Microbiological synthesis of stereoisomeric 7(/)-hydroxytestololactones and 7(/)-hydroxytestolactones

摘要

Microbiological synthesis of 7- and 7-hydroxy derivatives of testololactone and testolactone was developed based on bioconversion of dehydroepiandrosterone (DHEA) by fungus of Isaria fumosorosea VKM F-881 with subsequent modification of the obtained stereoisomers by actinobacteria. The first stage included obtaining of the stereoisomers of 3,7(/)-dihydroxy-17a-oxa-D-homo-androst-5-en-17-ones in the preparative amounts. Then the conversion of 7-hydroxylated D-lactones obtained by selected actinobacteria of Nocardioides simplex VKM Ac-2033D, Saccharopolyspora hirsuta VKM Ac-666, and Streptomyces parvulus MTOC Ac-21v was studied. Under the transformation of 3,7-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one and its corresponding 7-stereoisomer by N. simplex VKM Ac-2033D and S. hirsuta VKM Ac-666 the 7- and 7-hydroxy-17a-oxa-D-homo-androst-4-ene-3,17-dione (7- and 7-hydroxytestololactone), 7- and 7-hydroxy-17a-oxa-D-homo-androsta-1,4-diene-3,17-dione (7- and 7-hydroxytestolactone) were obtained with molar yields in a range of 60.3-90.9 mol%. The crystalline products of 7-hydroxytestololactone, 7-hydroxytestolactone, and their corresponding 7-hydroxy stereoisomers were isolated, and their structures were confirmed by mass spectrometry and H-1-NMR spectroscopy analyses. The strain of Str. parvulus MTOC Ac-21v transformed 3,7(/)-dihydroxy-17a-oxa-D-homo-androst-5-en-17-ones into the corresponding 3-keto-4-ene analogs and did not show 3-ketosteroid 1(2)-dehydrogenase activity. The activity of actinobacteria towards steroid D-lactones was hitherto unreported.The results contribute to the knowledge of metabolic versatility of actinobacteria capable of transforming steroid substrates and may be applied in the synthesis of potential aromatase inhibitors.