Effects of amine ligand bulk and hydrogen bonding on the rate of reaction of platinum(II) diamine complexes with key nucleotide and amino acid residues

NMR spectroscopy has been used to observe the effects of the amine ligand on the rate of reaction of platinum diamine and triamine complexes with DNA and protein residues. Whereas [Pt(dien)Cl]Cl and [Pt(dien)(D(2)O)](2+) have been known to react faster with thioether residues such as N-AcMet than with 5'-GMP, we found that [Pt(Me(4)en)(D(2)O)(2)](2+) appeared to react faster with 5'-GMP. To quantitatively assess the factors influencing the rates of reaction, rate constants at pH 4 were determined for the reactions of [Pt(en)(D(2)O)(2)](2+) [en = ethylenediamine] and [Pt(Me(4)en)(D(2)O)(2)](2+) with N-AcMet, N-AcHis, 5'-GMP, and Guo (guanosine). In each case the less bulky complex ([Pt(en)(D(2)O)(2)](2+)) reacts more quickly than does the bulkier [Pt(Me(4)en)(D(2)O)(2)](2+), as expected. Both complexes reacted faster with 5'-GMP; however, analysis of the rate constants suggests that the [Pt(en)(D(2)O)(2)](2+) complex favors reaction with 5'-GMP due to hydrogen bonding with the 5'-phosphate, whereas [Pt(Me(4)en)(D(2)O)(2)](2+) disfavors reaction with N-AcMet due to steric clashes. Bulk had relatively little effect on the rate constant with N-AcHis, suggesting that peptides or proteins that coordinate via His residues would not have their reactivity affected by bulky diamine ligands.     

Kinetics and mechanism of the substitution reactions of [PtCl(bpma)]<Superscript>+</Superscript>, [PtCl(gly-met-<Emphasis Type="Italic">S,N,N</Emphasis>)] and their aqua analogues with <Emphasis Type="SmallCaps">l</Emphasis>-methionine,glutathione and 5′-GMP

The substitution reactions of [PtCl(bpma)]+, [PtCl(gly-met-S,N,N)], [Pt(bpma)(H(2)O)](2+) and [Pt(gly-met-S,N,N)(H(2)O)](+) [where bpma is bis(2-pyridylmethyl)amine and gly-met-S,N,N is glycylmethionine] with L-methionine, glutathione and guanosine 5'-monophosphate (5'-GMP) were studied in aqueous solutions in 0.10 M NaClO(4) under pseudo-first-order conditions as a function of concentration and temperature using UV-vis spectrophotometry. The reactions of the chloro complexes were followed in the presence of 10 mM NaCl and at pH approximately 5, whereas the reactions of the aqua complexes were studied at pH 2.5. The [PtCl(bpma)]+ complex is more reactive towards the chosen nucleophiles than [PtCl(gly-met-S,N,N)]. Also, the aqua complexes are more reactive than the corresponding chloro complexes. The activation parameters for all the reactions studied suggest an associative substitution mechanism. The reactions of [PtCl(bpma)]+ and [PtCl(gly-met-S,N,N)] with 5'-GMP were studied by using (1)H NMR spectroscopy at 298 K. The pK (a) value of the [Pt(gly-met-S,N,N)(H(2)O)]+ complex is 5.95. Density functional theory calculations (B3LYP/LANL2DZp) show that in all cases guanine coordination to the L(3)Pt fragment (L(3) is terpyridine, bpma, diethylenetriamine, gly-met-S,N,N) is much more favorable than the thioether-coordinated form. The calculations collectively support the experimentally observed substitution of thioethers from Pt(II) complexes by N7-GMP. This study throws more light on the mechanistic behavior of platinum antitumor complexes.     

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques

The reactions of cis-[PtCl(NH3)2(H2O)]+ with L-methionine have been studied by 1D 195Pt and 15N NMR, and by 2D[1H, 15N] NMR. When the platinum complex is in excess, the initial product, cis-[PtCl(NH3)2(Hmet-S)]+ undergoes slow ring closure to [Pt(NH3)2(Hmet-N,S)]2+. Slow ammine loss then occurs to give the isomer of [PtCl(NH3)(Hmet-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3)(Hmet-S)2]+ isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)2]2+. Near pH 7, methionine is unreactive toward cis-[PtCl(OH)(NH3)2]. By contrast, L-cysteine reacts readily with cis-[PtCl(OH)(NH3)2] at pH 7, but there were many reaction products, including bridged species. Cis-[PtCl(OH)(NH3)2] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 microM), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important.     

Multinuclear NMR spectroscopy and antitumor activity of novel platinum(II) complexes with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines

Novel platinum(II) complexes with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have been synthesized and characterized by infrared and multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N, 195Pt). The complexes are of two types: [PtCl2(L)2] and [PtCl2(NH3)(L)], where L=5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp) and 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp). Significant 15N NMR upfield shifts (92-95 ppm) were observed for N(3) atom indicating this nitrogen atom as a coordination site. The molecular structure suggest that Pt(II) ion has the square planar geometry with N(3) bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines, N-bonded second ligand (NH3 for cis-[PtCl2(NH3)(L)] or, respectively, 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines for cis-[PtCl2L2]) and two cis chloride anions. The antiproliferative activity in vitro of complexes (1-4) have been tested against the cells of four human cell lines: SW707 rectal adenocarcinoma, A549 non-small cell lung carcinoma, T47D breast cancer and HCV29T bladder cancer. The results indicate a moderate antiproliferative activity of (4) against the cells of rectal, breast and bladder cancer and a marked and selective cytotoxic effect of (1-3) against the cells of all studied human cancer lines.     

The fate of platinum(II) and platinum(IV) anti-cancer agents in cancer cells and tumours

SRIXE mapping has been used to gain insight into the fate of platinum(II) and platinum(IV) complexes in cells and tumours treated with anticancer active complexes to facilitate the development of improved drugs. SRIXE maps were collected of thin sections of human ovarian (A2780) cancer cells treated with bromine containing platinum complexes, cis-[PtCl(2)(3-Brpyr)(NH(3))] (3-Brpyr=3-bromopyridine) and cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] (OAcBr=bromoacetate), or a platinum complex with an intercalator attached cis-[PtCl(2)(2-[(3-aminopropyl)amino]-9,10-anthracenedione)(NH(3))]. After 24h the complexes appear to be localised in the cell nucleus with a lower concentration in the surrounding cytoplasm. In cells treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] the concentration of bromine was substantially higher than in control cells and the bromine was co-localised with the platinum consistent with the 3-bromopyridine ligand remaining bound to the platinum. The cells treated with cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] also showed an increased level of bromine, but to a much lesser extent than for those treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] suggestive of substantial reduction of the platinum(IV) complex. Maps were also collected from thin sections of a 4T1.2 neo 1 mammary tumour xenograft removed from a mouse 3h after treatment with cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)] and revealed selective uptake of platinum by one cell.     

Study of the reactions between platinum(II) complexes and L-methionine in the presence and absence of 5'-GMP

The reactions of the platinum(II) complexes, [Pt(dien)(H(2)O)](2+), [PtCl(dien)](+) and [PtBr(dien)](+) (dien is diethylenetriamine) with some biologically relevant ligands such as inosine (INO), inosine-5'-monophosphate (5'-IMP), guanosine-5'-monophosphate (5'-GMP), glutathione (GSH) and l-methionine (S-meth), have been studied by UV-Visible spectrophotometry and (1)H NMR spectroscopy. Kinetic and thermodynamic parameters of these reactions were determined. Competitive reactions of [PtCl(dien)](+) with l-methionine and 5'-GMP demonstrated initially rapid formation of [Pt(dien)(S-meth)](2+) followed by displacement of l-methionine by 5'-GMP. In the later stages the concentration of [Pt(dien)(N7-GMP)](2+) is predominant. The results are analyzed in reference to the anti-tumour activity of Pt(II) complexes.     

Platinum complexes with one radiosensitizing ligand [PtCl2(NH3) (sensitizer)]: radiosensitization and toxicity studies in vitro

Complexes of general formula [PtCl2(NH3)L] with one radiosensitizing ligand per platinum are compared with ligand L alone, complexes with two radiosensitizers per platinum [PtCl2L2], and their analogs with NH3 ligands, with respect to radiosensitizing properties and toxicity in CHO cells. Radiosensitizing ligands, L, were misonidazole, metronidazole, 4(5)-nitroimidazole, and 2-amino-5-nitrothiazole, and the ammine analogs were cis- and trans-DDP [diamminedichloroplatinum(II)] and the monoammine, K[PtCl3(NH3)]. Results are related to a previous study on plasmid DNA binding by these series. The toxicity of the mono series [PtCl2(NH3)L], attributable to DNA binding, is much higher than the corresponding bis complexes, [PtCl2L2]. For L = misonidazole, toxicity is similar to the monoammine, but higher in hypoxic than in aerobic cells. trans-[PtCl2(NH3)-(misonidazole)] is more toxic than the cis isomer. Except for L = 4(5)-nitroimidazole, the complexes [PtCl2(NH3)L] are more toxic than L in air and hypoxia. Hypoxic radiosensitization by the mono complexes is comparable to the monoammine and is not better than free sensitizers, again except for L = 4(5)-nitroimidazole. Significantly lower sensitization is observed in oxic cells. The bis complexes [PtCl2L2], which do not bind to DNA as well as the mono complexes, are less effective radiosensitizers and less toxic than the [PtCl2(NH3)L] series.     

The binding of platinum complexes to tuna cytochrome c.

The binding of [PtCl4]2- and cis-[PtCl2(NH3)2] to methionine-65 of tuna cytochrome c was investigated by 1H n.m.r. The modification at methionine-65 is shown to cause an extremely small structural perturbation to the protein at the site of modification.     

Synthesis, structure, and reactivity of monofunctional platinum(II) and palladium(II) complexes containing the sterically hindered ligand 6-(methylpyridin-2-yl)acetate

Three complexes containing the novel, sterically hindered ligand 6-(methylpyridin-2-yl)acetate (PICAC) have been synthesized and characterized: [Pt(NH3)2(PICAC-N,O)]NO3 (1), [Pt(en)(PICAC-N,O)]NO3 (2), and [Pd(en)(PICAC-N,O)]NO3 (3) (en = ethane-1,2-diamine). The crystal structures of 2 and 3 have been determined. The two complexes are isostructural and exhibit a mixed [N3O] coordination. In both cases, PICAC forms a sterically crowded six-membered chelate. Signal multiplicities in 1H NMR spectra of 1-3 indicate that the N,O chelates are conformationally rigid on the NMR timescale as a result of the steric bulk of the pyridine derivative. Complex 2 undergoes facile ring opening in 0.1M NaCl solution at neutral pH, resulting in a zwitterionic species in which carboxylate oxygen has been replaced with chloride. The complex was identified by X-ray crystallography as [PtCl(en)(PICAC-N)] x H2O (4), which contains a "dangling" carboxylate group. In 4, the pyridine moiety adopts an almost perpendicular orientation relative to the platinum coordination plane. Likewise, complex 2 reacts rapidly with 5'-guanosine monophosphate (5'-GMP) to form the monofunctional adduct [Pt(en)(PICAC)(5'-GMP)] (5) (NMR, 25 degrees C, t(1/2) approximately 24 min). 2-D nuclear Overhauser enhancement spectroscopy (NOESY) and double quantum-filtered correlated spectroscopy (dqf-COSY) experiments (500 MHz) and variable temperature NMR spectroscopy confirm that adduct 5 exists as a 1:1 mixture of rotamers in solution as a result of the mutual repulsion between the cis-oriented pyridine and guanine bases. While 2 readily reacts with DNA nitrogen, its monofunctional adducts show no significant effect on the conformation of native DNA. Circular dichroism (CD) spectra recorded of platinum-modified calf-thymus DNA suggest that the structural damage produced by complex 2 does not mimic that produced by the clinical agent. Both the unusual reactivity and the inability to induce cisplatin-like DNA conformational changes are proposed to be responsible for the marginal biological activity of the new complexes.     

The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines

The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.     

Preparation of platinum(IV) complexes with dipeptide and diimine. X-ray crystal structure and 195Pt NMR spectra

We prepared platinum(IV) complexes containing dipeptide and diimine or diamine, the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complex, where -N,N,O means dipeptide coordinated as a tridentate chelate, dipeptide=glycylglycine (NH(2)CH(2)CON(-)CH(2)COO(-), digly, where two protons of dipeptide are detached when the dipeptide coordinates to metal ion as a tridentate chelate), glycyl-L-alanine (NH(2)CH(2)CON(-)CHCH(3)COO(-), gly-L-ala), L-alanylglycine (NH(2)CH CH(3)CON(-)CH(2)COO(-), L-alagly), or L-alanyl-L-alanine (NH(2)CHCH(3)CON(-)CHCH(3)COO(-), dil-ala), and diimine or diamine=bipyridine (bpy), ethylenediamine (en), N-methylethylenediamine (N-Me-en), or N,N'-dimethylethylenediamine (N,N'-diMe-en). In the complexes containing gly-L-ala or dil-ala, two separate peaks of the (195)Pt NMR spectra of the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complexes appeared in, but in the complexes containing digly or L-alagly, one peak which contained two overlapped signals appeared. One of the two complexes containing gly-L-ala and bpy, [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3), crystallized and was analyzed. This complex has the monoclinic space group P2(1)2(1)2(1) with unit cell dimensions of a=9.7906(3)A, b=11.1847(2)A, c=16.6796(2)A, Z=4. The crystal data revealed that this [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex has the near- (Cl, CH(3)) configuration of two possible isomers. Based on elemental analysis, the other complex must have the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) configuration. The (195)Pt NMR chemical shifts of the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex and the far- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex are 0 ppm and -19 ppm, respectively (0 ppm for the Na(2)[PtCl(6)] signal). The additive property of the (195)Pt NMR chemical shift is discussed. The (195)Pt NMR chemical shifts of [PtCl(dipeptide-N,N,O)(bpy)]Cl appeared at a higher field when the H attached to the dipeptide carbon atom was replaced with a methyl group. On the other hand, the (195)Pt NMR chemicals shifts of [PtCl(dipeptide-N,N,O)(diamine)] appeared at a lower field when the H attached to the diamine nitrogen atom was replaced with a methyl group, in the order of [PtCl(digly-N,N,O)(en)]Cl, [PtCl(digly-N,N,O)(N-Me-en)]Cl, and [PtCl(digly-N,N,O)(N,N'-diMe-en)]Cl.     

Sterically hindered cisplatin derivatives with multiple carboxylate auxiliary arms: synthesis and reactions with guanosine-5'-monophosphate and plasmid DNA.

Two novel sterically hindered cisplatin derivatives with the ligand L=NH(2)C(CH(2)CH(2)COOH)(3) were prepared: cis-PtCl(2)L(2) and cis-PtCl(2)L(NH(3)). The starting compound for the syntheses was NH(2)C(CH(2)CH(2)COOtBu)(3), also known as a building block for dendrimers. cis-PtCl(2)L(2) was prepared from K(2)PtCl(4) in an unusual two-phase reaction in water-chloroform, followed by deprotection of the tert-butyl protective groups with formic acid to yield a water-soluble complex. The mixed-ligand compound cis-PtCl(2)L(NH(3)) was prepared from [PPh(4)][PtCl(3)(NH(3))] in methanol, with subsequent deprotection in formic acid. DNA-binding properties of the two compounds were investigated using the model base guanosine-5'-monophosphate (5'-GMP) and pBR322 plasmid DNA. While cisplatin [cis-PtCl(2)(NH(3))(2)] induced an unwinding of 12 degrees in pBR322 plasmid DNA, cis-PtCl(2)L(NH(3)) induced only 3 degrees unwinding, which is indicative of a monofunctional binding mode. Remarkably, cis-PtCl(2)L(2) did not induce any distortion in plasmid DNA, which strongly suggests that the compound does not bind to DNA. Test reactions with 5'-GMP, monitored by 1H and 195Pt NMR, confirmed that cis-PtCl(2)L(2) is unable to bind to DNA, whereas cis-PtCl(2)L(NH(3)) binds only one nucleotide. Apparently, binding of platinum to nucleotides at the coordination site cis with respect to the ligand L is prevented by steric crowding. Thus, cis-PtCl(2)L(NH(3)) must bind DNA monofunctionally at the trans position. Besides, both compounds have a chloride replaced by one of the carboxylate arms, forming a a seven-membered chelate ring. In theory, cis-PtCl(2)L(2) could also form a second chelate ring, but this was not observed.     

Model platinum nucleobase and nucleoside complexes and antitumor activity: X-ray crystal structure of [PtIV(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-ethylguanine)Cl]NO3.H2O

A series of platinum(II) and (IV) monoadducts of the type [Pt(II)(DACH)LCl]NO3 and [Pt(IV)(DACH)trans-(X)2LCl]NO3 (where DACH=trans-1R,2R-diaminocyclohexane, L=adenine, guanine, hypoxanthine, cytosine, adenosine, guanosine, inosine, cytidine, 9-ethylguanine (9-EtGua), or 1-methylcytosine and X=hydroxo or acetato ligand) have been synthesized and characterized by elemental analysis and by 1H and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the model nucleobase complex [Pt(IV)(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-EtGua)Cl]NO3.H2O was determined using a single crystal X-ray diffraction method. The compound crystallized in the monoclinic space group P2(1), with a=10.446(2) A, b=22.906(5) A, c=10.978(2) A, Z=4, and R=0.0718, based upon the total of 11,724 collected reflections. In this complex, platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogen of DACH, whereas, the other two equatorial positions occupied by chloride ion and 9-ethylguanine. The remaining two axial positions were occupied by the oxygen atoms of acetato ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. Some of these synthesized models of DACH-Pt-DNA adducts have good in vitro cytotoxic activity against the cisplatin-sensitive human cancer ovarian A2780 cell line (IC50=1-8 microM). Interestingly, a substituted nucleobase (9-ethylguanine) adduct was over 6-fold more potent than regular adducts. The cross-resistance factor against the 44-fold cisplatin-resistant 2780CP/clone 16 cells was about 3-9; thus, the cytotoxicity of adducts was indicative of low potency, but the resistance factors were also substantially low. These results suggest that DNA adducts of DACH-Pt are cytotoxic with low cross-resistance.     

Preparation, cytotoxicity and interactions with nucleophiles of three isomeric transplatinum complexes containing methylpiperidine ligands

Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicities of the three isomers against these cell lines. The interactions of the three complexes with reduced glutathione (GSH) and with ubiquitin (Ub), as a model protein, were studied. The trans-[PtCl2(NH3)(2-methylpiperidine)] reacted approximately twice as slowly with GSH as did the other two isomers. In the 1:1 interactions of the three complexes with ubiquitin (Mr = 8565 amu), trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)] attained 100% modification while trans-[PtCl2(NH3)(2-methylpiperidine)] reached only less than 50% modification. Trans-[PtCl2(NH3)(2-methylpiperidine)] reacts significantly less efficiently with GSH and proteins than the other two isomers yet this is not reflected in the cytotoxicity values. These results indicate that for these complexes, in these cell lines, cytosolic detoxification probably does not play a dominant role in determining the cytotoxicity of the complexes.     

Molecular orbital study of complexes of zinc(II) with sulphide, thiomethanolate, thiomethanol, dimethylthioether, thiophenolate, formiate, acetate, carbonate, hydrogen carbonate, iminomethane and imidazole. Relationships with structural and catalytic zinc in some metallo-enzymes.

Geometry optimization and energy calculations have been performed at the density functional B3LYP/LANL2DZ level on hydrogen sulfide (HS-), dihydrogensulfide (H2S), thiomethanolate (CH3S-), thiomethanol (CH3SH), thiophenolate (C6H5S-), methoxyde (CH3O-), methanol (CH3OH), formiate (HCOO-), acetate (CH3COO-), carbonate (CO3(2-)), hydrogen carbonate (HCO3-), iminomethane (NH=CH2), [ZnS], [ZnS2]2-, [Zn(HS)]+, [Zn(H2S)]2+, [Zn(HS)4]2-, [Zn(CH3S)]+, [Zn(CH3S)2], [Zn(CH3S)3]-, [Zn(CH3S)4]2-, [Zn(CH3SH)]2+, [Zn(CH3SCH3)]2+, [Zn(C6H5S)]+, [Zn(C6H5S)2], [Zn(C6H5S)3]-, [Zn(HS)(NH=CH2)2]+, [Zn(HS)2(NH=CH2)2], [Zn(HS)(H2O)]+, [Zn(HS)(HCOO)], [Zn(HS)2(HCOO)]-, [Zn(CH3O)]+, [Zn(CH3O)2], [Zn(CH3O)3]-, [Zn(CH3O)4]2, [Zn(CH3OH)]2+, [Zn(HCOO)]+, [Zn(CH3COO)]+, [Zn(CH3COO)2], [Zn(CH3COO)3]-, [Zn(CO3)], [Zn(HCO3)]+, and [Zn(HCO3)(Imz)]+ (Imz, 1,3-imidazole). The computed Zn-S bond distances are 2.174A for [ZnS], 2.274 for [Zn(HS)]+, 2.283 for [Zn(CH3S)]+, and 2.271 for [Zn(C6H5S)]+, showing that sulfide anion forms stronger bonds than substituted sulfides. The nature of the substituents on sulfur influences only slightly the Zn-S distance. The optimized tetra-coordinate [Zn(HS)2(NH=CH2)2] molecules has computed Zn-S and Zn-N bond distances of 2.392 and 2.154A which compare well with the experimental values at the solid state obtained via X-ray diffraction for a number of complex molecules. The computed Zn-O bond distances for chelating carboxylate derivatives like [Zn(HOCOO)]+ (1.998A), [Zn(HCOO)]+ (2.021), and [Zn(CH3COO)]+ (2.001) shows that the strength of the bond is not much influenced by the substituent on carboxylic carbon atom and that CH3- and HO- groups have very similar effects. The DFT analysis shows also that the carboxylate Ligand has a preference for the bidentate mode instead of the monodentate one, at least when the coordination number is small.     

Influence of the position of substituents in the cytotoxic activity of trans platinum complexes with hydroxymethyl pyridines

The synthesis and chemical characterization of two trans platinum complexes, (1) trans-[PtCl(2)NH(3)(2-hydroxymethylpyridine)] and (2) trans-[PtCl(2)NH(3)(3-hydroxymethylpyridine)], are described. The structures and chemical behaviour of these compounds have been compared to those of their isomer (3) trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] previously studied. X-ray structures of all of them were solved and some interesting differences were found. The values of the dihedral angle (85 degrees , 57 degrees and 42 degrees for 1, 2 and 3, respectively) demonstrate how important is the position of substituent from a structural point of view. Studies of circular dichroism (CD), electrophoretic mobility (EM) in agarose gel and atomic force microscopy (AFM) showed differences in the modifications caused by the three complexes on DNA. Studies of antiproliferative activity of complexes 1 and 2 against cell tumour lines (HL-60) and apoptosis assays have also been carried out, showing that 1 as well as 2 are far less active than the previously described complex 3 (IC(50)=19; 19 and 3 microM, respectively). This fact probes that slight modifications on the drug's design may generate significant differences in the final antitumour activity by modifying the DNA-drug adducts, performance of resistance mechanisms and all the factors that play a fundamental role in Pt complexes' cytotoxicity.     

Mechanism of the reversal reaction of platinated DNA with thiourea studied by platinated 5'-GMP

The reversal reactions of cis-[Pt(NH3)2(5'-GMP)2] 2-(1) and trans-[Pt(NH3)2(5'-GMP)2] 2-(2) with thiourea were examined by reversed phase HPLC and monothioureido intermediate cis-[Pt(NH3)2(5'-GMP) (tu)] (4) was detected. This result suggested that Pt-[5'-GMP-N(7)] bond was more labile than Pt-NH3 bond and the release of ammonia from cis-Pt(II)-DNA base complexes is a result of trans-labilizing effect of sulfur containing molecule displaced with DNA base.     

Studies of interactions between platinum(II) complexes and some biologically relevant molecules

The reactions of Pt(II) complexes, cis-[Pt(NH3)2Cl2], [Pt(terpy)Cl]+, [Pt(terpy)(S-cys)]2+, and [Pt(terpy)(N7-guo)]2+, where terpy=2,2':6',2'-terpyridine, S-cys=L-cysteine, and N7-guo=guanosine, with some biologically relevant ligands such as guanosine-5'-monophosphate (5'-GMP), L-cysteine, glutathione (GSH) and some strong sulfur-containing nucleophiles such as diethyldithiocarbamate (dedtc), thiosulfate (sts), and thiourea (tu), were studied in aqueous 0.1 M Hepes at pH of 7.4 using UV-vis, stopped-flow spectrophotometry, and 1H NMR spectroscopy.     

Structure and solution behaviour of cyclooctadiene complexes of platinum(II)

The substitution behaviour of [PtCl(R)(COD)] (R⁻ = Me and Fc) complexes, by the stepwise addition of phosphine ligands, L (L = PPh₃, PEt₃ and P(NMe₂)₃), were investigated in situ by ¹H and ³¹P NMR spectroscopy. Addition of less than two equivalents of the phosphine ligand results in the formation of dimeric molecules with the general formula trans-[Pt(R)(μ-Cl)(L)]₂ for the sterically demanding systems where R⁻ = Me/L = P(NMe₂)₃ and R⁻ = Fc/L = PEt₃, PPh₃ and P(NMe₂)₃ while larger quantities resulted in cis- and trans mixtures of mononuclear complexes being formed. In the case of the relatively small steric demanding, strongly coordinating, PEt₃ ligand the trans-[PtCl(R)(PEt₃)₂] mononuclear complexes were exclusively observed in both cases. The crystal structures of the two substrates, [PtCl(R)(COD)] (R⁻ = Me or Fc), as well as the cis-[PtCl(Fc)(PPh₃)₂] substitution product are reported.