BIOTRANSFORMATION OF EXISTING DRUGS- WAY FORWARD FOR COST EFFECTIVE LEAD DISCOVERY

M. Iqbal Choudhary and Atta-ur-Rahman

H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

Abstract

The biotransformation is a vast field of biotechnology, including both enzymatic and microbial catalysis. Biotransformation is a key tool for the production of different chemicals used in agriculture, pharmaceuticals, food, and polymer production. It plays an important role in the drug discovery and development process. Biotransformation is an excellent way to modify the structures of compounds which are sometime difficult to achieve by synthetic means due to inherent complexity. There are numerous advantages of microbial synthesis over chemical synthesis. Economically biotransformation competes the chemical synthesis for the modification of compounds because in presence of many functional groups biotransformation does not require additional steps of protection and deprotection like chemical synthesis, and hence cost effective.

Our research group has reported biotransformation of various drugs such as drostanolone ennanthate, mibolerone, methanolone enanthate, and medrysone. Biotransformation of drostanolone ennanthate resulted in to five new and three known metabolites. The metabolites showed a varying degree of cytotoxicity against HeLa (human cervical carcinoma) with IC₅₀ values ranges from 64.3 to 19.6 µM, PC3 (human prostate carcinoma) with IC₅₀ values ranges from 96.2 to 51.8 µM, H460 (human lung cancer) with IC₅₀ ranges from 44.4 to 5.0 µM, and HCT116 (human colon cancer) with IC₅₀ values ranges from 80.9 to 3.1 µM. These compounds did not show cytotoxic effect against 3T3 normal cell line (mouse fibroblast).

Biotransformation of mibolerone, an anabolic androgenic drug, yielded seven new and one known metabolite. Mibolerone was also found to be significantly active against Leishmania major promastigotes (IC₅₀ = 29.64 ± 0.88 µM). Its transformed products showed a weak leishmanicidal activity. In addition, mibolerone and its metabolite with an additional hydroxyl group at C14 exhibited potent cytotoxicity against HeLa cancer cell line with IC₅₀ = 35.7 and 34.16 µM, respectively. The other metabolites of mibolerone showed moderate to weak cytotoxicity agisn HeLa cancer cell line. Most of its metabolites showed no cytotoxicity against 3T3 cell line.

Biotransformation of methanolone enanthate, an anabolic androgenic steroid, led to the synthesis of three new, and three known metabolites. All these metabolites were evaluated for their immunomodulatory activities. The substrate was found to be inactive, whileits new metabolites showed a potent inhibition of ROS generation by whole blood with IC₅₀ ranges from 8.60 to 7.05 lg/mL, as well as from isolated polymorphonuclear leukocytes (PMNs) with IC₅₀ ranges from 14.0 to 4.70 lg/mL. All metabolites were found to be non-toxic to 3T3 mouse fibroblast cells.

Biotransformation of medrysone, an anti-inflammatory drug resulted in to seven new metabolites. The substrate and its metabolites showed strong inhibition of the proliferation of T-cells with IC₅₀ values between 0.2 to 20.0 µg/mL, and also inhibited the production of pro-inflammatory cytokine TNF-α.

Bitransformation of exemestane, an anticancer drug, resulted into three new and one known metabolite. The transformed metabolites were also evaluated for cytotoxic activity by using a cell viability assay against cancer cell lines (HeLa and PC3).

During this presentation, underlying philosophy and approach of our research on cost-effective discovery of lead molecules will be discussed.