Shengrong Li

Side-chain oxysterol regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A reductase activity

Side-chain oxysterols are known to be potent inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, a key regulatory enzyme in the biosynthesis of sterols. Structural variations in the side-chain oxysterols influence enzyme inhibition. Under certain conditions, biological systems have been induced to produce side-chain oxysterols, adding support to the hypothesis that oxysterols may be natural regulators of sterol biosynthesis in the intact cell. Specific inhibition of sterol biosynthesis is of interest as it may prove useful in the prevention or reversal of various cardiovascular disease states, as well as in the control of normal and abnormal cell growth.

Synthesis of new steroidal isoxazoles: inhibitors of estrogen synthase

A novel class of steroidal A/B ring isoxazoles have been prepared by two independent reaction schemes using 3 beta,17 beta-diacetoxyandrost-5-ene (1) and 3 beta,17 beta-diacetoxyandrost-4-en-6-one (4) as synthetic precursors. The key common intermediate in these syntheses, 3 beta,17 beta-diacetoxyandrost-4-eno[6,5,4-c,d] isoxazole (3), was prepared by synthetic methods described in both schemes. Further chemical modification of 3 yielded 3 beta,17 beta-dihydroxyandrost-4-eno[6,5,4-c,d] isoxazole (6), androst-3,17-dione-4-eno[6,5,4-c,d] isoxazole (7), and 17 beta-hydroxyandrost-3-one-4-eno[6,5,4-c,d] isoxazole (9). Human placental estrogen synthase (aromatase) bioassays were conducted to obtain the following IC50 values resulting from a 50% reduction of enzymatic activity: 6, 120.5 microM; 7, 1.889 microM. 9, 18.57 microM.

Design and action of steroidal aromatase inhibitors

The biosynthesis of estrogens involves three sequential hydroxylations, progressing from cholesterol, that are mediated by an enzyme complex referred to as aromatase. The last steps in this sequence involve aromatization of the A ring of the steroid nucleus. Compounds that inhibit aromatase have potential applications in the treatment of advanced estrogen-dependent mammary carcinoma and prostatic hyperplasia. The enzyme aromatase is currently a priority target for the development of active-site directed inhibitors. A number of steroid inhibitors may inactivate aromatase by diverse interactions with the enzyme and include competitive inhibitors, affinity labelling agents, and mechanism-based inhibitors (“suicide substrates”). By designing steroidal analogs with substituents at various positions on the steroid nucleus, information has been obtained on the structural requirements needed for favorable interactions with the enzymatic sites.

Facile β-Epoxidation of Unsaturated Steroids with Permanganateion

Abstract A mixture of KMnO4-CuSO4 in refluxing methylene chloride, in the presence of a small amount of water and tert-butanol, has been found to be a highly β-selective high-yield epoxidation reagent for Δ4, Δ5 and Δ7 unsaturated steroids. The Δ8 unsaturated steroid 24,25-dihydrolanosterol acetate underwent allylic oxidation under these conditions.

The synthesis of N-aryl androsterone pyrazoles as aromatase inhibitors

Abstract N-aryl androsterone pyrazoles, which showed a good inhibitory activity against aromatasc, were synthesized.