resonance imaging (MRI), the use of chelating agents in unravelling the biochemistry of reactive
oxidative species (ROS) and the control and measurement of intracellular calcium ions. It is in the
recent applications that there have been the greatest developments over the last ten years.
An Antimitochondrial Silver Complex
Authors: Berners-Price Susan J. , Collier Doreen C. , Mazid Muhammed A. , Sadler Peter J. , Sue Rodney E. , Wilkie David
Published: March 2007

The silver(I) complex [Ag(eppe)2]NO3
(eppe = Et2PCH2CH2PPh2) is shown by X‐ray
crystallography to be tetrahedral with Ag ‐ PEt2
and Ag ‐ P Ph2
bond lengths of 2.482 and 2.518 Å,
respectively. The complex is selectively antimitochondrial and inhibits the growth of a number of
yeast strains in non‐fermentable media at concentrations as low as 2.5 μΜ
and induces the
mitochondrial mutation petite The effect is largely reversed by the presence of aspirin. The complex
is shown to be stable in the cell culture media and in the presence of glutathione, but readily reacts
with disulfides of oxidized glutathione and serum albumin. Surprisingly, neither [Au(eppe)2]Cl nor
[Au(dppe)2]Cl (dppe = Ph2PCH2CH2PPh2) showed any mitochondrial selectivity in the same
screening protocol.
Efficacy of 5‐FU Combined to Na[trans‐RuCl4(DMSO)Im] , A Novel Selective Antimetastatic Agent, on theSurvival Time of Mice With P388 Leukemia, P388/DDP subline and MCaMammary Carcinoma
Authors: Coluccia M. , Sava G. , Salerno G. , Bergamo A. , Pacor S. , Mestroni G. , Alessio E.
Published: March 2007

The combinational treatment between the selective antimetastatic agent, sodium‐trans‐rutheniumtetrachloridedimethylsulfoxideimidazole,
Na[trans‐RuCl4(DMSO)Im], and the cytotoxic drug
5‐fluorouracil (5‐FU) on primary tumor growth and on the survival time of experimental tumors results
in an effect significantly greater than that of each single agent used alone either with the solid
metastasizing MCa mammary carcinoma of the CBA mouse or with the lymphocytic leukemia P388
and its platinum resistant P388/DDP subline. Thus the inorganic compound Na[trans‐RuCl4(DMSO)Im], known for its potent and selective antimetastatic effects, positively interacts with
the antitumor action of an organic anticancer agent such as 5‐FU on both a solid metastasizing
tumor and a tumor of lymphoproliferative type. In particular, the effects of the combinational
treatment on the survival time of tumor bearing mice seem to be related to the selective
antimetastatic activity of the ruthenium complex that joins the potent cytotoxicity of 5‐FU for the
tumor. Moreover, these data show that Na[trans‐RuCl4(DMSO)Im] is almost as effective on the
subline of P388 made resistant to cisplatin as it was on the parental line.
Synthesis of 4‐Amino‐1‐Hydroxy‐Butane‐1,1‐Diphosphonate (AHBDP) ‐ Stannous Complexes for the Preparation of Ahbdp‐Sn(II)‐Tc and itsBiodistribution in Rats
Authors: Mankhetkorn Samlee , Blanchot Caroline , Duran-Cordobes Muriel , El Manouni Driss , Leroux Yves , Moretti Jean-Luc
Published: March 2007

The new potential tracer of bone imaging, AHBDP‐Sn(II)‐TcO.3H2O
was synthesized by
reducing the
to TcO2+
in the presence of AHBDP and Sn(ll)’s reducing agent. We found that
tin rapidly forms a stable complex with AHBDP, giving AHBDP‐Sn(II).3H2O. In the excess of AHBDP‐Sn(ll).3H2O, the AHBDP‐Sn(II).3H2O coordinates with TcO2+ to give AHBDP‐Sn(II)‐TcO.3H2O
which could polymerise or oligomerise to give hydrophobic species. The overall process appears as
a first‐order reaction (K= 0.67 ± 0.005s−1). In rats, the fixation of AHBDP‐Sn(II)‐99m
TcO. 3H2O on
bone is homogeneous and the scintigraphic images have the same quality as those of
1‐hydroxymethane‐1,1‐diphosphonate‐Technetium (HMDP‐99mTc). The activity in non‐target
organs was neglible.
The Binding of Platinum (II) Complexes to Rabbit Skeletal MuscleG‐Actin Induces Conformation Changes
Authors: Zou Juan , An Fang , Liu Gang , Wang Kui
Published: March 2007

The binding of cis‐diamminedichloroplatinum (DDCP) and cis‐diaquodiammine platinum (DADP) to
rabbit skeletal muscle G‐actin and the consequent conformation changes were studied as the function of the
Pt/actin molar ratio (R) and time by intrinsic and NPM labeled fluorescence, CD spectra as well as gelfiltration
chromatography. The results indicated that the unhydrolyzed DDCP can react with G‐actin in
presence of Cl-
ion. The reaction differs from that of its hydrolysis product DADP in a higher specificity and
a lower capacity. Both of them induced exposure of the tryptophane residues and labeled Cys374 and the
increase in α‐helix content depending on R, but the conformation changes caused by DADP are more
significant than DDCP at the same R. These are related to the binding of DADP to groups other than thiols.
The rate constants of conformation change suggested that DADP quenched the intrinsic fluorescence more
rapid. The temporal change in fluorescence of NPM labeled actin has a biphasic feature: in the first 16
minutes, the fluorescence was quenched, then it recovered slowly, indicating a multi‐step reaction including
high affinity platinum binding →
labeled Cys374 moving to hydrophilic environment → low affinity platinum
binding → Cys374‐related conformation compacting in sequence.
Platinum(II)‐Acyclovir Complexes: Synthesis, Antiviral andAntitumour Activity
Authors: Coluccia M. , Boccarelli A. , Cermelli C. , Portolani M. , Natile G.
Published: March 2007

A platinum(II) complex with the antiviral drug acyclovir was synthesized and its
antiviral and anticancer properties were investigated in comparison to those of acyclovir and
cisplatin. The platinum‐acyclovir complex maintained the antiviral activity of the parent
drug acyclovir, though showing a minor efficacy on a molar basis (ID50 = 7.85 and 1.02 μΜ
for platinum‐acyclovir and cisplatin, respectively). As anticancer agent, the platinum‐acyclovir
complex was markedly less potent than cisplatin on a mole‐equivalent basis, but it
was as effective as cisplatin when equitoxic dosages were administered in vivo to P388
leukaemia‐bearing mice (%T/C = 209 and 211 for platinum‐acyclovir and cisplatin,
respectively). The platinum‐acyclovir complex was also active against a cisplatin‐resistant
subline of the P388 leukaemia (%T/C = 140), thus suggesting a different mechanism of
action. The DNA interaction properties (sequence specificity and interstrand cross‐linking
ability) of platinum‐acyclovir were also investigated in comparison to those of cisplatin and
[Pt(dien)Cl]+, an antitumour‐inactive platinum‐triamine compound. The results of this study
point to a potential new drug endowed, at the same time, with antiviral and anticancer
activity and characterized by DNA interaction properties different from those of cisplatin.
The Relationship Between Cytokine Regulation and Anti‐InflammatoryAction of Amine‐Carboxyborane in L929 Fibroblasts and IC‐21Macrophages
Authors: Murphy Margaret E. , Shrewsbury Robert P. , Sood Anup , Spielvogel Bernard F. , Elkins Amy L. , Hall Iris
Published: March 2007

The amine‐carboxyboranes anti‐inflammatory agents were shown to block
TNFα release at 90 min. and IL‐1 release at 5 hr. from macrophages.
The agenst competed with L929 fibroblasts high affinity receptors for
endogenous cytokines which regulate the inflammation process. Blocking
the TNFα
receptor at 90 min. by the agents from 10 to 50  μΜ
, resulted in
lysosomal hydrolytic enzyme inhibition and lowering of prostaglandin
synthesis as well as reductions in calcitonin high affinity receptor
binding and calcium influx into the cells. IL‐1 receptors when blocked
by the agents at 5 hr. resulted in a reduction of NAG activity and
leukotriene synthesis. An elevation of proline incorporation into
collagen occurred at 90 min. and 24 hr. in the presence of the agents.
Thienothiopyransulfonamides as Complexing Agents for thePreparation of Dual Carbonic Anhydrase Inhibitors
Authors: Supuran Claudiu T.
Published: March 2007

Co(II); Zn(II) and Cu(II) complexes of two new sulfonamide carbonic anhydrase (CA) inhibitors,
derivatives of thienothiopyran‐2‐sulfonamide, were prepared and characterized by analytic, spectroscopic,
magnetic and conductimetric measurements. The new complexes are more potent CA inhibitors than the
parent sulfonamides, with IC50
values around 0.1 nM, against isozyme CA II.
Metal Complexes of 1,3,4‐Thiadiazole‐2,5‐Disulfonamide are StrongDual Carbonic Anhydrase Inhibitors, although the Ligand Possessesvery Weak such Properties
Authors: Supuran Claudiu T.
Published: March 2007

Coordination compounds of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 1,3,4‐thiadiazole‐2,5‐disulfonamide as ligand were synthesized and characterized by IR and UV spectroscopy, conductimetry and
thermogravimetry. The parent ligand is a very weak carbonic anhydrase (CA) inhibitor, although it
constituted the lead for developing important classes of diuretics. The complex derivatives behave as much
stronger CA inhibitors, with IC50
values around 10−8
M against isozyme CA II, and 10−7 M against isozyme
CAI.
Synthesis and Characterizationof New Ethylenediamine Platinum(IV) Complexes ContainingLipophilic Carboxylate Ligands
Authors: Galanski M. , Keppler B. K.
Published: March 2007

A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt(IV)enX2A2
, with X2  =
cyclobutane‐1,1‐dicarboxylato (CBDCA), dichloro or bis(decanoato) and A = acetato,
dodecanoato, tetradecanoato, hexadecanoato, octadecanoato, adamantanecarboxylato (Ad) or
3α, 12α
‐diformoxy‐5β‐cholato (DFCA) were synthesized and characterized by elemental analysis,
infrared and NMR ( 1H and  13C)
spectroscopic techniques.
Previous platinum(IV) compounds were usually restricted to trans‐dihydroxo or trans‐dichloro
platinum(IV) complexes. Recently trans‐dicarboxylato platinum(IV) complexes with mainly acetate,
trifluoracetate or short‐chain carboxylate groups (<11 carbons) in the axial position have been
described in the literature[1,2,3].
In this paper we report on the synthesis and characterization of a new class of ethylenediamine
platinum(IV) compounds that have high lipophilic long‐chain carboxylate ligands either in the axial
or equatorial position. The platinum(IV) compounds with the lipophilic trans‐carboxylate ligands in
the axial position were prepared by acylation of the trans‐dihydroxo platinum(IV) species using an
acyl halide in the presence of pyridine. In contrast to previous publications[1]
the yields were
excellent (up to 94%!).
The Effects of Boron Derivatives on Lipid Absorption from theIntestine and on Bile Lipids and Bile Acids of Sprague Dawley Rats
Authors: Hall Iris H. , Reynolds David J. , Wong O. T. , Sood A. , Spielvogel B. F.
Published: March 2007

N,N‐dimethyl‐n‐octadecylamine borane
at 8 mg/kg/day, tetrakis‐u‐(trimethylamine
boranecarboxylato)‐bis(trimethyl‐carboxyborane)‐dicopper(II)
at 2.5 mg/kg/day and
trimethylamine‐carboxyborane
at 8 mg/kg/day were evaluated for their effects on bile lipids, bile
acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal
enzyme activities involved in lipid metabolism. The agent administered orally elevated rat bile
excretion of lipids, e.g. cholesterol and phospholipids, and compounds and increased the bile
flow rate. These agents altered the composition of the bile acids, but there was no significant
increase in lithocholic acid which is most lithogenic agent in rats. The three agents did decrease
cholesterol absorption from isolated in situ intestinal duodenum loops in the presence of drug.
Hepatic and small intestinal mucosa enzyme activities, e.g. ATP‐dependent citrate lyase, acyl
CoA cholesterol acyl transferase, cholsterol‐7‐α
‐hydroxylase, sn glycerol‐3‐phosphate acyl
transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase, were reduced. However,
the boron derivatives and decreased hepatic HMG‐CoA reductase activity, the regulatory
enzyme for cholesterol synthesis, but the compounds had no effects on small intestinal mucosa
HMG‐CoA reductase activity. There was no evidence of hepatic cell damage afforded by the
drugs based on clinical chemistry values which would induce alterations in bile acid concentrations
after treatment of the rat.
Stimulation of Phospholipase A2 by Toxic Main Group HeavyMetals: Partly Dependent on G‐proteins?
Authors: Krug H. F.
Published: March 2007

Organometals induce platelet aggregation and inorganic metal ions such as Cd2+
or Pb2+ sensitise
human blood platelets to aggregating agents and this action is associated with the liberation of arachidonic
acid and eicosanoid formation. The same mechanism is observed using human leukaemia cells (HL‐60)
when treated with MeHgCl or Et3PbCl
. The fatty acid liberation within human platelets and HL‐60 cells
could only be inhibited with phospholipase A2 inhibitors of different specificity.

Preincubation of the cells with pertussis toxin reduces the activation induced by Et3PbCl to a great
extent. The non‐catalytic B subunit, that only mediates the binding of the toxin to the cell membranes, has
no effect at all. When summarised, these results suggest that one possible mechanism for the stimulation of
phospholipase A2 by Et3PbCl functions via a G‐protein dependent pathway.
Tin‐Based Antitumour Drugs: New Developments
Authors: Gielen Marcel
Published: March 2007

An overview of the in vitro test results on several human tumour cell lines of several series of
organotin compounds synthesized at the Free University of Brussels VUB. Several compounds
exhibit excellent antitumour activities. in vivo screening also gave very promising results.
The Interaction of the Antitumor ComplexesNa[trans‐RuCl4(DMSO)(Im)] and Na[trans‐RuCl4(DMSO)(Ind)] WithApotransferrin: a Spectroscopic Study
Authors: Messori Luigi , Kratz Felix , Alessio Enzo
Published: March 2007

The interaction of two antitumor ruthenium(III) complexes,‐Na[trans‐RuCl4(DMSO)(Im)] and
Na[trans‐RuCl4(DMSO)(Ind)]‐ with human serum apotransferrin (apoTf) was investigated through
a number of spectroscopic techniques such as UV‐Vis absorption, CD and  1H NMR
spectroscopy. Interestingly, the hydrolysis profiles of these complexes in a physiological buffer
are markedly affected by the presence, in solution, of apoTf suggesting the occurrence of a
specific interaction of their respective hydrolysis products with the protein. The formation of
stable adducts with apotransferrin has been demonstrated by CD spectroscopy, and additional
information obtained through  1H NMR of the hyperfine shifted signals. The bound ruthenium(III)
species may be detached from these adducts by addition of excess citrate at low pH. The
behavior of the investigated ruthenium(III) complexes with apoTf is compared with that of the
recently described and strictly related ru-im and ru-ind antitumour complexes, and discussed in
the frame of general strategies of drug targeting.
Complexes With Biologically Active Ligands. Part 61 Ni(II)Coordination Compounds of Hydrazine and Heterocyclic Sulfonamidesas Inhibitors of the Zinc Enzyme Carbonic Anhydrase
Authors: Borràs Joaquin , Casanova Javier , Cristea Teodora , Gheorghe Adriana , Scozzafava Andrea , Supuran Claudiu T. , Tudor Violeta
Published: March 2007

Ternary Ni(II) complexes of hydrazine and eight heterocyclic sulfonamides possessing carbonic
anhydrase (CA) inhibitory properties, were prepared and characterized by elemental analysis, spectroscopic,
magnetic, thermogravimetric, and conductimetric measurements. The complexes behave as strong inhibitors
for two isozymes (I and II) of carbonic anhydrase.
Boronated Pyrimidines and Purines as Cytotoxic, Hypolipidemic andAnti‐Inflammatory Agents
Authors: Hall Iris H. , Burnham Bruce S. , Elkins Amy , Sood Anup , Powell Walda , Tomasz Jeno , Spielvogel Bernard F.
Published: March 2007

The simple boronated bases, e.g. cytosine, adenine and guanine,
containing no sugar residues retained good pharmacological activity as
hypolipidemic, anti‐neoplastic and anti‐inflammatory agents in mice at 8
mg/kg. Their activities were generally identical to their respective
nucleoside derivatives. Interestingly the boronated acyclovir derivative
was a very potent hypolipidemic agent achieving better activity than
clofibrate and lovastatin. The boronated adenine derivatives appeared
to have the best anti‐inflammatory activity in reducing local edema and
analgesic effects. The agents were active against the growth of murine
and human leukemias and human HeLa‐S3 suspended uterine carcinoma. Only
the boronated adenine derivatives were effective in blocking the growth
of human SW480 adenocarcinoma and the KB nasopharynx.
Effects of Hypoxia and Transferrin on Toxicity and DNA Binding ofRuthenium Antitumor Agents in Hela Cells
Authors: Frasca D. , Ciampa J. , Emerson J. , Umans R. S. , Clarke M. J.
Published: March 2007

Nuclear DNA binding and inhibition of growth of HeLa cells in culture were
determined after 24 h incubation with the ruthenium anticancer agents cis‐Cl
(CCR) and (ImH)trans‐[(Im)2Cl4Ru] (ICR) as a function of [Ru], Po2, and added transferrin.
Consistent with the “activation‐by‐reduction” hypothesis, cytotoxicity and DNA binding for
both complexes increased under reduced oxygen conditions. Consistent with the “transferrin‐
transport” hypothesis, inhibition of cell growth also increased with added transferrin for
both complexes. Despite their differences in charge, reduction potentials and substitution
rates, both complexes behaved remarkably similarly indicating a common mechanism of
action for both. Under atmospheric Conditions (Po2 = 159 torr), CCR inhibited HeLa cell
growth with IC50 = 3.5 μM, while that for ICR was 2.0 μM. The binding of both complexes
to DNA (RuDNA/PDNA) correlated with toxicity and was approximately linear in the concentration
of the ruthenium complex in the culture medium, [Ru]. For both complexes, IC50
values decrease and DNA binding increases with decreasing log(Po2). In general, DNA
binding at all oxygen pressures for both complexes is in the range of one Ru per 1000‐2000
DNA base pairs at [Ru] = IC50.
1,3,4‐Thiadiazole Derivatives. Part 91. Synthesis and BiologicalActivity of Metal Complexes of 5‐(2‐Aminoethyl)‐2‐Amino‐1,3,4‐Thiadiazole
Authors: Barboiu Mihai , Cimpoesu Marilena , Guran Cornelia , Supuran Claudiu T.
Published: March 2007

Metal complexes of the title ligand (L) containing Co(II), Ni(II) and Cu(II) were prepared and
characterized by elemental analysis, IR, electronic spectroscopy and conductimetry. The new derivatives,
possessing the following formulae, CuL2(OH) 2, NiL2Cl2, and showed in vitro antifungal activity
against Aspergillus and Candida spp.
Complexes With Biologically Active Ligands. Part 71 Synthesis andFungitoxic Activity of Metal Complexes Containing 1,3,5‐tris‐(8‐Hydroxyquinolino)‐ Trichlorocyclo‐Triphosphazatriene
Authors: Barboiu Mihai , Guran Cornelia , Jitaru Ioana , Cimpoesu Marilena , Supuran Claudiu T.
Published: March 2007

Complexes containing 1,3,5‐tris‐(8‐hydroxyquinolino)‐trichlorocyclotriphosphazatriene, a new
cyclophosphazene ligand, and Co(II), Cu(II) and Ni(II) were prepared. The new complexes, having the general
formula [MLCl2], [ML2]Cl2, (M=Cu, Co, Ni); [NiLAc], [NiL2Ac]Ac and [ML3]X3 (M=Ni, Co, X=Cl, Ac)
were characterised by elemental analysis, electronic‐, IR spectroscopy, and electrical conductivity
measurements. Some of them inhibited the growth of several fungi species (Aspergillus and Candida spp.)
Complexes With Biologically Active Ligands. Part 1. Synthesis ofCoordination Compounds of Diazoxide With Transition‐ andMain‐Group Cations
Authors: Supuran Claudiu T.
Published: March 2007

Complexes of diazoxide (3‐methyl‐7‐chloro‐1,2,4‐benzothiadiazine‐1,1‐dioxide) ‐ an antihypertensive
and hyperglycemic pharmacological agent ‐ with a series of transition‐ and main‐group di‐, triand
tetravalent metal ions were prepared and characterized by elemental analysis, spectroscopic,
thermogravimetric, magnetic and conductimetric measurements. The complexes were tested as inhibitors of
the enzyme carbonic anhydrase (CA), proving modest activity towards CA II and better inhibition of CA I.
Carbonic Anhydrase Interaction With Lipothioars Enites: A NovelClass of Isozymes I and II Inhibitors
Authors: Timotheatou Despina , Ioannou Panayiotis V. , Scozzafava Andrea , Briganti Fabrizio , Supuran Claudiu T.
Published: March 2007

The interaction of carbonic anhydrase (CA) isozymes I and II with a series of As(III) derivatives,
dialkyl and diaryl rac‐2,3‐dimyristoyloxypropyldithioarsonites, was investigated kinetically and
spectrophotometrically, utilizing the native and Co(II)‐substituted enzymes. Depending on the substitution
pattern at the ‐As(SR) 2 moiety of the investigated derivatives, inactive compounds were found for R = phenyl
or naphthyl, and active ones for derivatives containing carboxyl groups (R = CH2COOH, cysteinyl and
glutathionyl). Together with the arsonolipids previously investigated, the active compounds of this series ‐
the "lipothioarsenites"‐ constitute a novel class of CA inhibitors that bind to the metal ion within the
enzyme active site, as proved by changes in the electronic spectra of adducts of such inhibitors with
Co(II)CA.
Reactions of the Antiarthritic Drug Aurothiomalate WithPhenylmercury(II) Compounds: NMR Studies
Authors: Graham Garry G. , Gordon Diarmaid , Sadler Peter J.
Published: March 2007

Clinical formulations of the antiarthritic drug aurothiomalate sometimes contain
phenylmercury(ll) compounds as antimicrobial preservative agents and, in the presence of para‐chloromercuri‐benzoate, aurothiomalate is a potent inhibitor of collagenase. By  1H NMR
spectroscopy, para‐hydroxymercuribenzoate and para‐hydroxymercuriphenylsulphonate were
shown to react with aurothiomalate by complexing only with the terminal thiomalate of
aurothiomalate oligomers, thereby converting them to ring complexes. The reaction was also
detected by UV spectroscopy. The arylmercury complexes produced no change in the bulk of the
thiomalate residues of aurothiomalate indicating considerable stability of the polymeric structure of
aurothiomalate in which each gold is bound to two thiolate residues. The potent inhibition of the
mercurial induced collagenase activity may be due either to aurothiomalate or to a complex formed
between the terminal thiomalate residues with the arylmercurial. The arylmercury complexes may be unsuitable as antimicrobials in solutions of aurothiomalate because of complexation with the
terminal thiomalate residues.
The Effects of Amine‐Carboxyborane Related Derivatives on UMR‐106Bone Metabolism
Authors: Murphy Margaret E. , Elkins Amy L. , Shrewsbury Robert P. , Sood Anup , Spielvogel Bernard F. , Hall Iris H.
Published: March 2007

The amine‐carboxyboranes and related derivatives have been shown to be
potent anti‐inflammatory and anti‐osteoporosis agents. Their action in
part appears to be mediated by the modulation of cytokines, e.g. TNFα
or IL‐1. Previous studies have demonstrated that LPS induced
macrophages release of TNFα maximally at 60 to 90 min. and IL‐1 from 5
to 8 hr. The amine‐carboxyboranes reduced significantly the release of
these cytokines but also blocked TNFα high affinity binding to UMR‐106
receptor at 90 min. at 10 μM, and IL‐1 high affinity binding at 5 hr. at
12.5 μM. In addition, the agents suppressed IL‐8 binding to CHO K1 high
affinity receptor at 24 hr. at 50 μM and IL‐2 binding to HuT‐8 receptors
at 25 μM at 90 min. and 5 hr. Correlation of metabolic events
associated with osteoporosis showed that at 90 min., when TNFα receptor
binding was reduced by the agents, calcium uptake into UMR‐106 cells was
reduced at 10 μM as well as the acid and alkaline phosphatases, and the
prostaglandin cyclo‐oxygenase activities and adhesion of leukocytes and
macrophages to UMR‐106 cell monolayers. At 5hr. when the agents reduced
IL‐1 binding to UMR‐106 receptors, calcitonin and 1,25‐dihydrovitamin D3
binding was reduced by the agents as was acid and alkaline phosphatase,
and 5′‐lipoxygenase activities and white blood cell adhesion. At this
time calcium uptake and proline incorporation was increased
significantly by the agents. At later times e.g. 18‐48 hr. calcium
uptake was still increased, and NAG activity was inhibited in the
presence of the agents. These effects may be related more to the
inhibition of other cytokine receptor binding, e.g. IL‐8. Thus, many of
the observed metabolic effects of amine‐carboxyboranes as antiosteoporosis
agents can be correlated with their inhibition of cytokine
high affinity binding to target cell receptors.
Complexes With Biologically Active Ligands. Part 2. Preparation ofCopper(II) Complexes of Positively‐Charged Derivatives of Aminoglutethimide
Authors: Supuran Claudiu T.
Published: March 2007

Cu(II) complexes of 1‐[4‐(3‐ethyl‐piperidine‐2,6‐dione)‐3‐yl]‐phenyl‐2,4,6‐trisubstituted
pyridinium perchlorates, containing alkyl, aryl and combinations of these two types of moieties in their
molecule were synthesized and characterized by elemental analysis, spectroscopy, magnetic,
thermogravimetric and conductimetric measurements. In these complexes, Cu(II) ions are in octahedral
geometry with four water molecules occupying the equatorial coordination sites and the two organic ligands
in deprotonated state the remaining axial ones. The donor atom of these ligands is constituted by the ionized
nitrogen of the glutarimide moiety. The new derivatives possess weak inhibitory activity towards the zinc
enzyme carbonic anhydrase.
Anti‐Tumor Activity, In Vitro and In Vivo, of SomeTriphenylphosphinegold(I) Thionucleobases
Authors: Webster Lorraine K. , Rainone Silvina , Horn Ernst , Tiekink Edward R. T.
Published: March 2007

The [Ph3PAu(6‐MP)] complex, where 6‐MPH is 6‐mercaptopurine, is active against the cisplatinresistant
cell line, mouse leukaemia L1210/DDP, as is the precursor compound [Ph3PAuCl],
suggesting that the thiolate is not critical for activity. Against the human cell lines, FaDu (squamous
cell carcinoma) and SKOV‐3 (ovarian carcinoma), both [Ph3PAu(6‐MP)] and [Ph3PAu(6‐TG)],
where 6‐TGH is 6‐thioguanine, were active. [Ph3PAu(6‐MP)] was active against a murine PC6
plasmacytoma, but not as active as cisplatin.
Porphyrins and Metalloporphyrins: Potential Hypoxic Agents
Authors: James B. R. , Meng G. G. , Posakony J. J. , Ravensbergen J. A. , Ware C. J. , Skov K. A.
Published: March 2007

Synthetic water‐soluble porphyrins and their metalloporphyrin derivatives with Co(III), Cu(II), Ru(II)
and Pt(II), containing various functional groups within the meso‐positions of the porphyrin, were
synthesised and evaluated as hypoxic agents, especially as cytotoxins and radiosensitisers. Cobalt
complexes of the porphyrins containing positively charged methylpyridinium groups showed
selective toxicity toward hypoxic Chinese Hamster Ovary (CHO) cells. The Co(III) complexes of the
cationic and the anionic porphyrins are all weak radiosensitisers toward hypoxic cells, the highest
sensitisation enhancement ratio (SER = 1.22, at 50 μM) being with a porphyrin complex containing a
cis‐arrangement of two nitro and two methylpyridinium meso‐substituents. A copper complex of a
tetracationic porphyrin showed slight radiosensitisation activity with an SER value of about 1.1. The
other metalloporphyrins showed no hypoxic selectivity or radiosensitisation activity. In total, over 50
porphyrin free bases have been synthesised, of which half are water‐soluble and have been
metallated; thus, the chemistry is now in place for further development of water‐soluble hypoxic
agents.
Complexes With Biologically Active Ligands. Part 91 Metal Complexes of 5‐Benzoylamino‐ and 5‐(3‐Nitrobenzoyl‐Amino)‐1,3,4‐Thiadiazole‐2‐Sulfonamide as Carbonic Anhydrase Inhibitors
Authors: Jitianu Andrei , llies Marc A. , Briganti Fabrizio , Scozzafava Andrea , Supuran Claudiu T.
Published: March 2007

Complexes containing the anions of 5‐benzoylamido‐1,3,4‐thiadiazole‐2‐sulfonamide and 5‐(3‐nitro‐benzoylamido)‐1,3,4‐thiadiazole‐2‐sulfonamid as ligands, and V(IV); Cr(III); Fe(III); Co(II); Ni(II); Cu(II) and Ag(I) were synthesized and characterized by standard procedures (elemental analysis; IR, electronic, and EPR spectroscopy; TG, magnetic and conductimetric measurements). The original sulfonamides and their metal complexes are strong inhibitors of two carbonic anhydrase (CA) isozymes, CA I and II.
Workshop on: Chemistry of Metals in Medicine ‐ The Industrial Perspective
Authors: Sadler Peter J.
Published: March 2007

The Workshop was attended by 61 participants from 20 countries. Most of the speakers were
industrialists and the Chairpersons and Discussion Leaders were academics.

The area “Chemistry of Metals in Medicine” has the potential for producing innovative, high quality, and original research.

This is a new and emerging area of biomedical chemistry. Small firms are already being established which are devoted to the new elemental medicine. Major pharmaceutical and healthcare industries too are becoming aware of the major impact which metal chemistry is likely to have on traditional organic pharmacology and of the new opportunities which it presents for advances including the development of metalloenzyme‐specific inhibitors, targeted radionuclide complexes for diagnosis and therapy, contrast agents for magnetic resonance imaging, safer mineral and vitamin supplements, new agents for the treatment of neurological, gastrointestinal and cardiovascular disease, skin conditions, cancer, and microbial and viral infections.

The European scientific and technological research base in this area is potentially attractive for business. Industrial collaboration and cooperation can be accommodated within the COST framework.
Clinical Delivery of Therapeutic Agents Based on Metals
Authors: Fox John
Published: March 2007

Metals have been used in clinical practice for hundreds of years and for a variety of indications. Although potent agents whose activity may be adapted by manipulation of their chemistry and that of associated ligands, their use has been limited by toxic effects. There is now a burgeoning series of delivery technologies available which may be adapted to the administration of metal based drugs. Together with greater understanding of metal chemistry and their mechanisms of action in disease processes, there is an opportunity to increase the use of metals in medicine by targeting their action more effectively to the therapeutic site and/or protecting the body from toxic effects.
Radiometals in Diagnosis and Therapy
Authors: Burke James F.
Published: March 2007

Radiometals are the mainstay of both diagnostic and therapeutic nuclear medicine because the choice of radionuclide is primarily dictated by nuclear decay characteristics rather than chemistry.  99mTc is the most frequently used diagnostic radionuclide and requires coordination in a diversity of chemical disguises to permit imaging of a variety of tissues and disease states. Therapeutic nuclear medicine is less advanced but can provide significant benefits provided the radionuclide is accurately targetted.
Properties of Paramagnetic Metals in MRI
Authors: Schaefer Michel
Published: March 2007

The use of different metals in Magnetic Resonance Imaging will be briefly described.

This overview will be more a qualitative description than a full paper on this topic, in other words, this paper contributes to explaining how and why some metal ions have been chosen for MRI.

Paramagnetic compounds are currently used in clinical practice. The main differencesin the four gadolinium complexes come from their different chemical structures. The macrocyclic compounds display a high symmetry and rigidity and therefore a high level of stability.

All these four complexes display the same efficacyon the signal in MRI. In addition, they are very well tolerated.

The second main class of compounds consists of the iron oxide superparamagnetic particles. They are used in the detection of focal liver lesions. Through their action in dephasing the spin, they are used as negative enhancers.
Fe‐EDTA‐Bisamide and Fe‐ADR‐925, The Iron‐Bound Hydrolysis Product of the Cardioprotective Agent Dexrazoxane, Cleave DNA Via the Hydroxyl Radical
Authors: Magliery Thomas J. , Vitellaro Lizabeth K. , Diop Ndeye Khady , Marusak Rosemary A.
Published: March 2007

Use of the antitumor drug doxorubicin is limited by cardiomyopathic side‐effects
which are believed to be due to iron‐mediated hydroxyl radical generation. Dexrazoxane
reduces this cardiotoxicity, possibly by removal of iron from doxorubicin by the EDTA‐like
hydrolysis product of dexrazoxane, ADR‐925. However, EDTA‐diimides like dexrazoxane,
previously used as antitumor agents, are themselves carcinogenic, and recent studies have
found that Fe‐ADR‐925 can also promote hydroxyl radical production. This study
demonstrates that, like Fe‐EDTA, Fe‐ADR‐925 and a related desmethyl complex can cleave
plasmid DNA under Fenton conditions, and suggests by radical scavenger study that this
cleavage is probably via the hydroxyl radical. Differences in DNA cleavage dependence
upon concentrations of Fe‐EDTA, Fe‐ADR‐925 and Fe‐EDTA‐bisamide can be explained by differences in the solution chemistry of the complexes.
Carbonic Anhydrase Activators. Part 191 Spectroscopic and Kinetic Investigations for the Interaction of Isozymes I and II With Primary Amines
Authors: Briganti Fabrizio , Scozzafava Andrea , Supuran Claudiu T.
Published: March 2007

The interactions of Zn(II)‐ and Co(II)‐substituted carbonic anhydrase (CA) isozymes I and II with amine type activators such as histamine, serotonin, phenetylamine dopamine and benzylhydrazine have been investigated kinetically, and spectroscopically. All of such activators are of the non‐competitive type towards CO2 hydration and 4‐nitrophenylacetate hydrolysis for both human isozymes (HCA I and HCA II). The electronic spectra of the adducts of Co(II)CA with amine activators are similar to the spectrum of the previously reported Co(II)CAII‐phenol adduct, the only known competitive inhibitor towards CO2 hydration, where the phenol molecule binds into the hydrophobic pocket of the active site. This is a direct spectroscopic evidence that the activator molecules bind within the active site, but not directly to the metal ion. Recent X‐ray crystallographic data for the adduct of HCA II with histamine show that the activator molecule is bound at the entrance of the active site cavity, near to residues His 64, Asn 62 and Gln 92, where actively aids in shuttling protons between the active site and the environment. Similar arrangements probably occur for the other activators reported in the present paper.
Cytotoxic Action of Carboxyborane Heterocyclic Amine Adducts
Authors: Miller Merrill C. , Sood Anup , Spielvogel Bernard F. , Bastow Ken , Hall Iris H.
Published: March 2007

The heterocyclic carboxyborane amines were found to be potent cytotoxic agents in the murine L1210 lymphoid leukemia and human HeLa suspended carcinoma cells. These agents were observed to inhibit HeLa DNA topoisomerase II activity ~ 200 μM and L1210 topoisomerase II activity ≥ 100 μM. These agents did not cause DNA protein linked breaks themselves, but upon incubation for 14‐24 hr did enhance the ability of VP‐16 to cause cleavable complexes. The heterocyclic amineboranes inhibited DNA synthesis and caused DNA strand scission. They were additive with VP‐16 in affording these results as well as inhibiting colony growth of L1210 cells after co‐incubation for 1 hr. The agents inhibited in vitro PKC phosphorylation of both L1210 lymphoid leukemia and human topoisomerase II enzyme.
Carbonic Anhydrase Inhibitors. Part 461 Inhibition of Carbonic Anhydrase Isozymes I, II and IV With Trifluoromethylsulfonamide Derivatives and Their Zinc(II) and Copper(II) Complexes
Authors: Mincione Giovanna , Scozzafava Andrea , Supuran Claudiu T.
Published: March 2007

Reaction of aromatic/heterocyclic sulfonamides containing a free amino group with triflic
anhydride afforded compounds possessing trifluoromethanesulfonamido moieties in their molecule. The Zn(II) and Cu(II) complexes of these new sulfonamides were prepared and characterized by standard procedures (elemental analysis, spectroscopic, magnetic, thermogravimetric and conductimetric measurements). The new derivatives showed good inhibitory activity against three isozymes of carbonic anhydrase (CA), i.e., CA I, II and IV.