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Biotransformation of Oral Contraceptive Ethynodiol Diacetate with Microbial

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Biotransformation of Oral Contraceptive Ethynodiol Diacetate with Microbial Zafar et al. Chemistry Central Journal 2012, 6:109 http://journal.chemistrycentral.com/content/6/1/109 RESEARCH ARTICLE Open Access Biotransformation of oral contraceptive ethynodiol diacetate with microbial and plant cell cultures Salman Zafar1,2, Sammer Yousuf1, Hammad A Kayani1, Saifullah Saifullah1*, Saifullah Khan1, Abdullah M Al-Majid3 and M Iqbal Choudhary1,3* Abstract Background: Biotransformation by using microbial and plant cell cultures has been applied effectively for the production of fine chemicals on large scale. Inspired by the wealth of literature available on the biotransformation of steroids, we decided to investigate the biotransformation of ethynodiol diacetate (1) by using plant and microbial cultures. Results: The biotransformation of ethynodiol diacetate (1) with Cunninghamella elegans and plant cell suspension cultures of Ocimum basilicum and Azadirachta indica is being reported here for the first time. Biotransformation of 1 with Cunninghamella elegans yielded three new hydroxylated compounds, characterized as 17α-ethynylestr-4-en-3β,17β-diacetoxy-6α-ol (2), 17α-ethynylestr-4-en-3β,17β-diacetoxy-6β-ol (3), and 17α-ethynylestr-4-en-3β,17β-diacetoxy-10β-ol (4) and a known metabolite, 17α-ethynyl-17β-acetoxyestr-4-en-3-one (5). The biotransformation of 1 with Ocimum basilicum included hydrolysis of the ester group, oxidation of alcohol into ketone, and rearrangement of the hydroxyl group. Thus four major known metabolites were characterized as 17α-ethynyl-17β-acetoxyestr-4-en-3-one (5), 17α-ethynyl-17β-hydroxyestr-4-en-3-one (6), 17α-ethynyl-3 β-hydroxy-17β-acetoxyestr-4-ene (7) and 17α-ethynyl-5α,17β-dihydroxyestr-3-ene (8). Biotransformation of 1 with Azadirachta indica culture yielded compounds 5 and 6. Spectroscopic data of compound 8 is being reported for the first time. Structure of compound 6 was unambiguously deduced through single-crystal x-ray diffraction studies. Conclusion: Biotransformation of an oral contraceptive, ethynodiol diacetate (1), by using microbial and plant cell cultures provides an efficient route to the synthesis of a library of new steroids with potential contraceptive properties. These methods can be employed in the production of such compounds with high stereoselectivity. Keywords: Ethynodiol diacetate, Microbial transformation, Biotransformation, Ocimum basilicum, Azadirachta indica, Cunninghamella elegans, Cell suspension culture, Norethisterone, 17α-Ethynylestr-4-en-3β,17β-diacetoxy-6α-ol, 17α-Ethynylestr-4-en-3β,17β-diacetoxy-6β-ol, 17α-Ethynylestr-4-en-3β,17β-diacetoxy-10β-ol Background been employed for carrying out reactions at chemically Development of efficient, environmental friendly and inaccessible positions of organic compounds. Microbial cost effective routes to synthesize fine chemicals is the transformation of steroids has been extensively investi- need of the day. Biotransformation has been an exciting gated [1] and various hydroxylated derivatives have been area of research for decades. Enzymes from various produced on large scale [2]. Cell suspension cultures of sources, i.e., microorganisms, animal and plant cells, have plants have also been efficiently employed for the bio- transformation of organic compounds, e.g., steroids [3], * Correspondence: [email protected]; [email protected] terpenes [4,5], alkaloids [6] and flavonoids [7]. The reac- 1H. E. J. Research Institute of Chemistry, International Center for Chemical tions carried out by microbial and plant cultures include and Biological Sciences, University of Karachi, Karachi 75270, Pakistan hydroxylation, oxidation and reduction of alcohols, 3Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia ketones and C = C bond [8]. Full list of author information is available at the end of the article © 2012 Zafar et al.; licensee Chemistry Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zafar et al. Chemistry Central Journal 2012, 6:109 Page 2 of 8 http://journal.chemistrycentral.com/content/6/1/109 Ocimum basilicum L. (Lamiaceae) (sweet basil) is Biotransformation of 1 with microbial and plant cell cul- found mostly in Asia. It is used as a flavorant in food, tures has not been reported earlier. During the current perfumery, cosmetics and medicines [9]. There are some study, we investigated the metabolism of compound 1 with reports of biotransformation of chemical compounds a fungal and two plant cell cultures, which resulted in a with O. basilicum culture [10]. Azadirachta indica A. number of new 2–4 and known 5–8 metabolites. Juss. (Meliaceae) (Neem) is native to tropical and semi- tropical Asia. Cell suspension culture of Azadirachta Results indica has also been previously recruited for the struc- Microbial transformation of ethynodiol diacetate with tural transformation of dydrogesterone [11]. C. elegans Ethynodiol diacetate (1) is a semi synthetic steroidal drug, The 1H- and 13C-NMR chemical shifts of compounds used as an oral contraceptive. It inhibits the ovulation 2–5 are presented in Tables 1 and 2, respectively. Other process, and serves as a potent progestin. It provides ad- data is presented below: equate control of menstrual cyclicity in combination with an estrogen, and thus has a complete contraceptive prop- 17α-Ethynylestr-4-en-3β,17β-diacetoxy-6α-ol (2). 1 erty,eveninlowdoses[12].Thebiotransformationof1 has Colorless amorphous solid (5 mg, 0.5%). H-NMR 13 been previously studied in vivo in rhesus monkey [13] and (CD3OD, 300 MHz): Table 1, C-NMR (CD3OD, 75 baboon [14], and in vitro by rat and human liver cells [15]. MHz): Table 2. EI-MS m/z (rel. int., %): 400 (15, M+), Table 1 1H-NMR data of compounds 1-8 at 300 (compounds 2,3,4,5,7), 400 (compound 8) and 500 (compound 6) MHz; δ in ppm, J and W 1/2 in Hz COMPOUNDS Carbon 1 2 3 4 5 6 7 8 1 1.41, 2.05 1.12, 2.07, 1.36, 1.70 1.38, 1.94 1.52, 2.24 1.54, 2.25 1.74, 1.96 1.75, 1.92 2 2.01, 2.27 dt, J=13.4, 2.8 1.33, 1.94 1.46, 2.01 1.55, 1.83 2.21, 2.38 2.28, 2.37 1.95, 2.23 1.91, 1.98 3 5.20 br s, 4.05, m 5.20, m 4.01, m - - 4.14 m, 5.85d J =9.6 W1/2=19.6 (W1/2=17.4 Hz) (W1/2=22.8 Hz) (W1/2=15.6 Hz) W1/2=16.8 4 5.32 5.55, br s 5.55, br s, 5.40, br s 5.81 s 5.81 s 5.37 5.50 d J=9.6 (W1/2=9.7 Hz) (W1/2=17.2 Hz) (W1/2=9.37 Hz) 5 - ---- - -- 6 0.95, 1.68 4.12, br s 4.16, br s, 2.05, 2.41 2.27, 2.49 2.29, 2.45 dt, 1.67, 1.82 1.77, 1.82 (W1/2=9.6 Hz) (W1/2=17.1 Hz) J=14.5, 3.28 7 1.17, 1.80 2.05, 2.65 1.13, 1.87 0.90, 1.75 1.12, 1.83 1.06, 1.82 0.94, 1.73 1.15, 1.78 8 1.25 1.94 1.82 1.72 1.36 1.35 1.25 0.82 9 0.71 0.60 0.65 0.80 0.85 0.86 0.67 1.08 10 1.77 1.80 2.20 - 2.06 2.07 td, J=10.5, 4.7 1.75 1.47 11 1.25, 1.84 1.23, 1.85 1.59, 1.67 1.22, 1.91 1.23, 1.88 1.13, 2.02 0.78, 1.51 12 1.67, 1.82 1.65, 1.83 1.66, 1.84 1.66, 1.82 1.70, 1.87 1.63, 1.75 1.27, 2.04 1.54, 1.68 13- ---- - -- 14 1.51 1.50 1.52 1.48 1.54 1.51 1.50 1.42 15 1.31, 1.72 1.37, 1.67 1.27, 1.29 1.37, 1.72 1.33, 1.75 1.27, 1.54 1.32, 1.77 1.28, 1.67 16 1.98, 2.72 2.15, 2.65 2.04, 2.65 2.05, 2.65 1.97, 2.73 ddd, 1.98, 2.27 1.99, 2.70 ddd 1.94, 2.27 J=15, 9.6, 5.7 J=15, 6.0, 3.6 17- ---- -- 18 0.87, s 0.94, s 0.95, s 0.93, s 0.91, s 0.89, s 0.87, s 0.84, s 20- ---- - -- 21 2.55, s 2.94, s 2.97, s 2.95, s 2.57, s 2.55, s 2.55, s 2.55, s 22- ---- - 23 2.02 2.01, s 2.00, s 1.99, s 2.02 s 2.01 s 24 25 2.02 2.01, s 2.00, s 1.99, s Note: Assignments based on COSY, HMBC and HMQC spectra. Assignments shown without multiplicity means multiplet. Zafar et al. Chemistry Central Journal 2012, 6:109 Page 3 of 8 http://journal.chemistrycentral.com/content/6/1/109 13 – δ 13 Table 2 C-NMR data of compounds 1 8, MHz; in ppm Table 1, C-NMR (CDCl3, 75 MHz): Table 2. EI-MS: + Compounds m/z (rel. int., %) 340 (90, M ,C22H28O3), 298 (37), C12345678 231 (47), 119 (39), 110 (69), 91 (100), 79 (75), 1 27.7 27.0 24.1 34.7 26.6 26.6 25.6 19.2 55 (65). 2 34.9 32.5 28.2 29.1 36.5 36.5 34.9 20.8 Results of biotransformation of ethynodiol diacetate with 3 70.3 68.0 71.2 68.1 199.8 199.9 67.4 132.0 O.
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