Publication Date

Spring 2020

Advisor(s) - Committee Chair

Dr Kevin Williams (Director), Dr Blairanne Williams and Dr Lawrence Hill

Degree Program

Department of Chemistry

Degree Type

Master of Science

Abstract

Cisplatin and its analogues have been used and tested over decades for cancer treatment, but because of the serious side effects, it is important to find ways to overcome those side effect by synthesizing a novel platinum molecule. We have synthesized triamine complex and conducted its reaction with biomolecules such as 5’GMP and Methionine in the lab as well as conducted molecular mechanics (MM). MM methods are used for predicting and designing new structures and properties, and to model geometries of small molecules. MM and dynamics calculations have been used to study the 9 Ethylguanine and N-Ac-Lmethionine complexes with platinum triamine compound. The AMBER force field has been supplemented with previous modifications and has been further modified to include parameters for platinum bound to 2-(4-Methyl-1,4-diazepan-1-yl)ethanamine. By utilizing the modifications made previously to the AMBER force field, we were able to model the Chloro[2-(4-Methyl-1,4-diazepan-1-yl)ethanamine]platinum(II) complex with methionine and 9 Ethylguanine adducts. All possible rotamers were generated with the chiral centers in the molecule, minimum energy structures were calculated for all possible rotamers of target molecules. For the methionine adducts, we found that certain orientations of the methionine residue led to much lower energy structures, though no steric clashes have been observed for all rotamers, the differences in minimum energy structures of rotamers could help explain the experimental observation that an initial methionine product can be replaced by a more stable product. We modeled 9- ethylguanine products in which 9-EtG displaced either the chloride only or both the chloride and one nitrogen atom of the triamine ligand, as experimental results suggested both types of guanine products are possible. MM studies also suggested the reason for the molecule’s inclination towards the ring opening. Our synthesized platinum analogues showed high reactivity towards both the biomolecules.

Disciplines

Biochemistry, Biophysics, and Structural Biology | Chemistry | Computational Biology

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