AUTHOR=Choudhary M. Iqbal , Siddiqui Mahwish , Atia-tul-Wahab  , Yousuf Sammer , Fatima Narjis , Ahmad Malik S. , Choudhry Hani 

TITLE=Bio-Catalytic Structural Transformation of Anti-cancer Steroid, Drostanolone Enanthate with Cephalosporium aphidicola and Fusarium lini, and Cytotoxic Potential Evaluation of Its Metabolites against Certain Cancer Cell Lines

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00900

DOI=10.3389/fphar.2017.00900

ISSN=1663-9812

ABSTRACT=<p>In search of selective and effective anti-cancer agents, eight metabolites of anti-cancer steroid, drostanolone enanthate (<bold>1</bold>), were synthesized <italic>via</italic> microbial biotransformation. Enzymes such as reductase, oxidase, dehydrogenase, and hydrolase from <italic>Cephalosporium aphidicola</italic>, and <italic>Fusarium lini</italic> were likely involved in the biotransformation of <bold>1</bold> into new metabolites at pH 7.0 and 26°C, yielding five new metabolites, 2α-methyl-3α,14α,17β-trihydroxy-5α-androstane (<bold>2</bold>), 2α-methyl-7α-hydroxy-5α-androstan-3,17-dione (<bold>3</bold>), 2-methylandrosta-11α-hydroxy-1, 4-diene-3,17-dione (<bold>6</bold>), 2-methylandrosta-14α-hydroxy-1,4-diene-3,17-dione (<bold>7</bold>), and 2-methyl-5α-androsta-7α-hydroxy-1-ene-3,17-dione (<bold>8</bold>), along with three known metabolites, 2α-methyl-3α,17β-dihydroxy-5α-androstane (<bold>4</bold>), 2-methylandrosta-1, 4-diene-3,17-dione (<bold>5</bold>), and 2α-methyl-5α-androsta-17β-hydroxy-3-one (<bold>9</bold>), on the basis of NMR, and HREI-MS data, and single-crystal X-ray diffraction techniques. Interestingly, <italic>C. aphidicola</italic> and <italic>F. lini</italic> were able to catalyze hydroxylation only at alpha positions of <bold>1</bold>. Compounds <bold>1–9</bold> showed a varying degree of cytotoxicity against HeLa (human cervical carcinoma), PC3 (human prostate carcinoma), H460 (human lung cancer), and HCT116 (human colon cancer) cancer cell lines. Interestingly, metabolites <bold>4</bold> (IC<sub>50</sub> = 49.5 ± 2.2 μM), <bold>5</bold> (IC<sub>50</sub> = 39.8 ± 1.5 μM), <bold>6</bold> (IC<sub>50</sub> = 40.7 ± 0.9 μM), <bold>7</bold> (IC<sub>50</sub> = 43.9 ± 2.4 μM), <bold>8</bold> (IC<sub>50</sub> = 19.6 ± 1.4 μM), and <bold>9</bold> (IC<sub>50</sub> = 25.1 ± 1.6 μM) were found to be more active against HeLa cancer cell line than the substrate <bold>1</bold> (IC<sub>50</sub> = 54.7 ± 1.6 μM). Similarly, metabolites <bold>2</bold> (IC<sub>50</sub> = 84.6 ± 6.4 μM), <bold>3</bold> (IC<sub>50</sub> = 68.1 ± 1.2 μM), <bold>4</bold> (IC<sub>50</sub> = 60.4 ± 0.9 μM), <bold>5</bold> (IC<sub>50</sub> = 84.0 ± 3.1 μM), <bold>6</bold> (IC<sub>50</sub> = 58.4 ± 1.6 μM), <bold>7</bold> (IC<sub>50</sub> = 59.1 ± 2.6 μM), <bold>8</bold> (IC<sub>50</sub> = 51.8 ± 3.4 μM), and <bold>9</bold> (IC<sub>50</sub> = 57.8 ± 3.2 μM) were identified as more active against PC-3 cancer cell line than the substrate <bold>1</bold> (IC<sub>50</sub> = 96.2 ± 3.0 μM). Metabolite <bold>9</bold> (IC<sub>50</sub> = 2.8 ± 0.2 μM) also showed potent anticancer activity against HCT116 cancer cell line than the substrate <bold>1</bold> (IC<sub>50</sub> = 3.1 ± 3.2 μM). In addition, compounds <bold>1–7</bold> showed no cytotoxicity against 3T3 normal cell line, while compounds <bold>8</bold> (IC<sub>50</sub> = 74.6 ± 3.7 μM), and <bold>9</bold> (IC<sub>50</sub> = 62.1 ± 1.2 μM) were found to be weakly cytotoxic.</p>