4146-29-6

A series of 4- and/or 17α-substituted testosterone analogues has been incubated with the hydroxylating fungus Fusarium culmorum AM282. It was found that 19-norandrostenedione, 19-nortestosterone, 4-methoxytestosterone, 4-methyltestosterone, and 4-chloro-17α-methyltestosterone were hydroxylated exclusively or mainly at the 6β-position. The mixtures of 6β-, 15α-, and 12β- or 11α-monohydroxy derivatives were obtained from 17α-methyltestosterone and 17α-ethyl-19- nortestosterone - the substrates with alkyl group at C-17α. 4-Chlorotestosterone was predominantly hydroxylated at 15α-position, but the reaction was accompanied by the reduction of 4-en-3-one system, which proceeded in the sequence: reduction of ketone to 3β-alcohol and then reduction of the double 4,5 bond. The results obtained indicate an influence of stereoelectronic and steric effects of substitutes on regioselectivity of the hydroxylation of 4-en-3-one steroids by F. culmorum.

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Incubation of 19-nortestosterone 1 with Aspergillus wentii MRC 200316 for 5 days afforded 10β-hydroxy-19-nortestosterone 2 (2%), 6β-hydroxy-19- nortestosterone 3 (60%), and 14α-hydroxy-19-nortestosterone 4 (5%).

Therapeutic potential of nandrolone and its derivatives against leishmaniasis has been studied. A number of derivatives of nandrolone (1) were synthesized through biotransformation. Microbial transformation of nandrolone (1) with Cunninghamella echinulata and Cunninghamella blakesleeana yielded three new metabolites, 10β,12β,17β-trihydroxy-19-nor-4-androsten-3-one (2), 10β,16α,17β-trihydroxy-19-nor-4-androsten-3-one (3), and 6β,10β,17β-trihydroxy-19-nor-4-androsten-3-one (4), along with four known metabolites, 10β,17β-dihydroxy-19-nor-4-androsten-3-one (5), 6β,17β-dihydroxy-19-nor-4-androsten-3-one (6) 10β-hydroxy-19-nor-4-androsten-3,17-dione (7) and 16β,17β- dihydroxy-19-nor-4-androsten-3-one (8). Compounds 1-8 were evaluated for their anti-leishmanial activity. Compounds 1 and 8 showed a significant activity in vitro against Leishmania major. The leishmanicidal potential of compounds 1-8 (IC50 = 32.0 ± 0.5, >100, 77.39 ± 5.52, 70.90 ± 1.16, 54.94 ± 1.01, 80.23 ± 3.39, 61.12 ± 1.39 and 29.55 ± 1.14 μM, respectively) can form the basis for the development of effective therapies against the protozoal tropical disease leishmaniasis.

Biotransformation of steroids with 4-ene-3-one functionality such as progesterone (I), testosterone (II), 17α-methyltestosterone (III), 4-androstene-3,17-dione (IV) and 19-nortestosterone (V) were studied by using a fungal system belonging to the genera of Mucor (M881). The fungal system efficiently and quantitatively converted these steroids in regio- and stereo-selective manner into corresponding 6β,11α-dihydroxy compounds. Time course experiments suggested that the transformation was initiated by hydroxylation at 6β- or 11α-(10β-hydroxy in case of V) to form monohydroxy derivatives which upon prolonged incubation were converted into corresponding 6β,11α-dihydroxy derivatives. The fermentation studies carried out using 5 L table-top fermentor with substrates (I and II) clearly indicates that 6β,11α-dihydroxy derivatives of steroids with 4-ene-3-one functionality can be produced in large scale by using M881.

The fungus Cephalosporium aphidicola has been shown to hydroxylate testosterone, 19-nortestosterone, 1-dehydrotestosterone, 1α-methyltestosterone, androst-4-en-3-one, androst-4-en-3,17-dione and 17α-methyltestosterone predominantly at the C-6β position with a minor hydroxylation occurring at the C-14α position. 19-Nortestosterone was also hydroxylated at the C-10β position. In contrast to the hydroxylation of progesterone by this organism, hydroxylation at C-11α was a minor pathway.

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