Synthesis of potentially active quinoline derivatives against prostate cancer

Abstract

Prostate cancer is the major cause of death among elderly men all around the world. According to the recent reports, 15% of the US men are faced with prostate cancer and 3% of them lose their lives. Researches on prostate cancer have shown that increased levels of androgens are the primary reason for being prostate cancer. Testosterone and dihydrotestosterone are the two important male hormones which stimulate the androgen biosynthesis. Since those two hormones contribute to the progression of prostatic tumors, suppression of these hormones may be a good solution for the treatment of prostate cancer. In this respect, hormone therapy is generally preferred to treat prostate cancer, because inhibition of the target enzyme might be resulting in the total blockage of androgen biosynthesis in adrenal glands and testes. Many studies have indicated that CYP-17 enzyme catalyzes the last step of the androgen production; therefore, CYP-17 enzyme was selected as the primary target enzyme for the treatment of prostate carcinoma. With the help of computational software, steroidal and non steroidal inhibitors of CYP-17 enzyme were determined in Koc University. Due to the drawbacks of steroidal inhibitors, a non-steroidal lead compound was then chosen. Necessary modifications were done on the lead compound and molecular docking studies were performed for the derivatives of the lead molecule by using Autodock program. In this project, synthesis of quinoline derivatives as part of larger drug molecules potentially active against prostate cancer was targeted. Quinoline derivatives containing an amino group at the 8th position and an alkyl substitution at varying positions were synthesized using different approaches. Three derivatives were synthesized; 3-butylquinolin-8-amine, 4-butylquinolin-8-amine and 6-butylquinolin-8-amine. After the synthesis of those quinoline derivatives, in-situ coupling reactions were done with benzoic acid and naphthoic acid derivatives. All transformations of quinoline derivatives and coupling products were verified with 1D NMR and 2D NMR data.18 drug candidates were successfully synthesized and sent to Koc University for the biological testing.