guanosine-monophosphate and 1-2-cyclohexanediamine

A new chiral series of potential antitumor metal-based complexes 1-3(a and b) of L- and D-tryptophan have been synthesized and thoroughly characterized. Both enantiomers of 1-3 bind DNA noncovalently via phosphate interaction with slight preference of metal center for covalent coordination to nucleobases. The K(b) values of L-enantiomer, however, possess higher propensity for DNA binding in comparison with the D-enantiomeric analogs. The relative trend in K(b) values is as follows: 2(a) > 2(b) > 3(a) > 1(a) > 3(b) > 1(b). These observations together with the findings of circular dichoric and fluorescence studies reveal maximal potential of L-enantiomeric form of copper complex to bind DNA, thereby exerting its therapeutic effect. The complex 2a exhibits a remarkable DNA cleavage activity with pBR322DNA in the presence of different activators such as H(2) O(2) , ascorbic acid, 3-mercaptopropionic acid, and glutathione, suggesting the involvement of active oxygen species for the DNA scission. In vitro anticancer activity of complexes 1-3(a) were screened against 14 different human carcinoma cell lines of different histological origin, and the results reveal that 2a shows significant antitumor activity in comparison with both 1a and 3a and is particularly selective for MIAPACA2 (pancreatic cancer cell line).

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Circular Dichroism; Coordination Complexes; Copper; Cyclohexylamines; DNA; DNA Cleavage; Electron Spin Resonance Spectroscopy; Guanosine Monophosphate; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Organomercury Compounds; Reactive Oxygen Species; Spectrophotometry, Infrared; Stereoisomerism; Thymidine Monophosphate; Tryptophan; X-Ray Diffraction

A set of three oxaliplatin derivatives containing 1,2-trans-R,R-diaminocyclohexane (dach) as a spectator ligand and different chelating leaving groups X-Y, viz., [Pt(dach)(O,O-cyclobutane-1,1-dicarboxylate)], or Pt(dach)(CBDCA), [Pt(dach)(N,O-glycine)]+, or Pt(dach)(gly), and [Pt(dach)(N,S-methionine)]+, or Pt(dach)(L-Met), where L-Met is L-methionine, were synthesized and the crystal structure of Pt(dach)(gly) was determined by X-ray diffraction. The effect of the leaving group on the reactivity of the resulting Pt(II) complexes was studied for the nucleophiles thiourea, glutathione (GSH) and L-Met under pseudo-first-order conditions as a function of nucleophile concentration and temperature, using UV-vis spectrophotometric techniques. 1H NMR spectroscopy was used to follow the substitution of the leaving group by guanosine 5'-monophosphate (5'-GMP2-) under second-order conditions. The rate constants indicate for all reactions a direct substitution of the X-Y chelate by the selected nucleophiles, thereby showing that the nature of the chelate, viz., O-O (CBDCA2-), N-O (glycine) or S-N (L-Met), respectively, plays an important role in the kinetic and mechanistic behavior of the Pt(II) complex. The k1 values for the reaction with thiourea, L-Met, GSH and 5'-GMP2- were found to be as follows (10(3) k1, 37.5 degrees C, M(-1) s(-1)): Pt(dach)(CBDCA) 61 +/- 2, 21.6 +/- 0.1, 23 +/- 1, 0.352 +/- 0.002; Pt(dach)(gly) 82 +/- 3, 6.2 +/- 0.2, 37 +/- 1, 1.77 +/- 0.01; Pt(dach)(L-Met) (thiourea, GSH) 62 +/- 2, 24 +/- 1. The activation parameters for all reactions studied suggest an associative substitution mechanism.

Topics: Amino Acids; Chelating Agents; Crystallography, X-Ray; Cyclohexylamines; Glutathione; Guanosine Monophosphate; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Platinum Compounds; Thiourea

The use of a sterically hindered diamine ligand (Me(4)DACH) has allowed for the first time, the isolation and characterization, both in the solid state (X-ray crystallography) and in solution (circular dichroism), of pure DeltaHT rotamers of [Pt(Me(4)dach)(5'-GMP)(2)] (compounds 1 and 2 for R,R and S,S configurations of the Me(4)DACH ligand, respectively). Comparison of the CD spectra obtained for each rotamer, which differ only in the chirality of the Me(4)DACH ligand (R,R or S,S) or in the chirality of the HT conformation (Delta or Lambda), allowed us to conclude that, in the 200-350 nm range, the contributions to the overall CD spectrum that stem from diamine chirality and diamine-induced chirality of platinum d--d transitions or from sugar chirality are negligible relative to the exciton chiral coupling that occurs for pi-pi* transitions of the cis guanines. Accurate molecular structures of 1.10 D(2)O and 2.14 D(2)O (conventional crystallographic agreement indexes R(1) convergent to 2.07 % and 2.18 %, respectively) revealed that the crystallized rotamers have a DeltaHT conformation that is in agreement with all previously reported X-ray structures of [Pt(diamine)(nucleos(t)ide)(2)] complexes. This conformation allows the 5'-phosphate to be located in proximity to the Me(4)DACH ligand so that (P)O...HC(N) hydrogen-bond interactions exists in both complexes. For both structures, the canting of the guanine planes on the coordination plane is right-handed (R; canting angle (Phi) of 80.9 degrees and 73.2 degrees, respectively); this indicates that the canting direction is driven by the HT conformation chirality (Delta for both compounds) and not by the chirality of the carrier ligand (different for the two compounds). Density functional theory analysis of the conformational space as a function of Phi indicated a good agreement between the computed and experimental structures. The increase in energy for Phi values below 65 degrees and 55 degrees (for 1 and 2, respectively) is mainly due to the short intramolecular contacts between C(8)H and the cis N-Me groups on the same side of the platinum coordination plane.

Topics: Antineoplastic Agents; Circular Dichroism; Cyclohexylamines; Diamines; Guanosine Monophosphate; Hydrogen Bonding; Ligands; Models, Molecular; Molecular Conformation; Organoplatinum Compounds; X-Ray Diffraction