In the steroidogenesis pathway, cholesterol undergoes two major modifications at the C17 and C3 positions for the biosynthesis of adrenal (male sex hormones) and gonadal (mineralocorticoids) hormones. The C17–hydroxylation /17,20-lyastion and C3-hydroxy oxidation are catalyzed by CYP17A1 and 3β−HSD enzymes respectively. The formation of C3-oxo metabolite by 3β−HSD is essential for the further metabolism at C5 double bond by 5α-SRD enzyme to produce dihydrotestosterone (DHT), a most potent androgen. These androgenic metabolites are important for the development and maintenance of male sex characters. The abnormal production of androgens and their aberrant interaction with androgen receptor is known for the development and progression of prostate cancer disease.

Clinical anti-PC agents abiraterone and galaterone are 3-OH-Δ5-C17-heterocycles substituted steroids. Both agents exert their potent anti-PC activity by reducing androgen biosynthesis through CYP17A1 enzyme inhibition. Due to their structural similarities to endogenous steroids they also undergo metabolism at C3 position by 3β−HSD. Consequently, these two agents have short half-life on oral administration (t1/2~1h). Moreover, both agents suffer from low oral bioavailability (abi-37% and gal-19%), and thus require very high dose to show clinical efficacy.

To prevent metabolism by 3- HSD and further by 5-SRD enzymes, the metabolic soft-spot (C3–OH) was appended with imidazole ring to obtain metabolically stable agents with no compromise in anti-prostate cancer properties. This modification (VNPP433-3β) has significantly improved half-life (31 h) which is 24.75-fold superior to Gal’s half-life. Additionally, VNPP433-3β has improved oral absorption of 49.6% bioavailability which is 2.96 superior to Gal’s oral absorption.

In the current research we have synthesized various C3-azole compounds such as tetrazoles, triazoles, and diazole using cyclization method on stereospecific azide and amine intermediates. These newly synthesized compounds are under biological activity evaluation. We will be presenting rational behind the design novel C3 azoles, their synthetic detail, and pharmacokinetic data of our lead compound and possibly anti-cancer properties of compounds under study.