Synthesis of novel potent drug molecules active against prostate cancer and investigation of bioactive properties of cyclopolymers obtained by raft polymerization

Abstract

The first part of the thesis includes synthesis of novel potent drug molecules active against prostate cancer. Structure-based drug design (SBDD) approach was used to discover novel lead compounds active against CYP17 by the researchers Prof. Metin Türkay and Assoc. Prof. İ. Halil Kavaklı from the Koç University. They found a non-steroidal lead compound with the IC50 value of 35.65M. In this study, in order to increase the activity of the lead compound against the CYP17, lead optimization studies were done. Lead compound derivatives were evaluated on the computer generated model of CYP17. The compounds that have favorable energy values in docking studies were synthesized to be effective in nanomolar concentrations. Some of the synthesized compounds were subjected to biological tests in order to measure inhibitory effects of them on CYP17. IC50 value of the compounds that displayed favorable inhibitory activity on human CYP17 were calculated. As a result, a new compound with the IC50 value of 2.3 M was discovered. The activity of this compound is about fifteen times higher than the activity of the lead compound. The second part of the thesis includes the investigation of bioactive properties of cyclopolymers obtained by Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization. In this study, RAFT polymerization was applied to symmetrical difunctional monomers, alkyl -(hydroxymethyl)acrylate (RHMA) ether dimers (R=alkyl (ethyl, n-butyl, tert-butyl, cyclohexyl, isobornyl)). The livingness of the obtained cyclopolymers with tert-butyl and isobornyl ester groups was shown through successful block copolymerization studies with n-butyl acrylate where the former was used as the macro-chain transfer agent (macroCTA). Finally, the antibacterial activities of the obtained cyclopolymers were investigated using Staphylococcus aureus and Escherichia coli as test organisms.