Design and synthesis of drug molecules against prostate cancer

Abstract

Prostate cancer is a common disease in today’s world; especially in the western world it is the most prevalent cancer among men. It is believed that there is a correlation between prostate cancer and increased levels of certain hormones. It has been also observed that lowering androgen levels often makes prostate cancers shrink or grow more slowly, and therefore, the target of the treatment becomes the androgen removal. It is believed that effective inhibitors of the enzymes involved in testosterone and dihydrotestosterone (DHT) biosynthesis could be useful in the treatment of diseases associated with androgen excess in women and in the treatment of androgen-sensitive prostatic hyperplasia and cancer in men. In the biosynthesis of testosterone and DHT there is a common enzyme, 17-alpha hydroxylase C17,20-lyase (CYP17), utilized both in testicular and adrenal androgen synthesis. Therefore inhibition of this enzyme is a valuable technique to lower or, if possible, to eliminate the availability of androgens to the prostate. This project started with Structure Based Drug Design (SBDD) studies at Koc University using a computer generated model of the CYP17 enzyme where several thousands of molecules were subject to screening. In this screening study, the docking and binding energies were calculated and a lead compound was found. The in-vivo testing of the lead compound showed that the computer model’s prediction for the potential activity was right. To increase the observed activity (IC50= 35 micromolar) and specificity against the enzyme, the lead compound needed to be derivatized. The lead compound is constituted of two parts; the naphtyl and the phenyl subunits. In this study the aim was to synthesize lead compound derivatives which have branched alkyl susbstituents on the phenyl ring. Thus benzoic acids substituted with amino and/or methoxy groups were subjected to functionalization using different techniques to obtain branched alkyl groups on the phenyl unit. Among these, the reaction of the benzoic acid ester derivative with a Grignard reagent proved to be the best approach in the synthesis of the branched alkyl derivatives.