M. Iqbal Choudhary and Atta-ur-Rahman
International Center for Chemical and Biological Sciences, (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research) University of Karachi, Karachi-75270, Pakistan
The structural changes in a molecule brought about either by whole cell cultures of fungi or bacteria, isolated enzymes, and animals and plant cells is termed as biotransformation. Creating novel chemical space through biotransformation of existing drugs can be a faster way towards drug discovery. The process can successfully be utilized for the expansion of structural diversity around a pharmacophore. This can be an important tool in medicinal chemistry for the introduction or modification of specific functionalities at the positions difficult to access by conventional chemical methods. The use of biocatalysts offers a remarkable arsenal of highly chemo-, regio- and stereo-selective methods for chemical conversions, which are often difficult to achieve even from state-of-the-art synthetic procedures. In last two decades, this methodology has become an important tool for asymmetric synthesis, not only at the academic level but also at the industrial scale. There is a need to fully exploit the potential of biotransformation in creating new and novel chemical space for the discovery of lead molecules against prevalent diseases.
During our studies of creating chemical space, we structurally modified a large number of existing drugs and other compounds into their novel structural analogues by microbial and plant cell suspension cultures. The resulting metabolites have exhibited interesting biological activities, different from their precursors. The anabolic androgenic drug methenolone enanthate (brand names Primobolan and Primobolan Depot) is used for the treatment of the advanced breast carcinoma in the postmenopausal women as well by athletes to build the muscle strength. The biotransformation of metenolone enanthate by fungi led to the synthesis of six metabolites, these transformed products showed antiinflammatory potential in the oxidative burst assay and potent to moderate activity on proinflammatory cytokine TNF-α, produced by THP-1 cells. Similarly oxymetholon marketed as anadrol, is a synthetic anabolic steroid developed in 1960 by Zoltan 'Anadrol Z' F. It has been approved by the US Food and Drug Administration for the treatment of anemias caused by deficient red cell production. Its biotransformation with various fungi has resulted in the production of various new and a known metabolites. Oxymetholone and some of its metabolites showed anti-inflammatory activity. Exemestane (trade name aromasin) is a steroidal aromatase inhibitor, used for the treatment of breast cancer. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers. Exemestane was developed by an Italian company using commercially available boldenone (androsta-1,4-diene-17β-ol-3-one). After biotransformation of exemestane, the metabolites showed activity against Hela and PC3 cell lines. Melengestrol acetate, is used as a feed additive for feedlot heifers was found to be a potent anti-inflammatory agent along with its new transformed products. Tibolone is a synthetic steroid hormone drug, used for the treatment of endometriosis and hormone replacement therapy in post-menopausal women we have successfully biotransformed the drug into its new derivatives and identified them as potent alpha glucosidase inhibitors. These results showed drug repositioning of already marketed drugs and also showed that resulted new and known compounds can speed-ups the process of drug development.
During this presentation, underlying philosophy and approach of our research on cost-effective discovery of lead molecules by biotransformation will be discussed.