Aromatic carboxamides as non-steroidal inhibitors of CYP17 for the treatment of prostate cancer

Abstract

Cancer is the most common neoplasm of the prostate in developed countries. Since up to 80 % of Prostate Cancer (PCa) proliferation depends on androgens, most patients take hormone therapy as first choice of treatment. The PCa cell proliferation occurs due to binding of these androgens to androgen receptor (AR) that is overexpressed on PCa cells. Therefore, when the androgens are segregated from the tumor cells, the proliferation of PCa cell will stop. Although the androgens are secreted from three different sites, namely the testes, adrenal glands, and PCa cells, androgen production depends on catalysis by one enzyme, CYP17, which is also known as P450-C17. Being a pivotal enzyme in the biosynthetic route to steroidal hormones, CYP17 has a key role in the conversion of progesterone and pregnenolone to androstenedione and dehydroepiandrostenedione (DHEA) respectively, which constitute as the direct precursors of 5α-dihydrotestosterone (DHT) and testosterone (T). Although Abiraterone was launched as a potent steroidal CYP17 inhibitor, it interferes with other steroidogenic enzymes leading to side effects such as hypokalemia, hepatic dysfunction, oedema, and hypertension. Due to the potential side effects of steroidal CYP17 inhibitors resulting from inhibition of other steroid receptors, there is a certain need to develop nonsteroidal inhibitors. In this study, several derivatives of a nonsteroidal lead compound were designed and synthesized in order to optimize its interaction with CYP17 enzyme. Throughout optimization process, bioisosterism was utilized as a rational drug design approach. Quinoline moiety was chosen as center of interest as it was hypothesized that similar to other CYP17 inhibitors, it could bind well to iron of the heme group of CYP17 enzyme. In order to perform a structure-activity relationship (SAR) study, a systematic synthesis of n-butyl substituted 8-amnionquinolines was done. A library of final products was built by synthesizing several aromatic carboxamides via coupling aromatic amines with aromatic carboxylic acids.