trans-Platinum planar amine compounds with [N2O2] ligand donor sets: effects of carboxylate leaving groups and steric hindrance on chemical and biological properties

Replacement of NH3 by a planar amine L to give trans-[PtCl2(L)(L')] (L = NH3, L'= pyridine or substituted pyridine, quinoline, isoquinoline, thiazole; L = L'= pyridine, thiazole), greatly enhances the cytotoxicity of the transplatinum geometry. The "parent" compound trans-[PtCl2(NH3)2] is therapeutically inactive. Modification of the ligands to an [N2O2] donor set, where O represents an acetate leaving group, enhances the aqueous solubility while retaining the cytotoxicity of the parent chloride compounds. The effect of two mutual trans leaving groups with weak trans influence is to impart remarkable chemical stability on the structure. This strategy is analogous to the use of the inert dicarboxylate leaving groups in the clinical compounds carboplatin and oxaliplatin. In this paper, systematic modification of the steric effects of carrier pyridine groups and, especially, carboxylate leaving groups in trans-[Pt(O2CR)2(NH3)(pyr)] is shown to modulate aqueous solubility and hydrolysis to the activated aqua species. The results presented here demonstrate the utility of the "carboxylate strategy" in "fine-tuning" the chemical and pharmacokinetic properties in the design of clinically relevant transplatinum complexes.     

G-G base-pairing in nucleobase adducts of the anticancer drug cis-[PtCl2(NH3)(2-picoline)] and its trans isomer

cis-[PtCl2(NH3)(2-picoline)] (AMD473) is a sterically-hindered anticancer complex with a profile of chemical and biological activity that differs significantly from that of cisplatin. Adducts of AMD473 with neutral 9-ethylguanine (9-EtGH) and anionic (N1-deprotonated) 9-ethylguanine (9-EtG) as perchlorate and nitrate salts, and also a nitrate salt of the trans isomer (AMD443), were prepared and their structures determined by X-ray crystallography: cis-[Pt(NH3)(2-pic)(9-EtGH)2](ClO4)2 (1).2H(2)OMe(2)CO, cis-[Pt(NH3)(2-pic)(9-EtGH)2](NO3)2 (2).2H2O, cis-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (3),3.5 H2O, trans-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (4).8H2O. In all cases, platinum coordination is through N7 of neutral (1, 2) and anionic (3, 4) guanine. In each complex, the guanine bases are arranged in the head-to-tail conformation. In complex 1, there is an infinite array of six-molecule cycles, based on both hydrogen bonding and pi-pi stacking of the 2-picoline and guanine rings. Platinum(II) coordinated at N7 acidifies the N1 proton of neutral 9-ethylguanine (pKa = 9.57) to give pKa1 = 8.40 and pKa2 = 8.75 for complex 2, and pKa1 = 7.77 and pKa2 = 9.00 for complex 4. In complexes 3 and 4, three intermolecular hydrogen bonds are formed between neutral and deprotonated guanine ligands involving O6, N1 and N2 sites. Unusually, both of the platinated guanine bases of complexes 3 and 4 participate in this triple G triple bond G hydrogen bonding. This is the first report of X-ray crystal structures of nucleobase adducts of the promising anticancer drug AMD473.     

Factors governing the kinetic competition of nitrogen and sulfur ligands in cisplatin binding to biological targets

The kinetic competition of sulfur and nitrogen nucleophiles L in the substitution reactions of cisplatin derivatives, cis-[Pt(II)(NH(3))(2)(X)(OH(2))](n)(+) + L --> cis-[Pt(II)(NH(3))(2)(X)(L)](m)(+) + H(2)O (X = Cl(-), H(2)O), has been studied using density functional theory and continuum dielectric calculations. The calculations reveal an intrinsic kinetic preference of platinum(II) for nitrogen over sulfur ligands. However, biologically relevant substituents can mask this preference for nitrogen nucleophiles. Investigation of the activation free energies of the substitution reactions in dependence of the dielectric constant epsilon demonstrates the microenvironment to be crucial in the binding of cisplatin to its intracellular targets. The fused aromatic heterocycle of guanine stabilizes the transition state for platination at a smaller epsilon more efficiently than do the functional groups of amino acid residues. The results of this work suggest a relatively facile platination of guanine-N7 sites of DNA in regions of low epsilon, particularly in the proximity of histone cores.     

Pyridine-carboxylate complexes of platinum. Effect of N,O-chelate formation on model bifunctional DNA-DNA and DNA-protein interactions

This paper reports on the chemistry of platinum complexes containing bidentate pyridine-carboxylate (pyAc = pyridin-2-yl-acetate and picEt = pyridine-2-ethylcarboxylate, ethylpicolinate) (N,O) ligands. The pyridine-2-acetate and ethylpicolinate ligands form six- and five-membered chelates, respectively, upon formation of the Pt-carboxylate bond. In all reactions with picEt with various platinum complex starting materials, spontaneous de-esterification of the pendant carboxylate ester occurs to give directly the chelates K[PtCl(2)(pic-N,O)]-trans-[Pt(pic-N,O)(2)] and SP-4,2-[PtCl(pic-N,O)(NH(3))] without any evidence of intermediates. The de-esterification is solvent dependent, and molecular modeling was used to explain this reaction. The reactions of the geometric isomers of [PtCl(pyAc-N,O)(NH(3))] with 5'-guanosine monophosphate, 5'-GMP, and N-acetyl-l-methionine, AcMet, were investigated by NMR spectroscopy. The objective was to ascertain by model chemistry the feasibility of formation of ternary DNA-Pt-protein adducts in biology. Model nucleotide and peptide compounds were formed in situ by chloride displacement giving [PtL(pyAc-N,O)(NH(3))](+) (L = 5'-GMP or AcMet). Competitive reactions were then examined by addition of the complementary ligand L. Sulfur displacement of coordinated 5'-GMP was slow. For SP-4,3-[Pt(AcMet)(NH(3))(PyAc-N,O)](+), a rapid displacement of the sulfur ligand by 5'-GMP was observed, giving SP-4,2-[Pt(5'-GMP-N7)(pyAc-N,O)(NH(3))](+).     

Study of intramolecular competition between carboxylate and phosphonate for Pt(II) with the aid of a novel tridentate carboxylato-thioether-phosphonato ligand

The tridentate dianionic ligand 2-[2'-(hydroxyisopropoxyphosphoryl)phenylsulfanyl]benzoate (L(2-)) reacts with cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) to form an S,O-chelate in which the O-coordinated group is either carboxylate or phosphonate, depending on the degree of protonation of the complex. Carboxylate appears to be the stronger ligand, and the stoichiometric reaction between cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) and L(2-) yields the neutral species [Pt(L)(NH(3))(2)], with L bound by sulfanyl and carboxylate groups, both in solution and in the solid state. Upon protonation of [Pt(L)(NH(3))(2)], the stronger basicity of the carboxylate causes the Pt coordination to switch from carboxylate to phosphonate, and the uncoordinated carboxylate group becomes protonated. In methanolic solution, the first-order kinetics of this rearrangement could be observed by (31)P NMR spectroscopy. Both complexes-the carboxylate-bound neutral complex [Pt(L)(NH(3))(2)].H(2)O (triclinic, P1 (no. 2), a=9.529(6), b=9.766(6), c=12.299(7) angstroms, alpha=106.91(2), beta=101.71(2), gamma=102.05(2) degrees, Z=2) and the perchlorate salt of the phosphonate-bound complex [Pt(LH)(NH(3))(2)]ClO(4).H(2)O (monoclinic, P2(1)/c (no. 14), a=12.095(2), b=14.046(2), c=14.448(2) angstroms, beta=95.55(2) degrees, Z=4)-were characterized by X-ray crystallography.     

Heterometallic platinum(II) compounds with β-aminoethylferrocenes: synthesis, electrochemical behaviour and anticancer activity

A new family of heterometallic compounds 3-6 containing ferrocenyl and platinum(II) centers has been synthesized by reaction of 1-β-aminoethylferrocene (1) and 1,1'-bis(β-aminoethyl)ferrocene (2) with Pt(II) precursors. Using K(2)[PtCl(4)] as the Pt(II) source, the cis-square-planar neutral compounds [Fe{η(5)-C(5)H(4)(CH(2))(2)NH(2)}(2)PtCl(2)] (3) and [{Fe(η(5)-C(5)H(4)(CH(2))(2)NH(2))(η(5)-C(5)H(5))}(2)PtCl(2)] (5) were obtained. Reaction of cis-[PtCl(2)(dmso)(2)] with 1 and 2 resulted in the displacement of dmso and chloride ligands from the platinum coordination sphere, affording the cationic and neutral compounds [Fe{η(5)-C(5)H(4)(CH(2))(2)NH(2)}(2)Pt(dmso)Cl]Cl (4) and [Fe(η(5)-C(5)H(4)(CH(2))(2)NH(2))(η(5)-C(5)H(5))Pt(dmso)Cl(2)] (6). Compounds 3-6 were thoroughly characterized using multinuclear ((1)H, (13)C, (195)Pt) NMR, IR spectroscopy, ESI mass spectrometry and elemental analysis. Single-crystal X-ray analysis of heterometallic 6 confirmed the cis geometry of the molecule and revealed that the platinum atom is held in a perfect square-planar geometry. The electrochemical behaviour of the heterometallic compounds 3-6, which has been examined by cyclic (CV) and square wave (SWV) voltammetries in dichloromethane and dmso solution, is characterized by the reversible one-electron oxidation of the ferrocene moieties. The results of the biological activity studies revealed that the organometallic complex 5 is active against all cell lines with GI(50) values in the range 1.7-2.3 μM. When compared to the standard anticancer drug cisplatin, heterotrimetallic 5, possessing two aminoethylferrocenyl units coordinated to the Pt(II) center, showed a greater activity profile in the colon cancer cell line. Cell cycle studies revealed that the new mixed compound exhibits a mechanism of action different to cisplatin.     

Studies of the Intramolecular Aromatic-ring Stacking Interactions in the Ternary Platinum(Ⅱ) Complexes

The stability constants of some ternary mixed-ligand complexes, Pt(Phen)(CA) , where Phen=1,10-phenanthroline and CA- =carboxylate, were determined by means of potentiometric pH titration in aqueous solutions(I=0.1 mol/L, KNO3; 25 ℃), and the stability of them was compared with that of the corresponding binary complexes. It was revealed that the ternary complexes containing phenylalkane carboxylates ligands(PCA-) are much more stable than those formed with formate and acetate. The results indicate that there exist the intramolecular aromatic-ring interactions between the phenanthroline ring of Phen and the phenyl moiety of ligand PCA- in the ternary mixed-ligand Pt(Phen)(PCA)- complexes. The extent of the stacking interactions, which depends on the number of methylene groups between the phenyl moieties and the coordinated phenylalkane carboxylate groups, was calculated. The best-fitted stack was obtained for the complexes with 2-phenylacetate and 3-phenylpropionate as the ligands.     

Reaction of polynuclear platinum antitumor compounds with reduced glutathione studied by multinuclear (1H, 1H-15N gradient heteronuclear single-quantum coherence,and 195Pt) NMR spectroscopy

A possible explanation for the low bioavailability of platinum antitumor compounds is their high reactivity with the sulfur-containing tripeptide glutathione (GSH; deprotonated GSH = SG). GSH is located in the intracellular matrix of the cell with a normal concentration of 5-10 mM. In vivo, only a small fraction of the administered drug will migrate into the cell, resulting in relatively high concentrations of GSH compared to that of the drug. The products of the reactions of [[trans-PtCl(NH(3))(2)](2)-mu-[trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2)]](NO(3))(4) (BBR3464; 1,0,1/t,t,t, n = 6), [[trans-PtCl(NH(3))(2)](2)-mu-(H(2)N(CH(2))(6)NH(2))](NO(3))(2) (BBR3005; 1,1/t,t, n = 6), [[trans-PtCl(NH(3))(2)](2)-mu-(H(2)N(CH(2))(3)NH(2)(CH(2))(4)NH(2))]Cl(3) (BBR3571; 1,1/t,t-spermidine, n = 3, 4), and trans-[PtCl(2)(NH(3))(2)] (t-DDP) with reduced GSH in phosphate-buffered saline (pH 7.35) have been characterized by (1)H, (195)Pt, and (1)H(-)(15)N gradient heteronuclear single-quantum coherence NMR spectroscopy and high-performance liquid chromatography (HPLC) coupled with electrospray ionization time-of-flight mass spectrometry to determine likely metabolites of the complexes with GSH. Chemical shifts (NMR) and retention times (HPLC) established via analysis of the t-DDP profile served as a fingerprint to compare results obtained for the products afforded by the degradation of the polynuclear compounds by GSH. Identical kinetic profiles and chemical shifts between the metabolites and the t-DDP/GSH products allowed identification of the final product for the 1:2 Pt:GSH reaction as a dinuclear species [[trans-Pt(SG)(NH(3))(2)](2)-mu-SG], in which glutathione bridges the two platinum centers via only the sulfur atom.     

Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): preparative, structural, and electrochemical studies

The preparation and oxidation of the anticancer drug AMD473, cis-[PtCl2(NH3)(2-pic)] (2-pic = 2-methylpyridine), has been investigated. cis-[PtCl2(NH3)(2-pic)] is readily oxidized with peroxide to give the trans-dihydroxoplatinum(IV) complex cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)]. The crystal structure of this complex reveals that it is highly strained as a result of a steric clash between the methyl group of the 2-picoline ligand and an axial hydroxo ligand, with the Pt-N-C angle adjacent to this clash opened up to an unprecedented 138.6(6) degrees . Attempts at converting the dihydroxoplatinum(IV) complex to dichloro and diacetato analogues were unsuccessful with reaction with HCl leading to loss and protonation of the 2-picoline ligand to form the salt (2-picH)[PtCl5(NH3)] and the platinum(II) complex cis-[PtCl2(NH3)(2-pic)], both confirmed by crystallography. Electrochemical studies revealed that cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)] is reduced more readily (-714 mV vs Ag/AgCl) than its pyridine analogue cis,trans,cis-[PtCl2(OH)2(NH3)(pyridine)] (-770 mV vs Ag/AgCl) consistent with the steric clash in the former complex destabilizing the platinum(IV) oxidation state.     

Synthesis, characterization, and cytotoxicity of platinum(IV) carbamate complexes

The synthesis, characterization, and cytotoxicity of eight new platinum(IV) complexes having the general formula cis,cis,trans-[Pt(NH(3))(2)Cl(2)(O(2)CNHR)(2)] are reported, where R = tert-butyl (4), cyclopentyl (5), cyclohexyl (6), phenyl (7), p-tolyl (8), p-anisole (9), 4-fluorophenyl (10), or 1-naphthyl (11). These compounds were synthesized by reacting organic isocyanates with the platinum(IV) complex cis,cis,trans-[Pt(NH(3))(2)Cl(2)(OH)(2)]. The electrochemistry of the compounds was investigated by cyclic voltammetry. The aryl carbamate complexes 7-11 exhibit reduction peak potentials near -720 mV vs Ag/AgCl, whereas the alkyl carbamate complexes display reduction peak potentials between -820 and -850 mV vs Ag/AgCl. The cyclic voltammograms of cis,cis,trans-[Pt(NH(3))(2)Cl(2)(O(2)CCH(3))(2)] (1), cis,cis,trans-[Pt(NH(3))(2)Cl(2)(O(2)CCF(3))(2)] (2), and cis-[Pt(NH(3))(2)Cl(4)] (3) were measured for comparison. Density functional theory studies were undertaken to investigate the electronic structures of 1-11 and to determine their adiabatic electron affinities. A linear correlation (R(2) = 0.887) between computed adiabatic electron affinities and measured reduction peak potentials was discovered. The biological activity of 4-11 and, for comparison, cisplatin was evaluated in human lung cancer A549 and normal MRC-5 cells by the MTT assay. The compounds exhibit comparable or slightly better activity than cisplatin against the A549 cells. In MRC-5 cells, all are equally or slightly less cytotoxic than cisplatin, except for 4 and 5, which are more toxic.     

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device

Most low-molecular-weight platinum anticancer drugs have short blood circulation times that are reflected in their reduced tumor uptake and intracellular DNA binding. A platinum(IV) complex of the formula c, c, t-[Pt(NH 3) 2Cl 2(O 2CCH 2CH 2CO 2H)(O 2CCH 2CH 2CONH-PEG-FA)] ( 1), containing a folate derivative (FA) at an axial position, was prepared and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compound 1 was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH 2) through multiple amide linkages to use the SWNTs as a "longboat delivery system" for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular reduction of Pt(IV) to Pt(II). The ability of SWNT tethered 1 to destroy selectively FR(+) vs FR(-) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. That the SWNTs deliver the folate-bearing Pt(IV) cargos into FR(+) cancer cells by endocytosis was demonstrated by the localization of fluorophore-labeled SWNTs using fluorescence microscopy. Once inside the cell, cisplatin, formed upon reductive release from the longboat oars, enters the nucleus and reacts with its target nuclear DNA, as determined by platinum atomic absorption spectroscopy of cell extracts. Formation of the major cisplatin 1,2-intrastrand d(GpG) cross-links on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compound 1 is the first construct in which both the targeting and delivery moieties have been incorporated into the same molecule; it is also the first demonstration that intracellular reduction of a Pt(IV) prodrug leads to the cis-{Pt((NH 3) 2} 1,2-intrastrand d(GpG) cross-link in nuclear DNA.     

Binding of DNA purine sites to dirhodium compounds probed by mass spectrometry

The adducts formed between the antitumor active compounds [Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](BF(4))(2), Rh(2)(O(2)CCH(3))(4), and Rh(2)(O(2)CCF(3))(4) with DNA oligonucleotides have been assessed by matrix-assisted laser desorption ionization (MALDI) and nanoelectrospray (nanoESI) coupled to time-of-flight mass spectrometry (TOF MS). A series of MALDI studies performed on dipurine (AA, AG, GA, and GG)-containing single-stranded oligonucleotides of different lengths (tetra- to dodecamers) led to the establishment of the relative reactivity cis-[Pt(NH(3))(2)(OH(2))(2)](2+) (activated cisplatin) approximately Rh(2)(O(2)CCF(3))(4) > cis-[Pt(NH(3))(2)Cl(2)] (cisplatin) > [Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](BF(4))(2) > Rh(2)(O(2)CCH(3))(4) approximately Pt(C(6)H(6)O(4))(NH(3))(2) (carboplatin). The relative reactivity of the complexes is associated with the lability of the leaving groups. The general trend is that an increase in the length of the oligonucleotide leads to enhanced reactivity for Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](BF(4))(2) and Rh(2)(O(2)CCH(3))(4) (except for the case of [Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](2+), which reacts faster with the GG octamers than with the dodecamers), whereas the reactivity of Rh(2)(O(2)CCF(3))(4) is independent of the oligonucleotide length. When monitored by ESI, the dodecamers containing GG react faster than the respectiveAA oligonucleotides in reactions with Rh(2)(O(2)CCF(3))(4) and Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](BF(4))(2), whereas AA oligonucleotides react faster with Rh(2)(O(2)CCH(3))(4). The mixed (AG, GA) purine sequences exhibit comparable rates of reactivity with the homopurine (AA, GG) dodecamers in reactions with Rh(2)(O(2)CCH(3))(4). The observation of initial dirhodium-DNA adducts with weak axial (ax) interactions, followed by rearrangement to more stable equatorial (eq) adducts, was achieved by electrospray ionization; the Rh-Rh bond as well as coordinated acetate or acetonitrile ligands remain intact in these dirhodium-DNA adducts. MALDI in-source decay (ISD), collision-induced dissociation (CID) MS-MS, and enzymatic digestion studies followed by MALDI and ESI MS reveal that, in the dirhodium compounds studied, the purine sites of the DNA oligonucleotides interact with the dirhodium core. Ultimately, both MALDI and ESI MS proved to be complementary, valuable tools for probing the identity and stability of dinuclear metal-DNA adducts.     

Novel binding interactions of the DNA fragment d(pGpG) cross-linked by the antitumor active compound tetrakis(mu-carboxylato)dirhodium(II,II)

Insight into the N7/O6 equatorial binding interactions of the antitumor active complex Rh(2)(OAc)(4)(H(2)O)(2) (OAc(-) = CH(3)CO(2)(-)) with the nucleotide 5'-GMP and the DNA fragment d(pGpG) has been obtained by one- (1D) and two-dimensional (2D) NMR spectroscopy. The lack of N7 protonation at low pH values and the significant increase in the acidity of N1-H (pK(a) approximately 5.6 as compared to 8.5 for N7 only bound platinum adducts), indicated by the pH dependence study of the H8 (1)H NMR resonance for the HT (head-to-tail) isomer of Rh(2)(OAc)(2)(5'-GMP)(2), are consistent with bidentate N7/O6 binding of the guanine. The H8 (1)H NMR resonance of the HH (head-to-head) Rh(2)(OAc)(2)(5'-GMP)(2) isomer, as well as the 5'-G and 3'-G H8 resonances of the Rh(2)(OAc)(2) [d(pGpG)] adduct exhibit pH-independent titration curves, attributable to the added effect of the 5'-phosphate group deprotonation at a pH value similar to that of the N1 site. The enhancement in the acidity of N1-H, with respect to N7 only bound metal adducts, afforded by the O6 binding of the bases to the rhodium centers, has been corroborated by monitoring the pH dependence of the purine C6 and C2 (13)C NMR resonances for Rh(2)(OAc)(2)(5'-GMP)(2) and Rh(2)(OAc)(2) [d(pGpG)]. The latter studies resulted in pK(a) values in good agreement with those derived from the pH-dependent (1)H NMR titrations of the H8 resonances. Comparison of the (13)C NMR resonances of C6 and C2 for the dirhodium adducts Rh(2)(OAc)(2)(5'-GMP)(2) and Rh(2)(OAc)(2) [d(pGpG)] with the corresponding resonances of the unbound ligands at pH 8.0, showed substantial downfield shifts of Deltadelta approximately 11.0 and 6.0 ppm, respectively. The HH arrangement of the bases in the Rh(2)(OAc)(2) [d(pGpG)] adduct is evidenced by intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrum. The presence of the terminal 5'-phosphate group in d(pGpG) results in stabilization of one left-handed Rh(2)(OAc)(2) [d(pGpG)] HH1 L conformer, due to the steric effect of the 5'-group, favoring left canting in cisplatin-DNA adducts. Complete characterization of the Rh(2)(OAc)(2[d(pGpG)] adduct revealed notable structural features that resemble those of cis-[Pt(NH(3))(2) [d(pGpG)]]; the latter involve repuckering of the 5'-G sugar ring to C3'-endo (N-type) conformation, retention of C2'-endo (S-type) 3'-G sugar ring conformation, and anti orientation with respect to the glycosyl bonds. The superposition of the low energy Rh(2)(OAc)(2) [d(pGpG)] conformers, generated by simulated annealing calculations, with the crystal structure of cis-[Pt(NH(3))(2) [d(pGpG)]], reveals remarkable similarities between the adducts; not only are the bases almost completely destacked upon coordination to the metal in both cases, but they are favorably poised to accommodate the bidentate N7/O6 binding to the dirhodium unit. Unexpectedly, the two metal-metal bonded rhodium centers are capable of engaging in cis binding to GG intrastrand sites by establishing N7/O6 bridges that span the Rh-Rh bond.     

Selective recognition of configurational substates of zinc cyclam by carboxylates: implications for the design and mechanism of action of anti-HIV agents

The interaction of metal cyclams with carboxylate groups is thought to play an important role in their binding to the CXCR4 chemokine receptor and in their anti-HIV activity. Here we report the synthesis of acetate, phthalate, perchlorate and chloride complexes of Zn(II) cyclam (1,4,8,11-tetraazacyclotetradecane). The X-ray crystal structures of [Zn(cyclam)(phthalate)](n)(CH(3)OH)(2n) and [Zn(cyclam)(H(2)O)(2)](OAc)(2) contain octahedral Zn(II) centres. Phthalate acts as a bridging ligand in the former complex, binding through monodentate carboxylate groups, and giving rise to infinite chains in the lattice together with extensive hydrogen bonding between carboxylate donor oxygen atoms and amine and methanol acceptor atoms. The uncoordinated acetate groups and the aqua ligand in the acetate complex are also involved in a rich network of hydrogen bonds and this may account for the unusually long Zn[bond]O distance (2.27 A). In both crystalline complexes, the macrocycle adopts the trans-III (S,S,R,R) configuration. 1D (1)H NMR spectra of all four complexes have been fully assigned by a combination of 2D [(1)H, (1)H] COSY and TOCSY, and [(1)H, (13)C] and [(1 )H, (15)N] HSQC NMR data. In aqueous solution, the stable trans-III configuration found in the solid-state equilibrates slowly (hours at 298 K) with trans-I (R,S,R,S) and cis-V (R,R,R,R) configurations. The trans-III configuration is predominant in aqueous solution for both the chloride and perchlorate complexes, but for the acetate and phthalate complexes, the cis-V configuration dominates. Carboxylate groups appear to stabilize the cis-V configuration in solution through Zn(II) coordination and hydrogen bonding. Titration of the chloride Zn(II)-cyclam complex with acetate confirmed that carboxylates strongly induce formation of the cis-V configuration. This implies that carboxylates can exert a strong influence over configurational selectivity. Cyclam NH hydrogen bonding is prevalent both in the solid state and in solution, and is relevant to the anti-HIV activity of Zn(II) and other metal cyclam complexes and to their ability to recognize the CXCR4 transmembrane co-receptor.     

The chemistry of dinuclear analogues of the anticancer drug cisplatin. A DFT/CDM study

The mechanism of the formation of dinuclear platinum(II) mu-hydroxo complexes from cisplatin hydrolysis products, their interconversion, decomposition, and reactions with biomolecules has been explored using a combined DFT/CDM approach. All activation barriers for the formation of [cis-{Pt(NH(3))(2)(X)}-(mu-OH)-cis-{Pt(NH(3))(2)(Y)}](n)()(+) (X, Y = Cl, OH(2), OH) via nucleophilic attack of a hydroxo complex on an aqua complex are lower than the activation barriers for cisplatin hydrolysis. Considering therapeutic Pt(II) concentrations in tumors, however, only the reaction between two molecules of cis-[Pt(NH(3))(2)(OH(2))(OH)](+) (E) yielding [cis-{Pt(NH(3))(2)(OH(2))}-(mu-OH)-cis-{Pt(NH(3))(2)(OH)}](2+) (5) remains kinetically superior to cisplatin hydrolysis. 5 is strongly stabilized by intramolecular hydrogen bonding between the terminal aqua and hydroxo ligands, resulting in an unusually high pK(a) of 5 and a low pK(a) of its conjugate acid. Unimolecular cyclization of 5 yields the dimers [cis-{Pt(NH(3))(2)}(mu-OH)](2)(2+) (7a with antiperiplanar OH groups and 7b with synperiplanar OH groups). The electronic structure of several diplatinum(II) complexes has been analyzed to clarify whether there are metal-metal interactions. The overall reactivity to guanine (Gua) and dimethyl sulfide (Met, representing the thioether functional group of methionine) increases in the order 5 < 7a approximately 7b < mononuclear complexes, whereas the kinetic selectivity to Gua relative to Met increases in the order 7a approximately 5 < 7b approximately monocationic mononuclear complexes < dicationic mononuclear complex. The results of this work (i) help assess whether dinuclear metabolites play a role in cisplatin chemotherapy, (ii) elucidate the toxicity and pharmacological inactivity of [cis-{Pt(NH(3))(2)}(mu-OH)](2)(2+), and (iii) suggest future investigations of dinuclear anticancer complexes that contain one mu-hydroxo ligand.     

cis-[Pt(NH3)2(L)]2+/+ (L = Cl, H2O, NH3) binding to purines and CO: does pi-back-donation play a role?

The ability of cis-[Pt(NH(3))(2)(L)](2+/+), a molecular fragment of the anticancer drug cisplatin, to bind to purines and CO by pi-back-donation from Pt to the ligand was examined computationally. Optimized geometries and computed vibrational frequencies suggest that cis-[Pt(NH(3))(2)(L)](2+/+) (L = Cl, H(2)O, NH(3)) is a poor pi-donor and that pi-back-donation does not play an important role for Pt(II)-ligand interactions in general.     

Acetonimine and 4-imino-2-methylpentan-2-amino platinum(II) complexes: synthesis and in vitro antitumor activity

The reaction of [Pt(dmba)(PPh3)Cl] [where dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl] with aqueous ammonia in acetone in the presence of AgClO4 gives the acetonimine complex [Pt(dmba)(PPh3)(NH=CMe2)]ClO4 (1). The reaction of [Pt(dmba)(DMSO)Cl] with aqueous ammonia in acetone in the presence of AgClO4 gives a mixture of [Pt(dmba)(NH=CMe2)2]ClO4 (2) and [Pt(dmba)(imam)]ClO4 (3a) (where imam = 4-imino-2-methylpentan-2-amino). [Pt(dmba)(DMSO)Cl] reacts with [Ag(NH=CMe2)2]ClO4 in a 1:1 molar ratio to give [Pt(dmba)(DMSO)(NH=CMe2)]ClO4 (4). The reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone at 70 degrees C in the presence of KOH gives [Pt(dmba)(CH2COMe)(NH=CMe2)] (5), whereas the reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone in the absence of KOH gives [Pt(dmba)(imam)]Cl (3b). The reaction of [NBu4]2[Pt2(C6F5)4(mu-Cl)2] with [Ag(NH=CMe2)2]ClO4 in a 1:2 molar ratio produces cis-[Pt(C6F5)2(NH=CMe2)2] (6). The crystal structures of 1 x 2 Me2CO, 2, 3a, 5, and 6 have been determined. Values of IC50 were calculated for the new platinum complexes against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR) and breast cancers (T47D). At 48 h incubation time complexes 1, 4, and 5 show very low resistance factors against an A2780 cell line which has acquired resistance to cisplatin. 1, 4, and 5 were more active than cisplatin in T47D (up to 30-fold in some cases). The DNA adduct formation of 1, 4, and 5 was followed by circular dichroism and electrophoretic mobility.     

Divalent molybdenum complexes of the dipyrrolide ligand system. Isolation of a Mo2 unit with a 45 degree twist angle

The preparation of divalent Mo complexes of dipyrrolide dianions was carried out by reacting Mo(2)(acetate)(4) with the dipotassium salts of Ph(2)C(2-C(4)H(3)NH)(2) and 2-[1,1-bis(1H-pyrrol-2-yl)ethyl]pyridine. The two reactions respectively afforded the diamagnetic [[Ph(2)C(C(4)H(3)N)(2)](2)Mo(2)(OAc)(2)[K(THF)(3)][K(THF)]].THF (1) and [[(2-C(5)H(4) N)(CH(3))C(2-C(4)H(3)N)(2)]Mo(OAc)[K(THF)]](2).THF (2). Both compounds retained two acetate units in the dimetallic structure. Conversely, the reaction of Me(8)Mo(2)Li(4)(THF)(4) with Et(2)C(2-C(4)H(3)NH)(2) afforded the paramagnetic dimer [[Et(2)C(C(4)H(3)N)(2)](4)Mo(2)Li(2)][Li(THF)(4)](2).0.5THF (3). The paramagnetism is most likely caused by the 45 degree rotation of the two Mo(dipyrrolide) units with respect to each other and which, in turn, is caused by the presence of two lithium cations in the molecular structure.     

Studies on the photoactivation of two cytotoxic trans,trans,trans-diazidodiaminodihydroxo-Pt(IV) complexes

Light-activation of metal ion complexes to cytotoxic species is of interest due to the potential use in anticancer therapy. Two platinum complexes, trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)] (3) and trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] (4) were irradiated with either UV (λ = 366 nm) or white fluorescent light and the various photochemical and photobiological phenomena were characterized. HPLC coupled to UV/Vis and MS detection was used to identify photochemical species resulting from irradiation of 4 with UV and white light. These studies showed that various Pt(IV) and Pt(II) products formed during the photolysis. The mass spectra of Pt(IV) complexes showed Pt ions in both the positive as well as the negative mode while Pt(II) complexes resulted in only positively charged Pt(III) ions. Since cellular DNA is considered to be a key target for platinum antitumor drugs, the irreversible platination of calf thymus DNA by the photoactivated Pt(IV) complexes was followed by Atomic Adsorption spectrometry (AAS). The effect of adding chloride or biological reducing agents glutathione (GSH) and ascorbic acid on the rates of DNA platination where also studied. Upon activation by light, both compounds show similar binding behaviour to DNA, but the rates of DNA platination for 3 were faster than for 4. Both chloride and GSH protected DNA from platination by the photoactivated compounds; consistent with the trapping of reactive aqua-Pt species. The presence of ascorbate increased the level of platinum bound to DNA for photoactivated 4 but not for 3. Without photoactivation, little or no DNA platination was observed, either with or without ascorbate or GSH. Cytotoxicity studies with two human cancer cell lines underline the photochemotherapeutic potential of these compounds. Striking is the increase in cytotoxic potency with the replacement of an ammine by a pyridine ligand.