Theoretical studies of some anti cancer drugs

Abstract

The thesis focuses on the study of important molecular properties of drugs obtained from theoretical ab-initio calculation. The results in turn can be used for searching new drugs of improved properties. The main aspect is to obtain detailed information of some anticancer drugs (nitrogen mustards) for designing new drugs of high potency. The results of the investigation are presented in various chapters. All the chapters of the thesis include a brief summary, introduction, results and conclusion. Chapter I presents, the general introduction focusing on the importance of nitrogen mustards as anticancer agent and the necessity of analyzing the differences in alkylation of DNA by nitrogen mustards. The importance of theoretical study on anticancer drugs, in particular nitrogen mustards is also mentioned. The differences of the alkylating abilities of these drugs for understanding the anticancer properties are elaborately discussed. Furthermore, the involvement of aziridinium ion intermediate in the alkylation pathway of nitrogen mustards is reviewed for explaining the overall properties of drugs. Likewise, the effect of solvent environment on the electronic reorganization of drugs molecule as well as solvation energies are also highlighted and subsequently the necessity of investigating other properties like ionic effect on these drugs are also discussed. Chapter II gives a brief review of ab-initio molecular orbital calculation and the basis sets used in the investigation. The calculations obtained by using minimal basis sets are compared with the results of extended basis sets and the importance of polarization function in calculating the energies of different drugs is discussed. Chapter III mainly represents the study on the influence of substituents at N-4 of nitrogen mustard and analysis of the aziridinium ion intermediates with respect to these substituents are carried out. Herein the drugs used in the study are differentiated into two groups, the clinically used drugs and proposed drugs (15 designed drugs)....