REACTION OF A CHIRAL PLATINUM TRIAMINE COMPOUND WITH KEY AMINO ACID AND GUANINE ANALOG

Platinum compounds can exhibit cytotoxic activity through reaction with DNA; however, interaction with proteins and DNA bases, especially with methionine residues and Guanine analogs, is another common biological reaction. Our lab has synthesized Chloro[2-(4-Methyl-1,4- diazepan-1-yl) ethanamine]platinum(II) chloride ([Pt(L)Cl]Cl), which has a tridentate binding mode for the amine ligand. This study focused on the reaction of the chiral platinum triamine with key amino acids (methionine and 2-hydroxybutyric acid) and guanine analogs under different pH and temperature conditions. The mass spectrometry of N-AcMet Interaction with [Pt(L)Cl]+ showed a m/z of 542 and 579 for reactions at pH 4. The m/z of 542 suggests displacement of the chloride by the N-AcMet [Pt(L)(N-AcMet)] while 579 suggests displacement of one of the ligand nitrogen atoms [Pt(L)(N-AcMet)Cl]. By contrast, reactions at pH 7 showed [Pt(L)(N-AcMet)] as the only product, possibly due to the displacement of the Cl by water. The mass spectrometry of [Pt(L)Cl]+ with two ratios of methionine showed a m/z of 542 at physiologic pH. The mass spectrometry of the competition reaction of methionine and 5’ GMP showed m/z of 715 at physiological pH. Characteristic peaks in the 1H were observed for each of the products observed by mass spectrometry. Reactions with 2-hydroxy-4-(methylthio)butyrate, a methionine analog that lacks a nitrogen atom, showed similar reactivity patterns to that of N-AcMet, suggesting the nitrogen atom of the N-AcMet is not coordinating with the platinum atom. Our results indicate that when the chloride is still attached to the platinum, displacement of the chloride and amine nitrogen are both possible; it also showed that when you have two ratios of methionine interacting with [Pt(L)Cl]+ only one N-AcMet will coordinate with the platinum(II) complex to form [Pt(L)(N-AcMet)] at physiological pH, the competition reaction of N-AcMet with GMP indicates that GMP and N-AcMet will coordinate with the platinum(II) complex of [Pt(L)Cl]+ at both pH 4 and 7 to form [Pt(L)(N-AcMet)] and [Pt(L)(5’GMP)] as the major product at physiologic pH; d- GpG studies shows that it interacts with our synthesised compound; 1H NMR studies of the aquated dGpG when compared to the unquated shows that aquated is more ideal for interaction with our synthesized compound; aquated gives a monoadduct at both low pH and physiologic pH, unaquated studies showed the formation of a bisadduct at physiologic pH and a monoadduct at low pH, the proton NMR studies of the competition reaction of dGpG and N-AcMet interaction with the synthesized compound indicates that pH seven will give a bifunctional activity for the dGpG with more unreacted N-AcMet been seen, while pH four showed a monofunctional activity for the dGpG with More reacted methionine been seen.