Study on the Conversion of Natural Sterols into Useful Steroids

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In this project we have attempted to accumulate useful stroids such as C-24-carboxylic acid in the fermentation of cholesterol or sitosterol with a microorganism which is capable of degrading sterol side chain. For this purpose we have prepared several steroidal compounds as analogs of the C-24 acid, hoping their inhibitory action at a certain stage of multi-step enzymatic reactions in the sterol side chain degradation.The compounds synthesized are as follows: methyl 3 <beta> -hydroxy-chol-5-en-22-yn-24-oate (1), methyl 3 <beta> -hydroxychol-5-en-23-yne-24-carboxylate (2), methyl 23-bromo-3 <beta> -hydroxychol-5-en-24-oate (3), methyl 23,23-difluoro-3 <beta> -hydroxychol-5-ene-24-oate (4), methyl 24,24-difluoro-3 <beta> -hydroxychol-5-ene-24-carboxylate (5).When cholesterol was incubated with Mycobacterium sp. NRRL 3805 in the presence of these compounds, the formation of androst-4-ene-3,17-dione was decreased. Among them, compound (4) exhibited the strongest inhibitory action against the cholesterol degradation. In contrast, these compounds did not inhibit the cholesterol dagradation in the form of free acid instead of methyl ester. However, accumulation of intermediate sterols were not observed, which suggests that a feed-back inhibition which blocks 26-hydroxylation is operative.