Abstract
In search of selective and effective anti-cancer agents, eight metabolites of anti-cancer steroid, drostanolone enanthate (1), were synthesized via microbial biotransformation. Enzymes such as reductase, oxidase, dehydrogenase, and hydrolase from Cephalosporium aphidicola, and Fusarium lini were likely involved in the biotransformation of 1 into new metabolites at pH 7.0 and 26°C, yielding five new metabolites, 2α-methyl-3α,14α,17β-trihydroxy-5α-androstane (2), 2α-methyl-7α-hydroxy-5α-androstan-3,17-dione (3), 2-methylandrosta-11α-hydroxy-1, 4-diene-3,17-dione (6), 2-methylandrosta-14α-hydroxy-1,4-diene-3,17-dione (7), and 2-methyl-5α-androsta-7α-hydroxy-1-ene-3,17-dione (8), along with three known metabolites, 2α-methyl-3α,17β-dihydroxy-5α-androstane (4), 2-methylandrosta-1, 4-diene-3,17-dione (5), and 2α-methyl-5α-androsta-17β-hydroxy-3-one (9), on the basis of NMR, and HREI-MS data, and single-crystal X-ray diffraction techniques. Interestingly, C. aphidicola and F. lini were able to catalyze hydroxylation only at alpha positions of 1. Compounds 1–9 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 4 (IC50 = 49.5 ± 2.2 μM), 5 (IC50 = 39.8 ± 1.5 μM), 6 (IC50 = 40.7 ± 0.9 μM), 7 (IC50 = 43.9 ± 2.4 μM), 8 (IC50 = 19.6 ± 1.4 μM), and 9 (IC50 = 25.1 ± 1.6 μM) were found to be more active against HeLa cancer cell line than the substrate 1 (IC50 = 54.7 ± 1.6 μM). Similarly, metabolites 2 (IC50 = 84.6 ± 6.4 μM), 3 (IC50 = 68.1 ± 1.2 μM), 4 (IC50 = 60.4 ± 0.9 μM), 5 (IC50 = 84.0 ± 3.1 μM), 6 (IC50 = 58.4 ± 1.6 μM), 7 (IC50 = 59.1 ± 2.6 μM), 8 (IC50 = 51.8 ± 3.4 μM), and 9 (IC50 = 57.8 ± 3.2 μM) were identified as more active against PC-3 cancer cell line than the substrate 1 (IC50 = 96.2 ± 3.0 μM). Metabolite 9 (IC50 = 2.8 ± 0.2 μM) also showed potent anticancer activity against HCT116 cancer cell line than the substrate 1 (IC50 = 3.1 ± 3.2 μM). In addition, compounds 1–7 showed no cytotoxicity against 3T3 normal cell line, while compounds 8 (IC50 = 74.6 ± 3.7 μM), and 9 (IC50 = 62.1 ± 1.2 μM) were found to be weakly cytotoxic.
Highlights
Microbial transformation is one of the most important approaches for the structural transformation of various classes of organic compounds
Microbial transformation has been used as an important tool for the regio, chemo, and stereo-selective conversions of organic compounds which are difficult to achieve by conventional methods (Holland and Weber, 2000; Fernandes et al, 2003; Mihovilovic et al, 2003; Yildirim et al, 2003; Bartmanska et al, 2005; Borges et al, 2009; Choudhary et al, 2011; Ravindran et al, 2012)
Structures of metabolites were elucidated with the help of 1H- (400, 500, and 600 MHz), and 13C-NMR (100, 125, and 150 MHz) spectra, which were recorded on Bruker Avance-NMR spectrometers (France) in CD3OD, CD3COCD3 or DMSO-d6
Summary
Microbial transformation is one of the most important approaches for the structural transformation of various classes of organic compounds. This technique has been successfully employed in green chemistry, i.e. the drug discovery and development programs, providing an excellent source of compounds around core structures, followed by screening for various biological activities. Microbial transformation has been used as an important tool for the regio-, chemo-, and stereo-selective conversions of organic compounds which are difficult to achieve by conventional methods (Holland and Weber, 2000; Fernandes et al, 2003; Mihovilovic et al, 2003; Yildirim et al, 2003; Bartmanska et al, 2005; Borges et al, 2009; Choudhary et al, 2011; Ravindran et al, 2012). The presence of P450 cytochrome enzyme systems in fungi, makes whole-cell biocatalysis an efficient tool for stereo-, and regio-specific hydroxylation (Choudhary et al, 2005a; Tong and Dong, 2009; Kristan and RiŽner, 2012; Baydoun et al, 2014)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
