Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity (original) (raw)
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Journal of Medicinal Chemistry, 2005
Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (K i ) 50 and 38 nM and IC 50 ) 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5R-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a δ-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.
Synthesis of some novel androstanes as potential aromatase inhibitors
Steroids, 2011
Novel pyrazole and isoxazole derivatives (6–9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity
New D-modified androstane derivatives as aromatase inhibitors☆
Steroids, 2001
Starting from a 16-oximino derivative of 5-androstene the newly-synthesized 16-oximino-17-hydroxy-17-substituted derivatives 2-4 gave by the Beckmann fragmentation reaction the corresponding D-seco derivatives 6 -9. Besides, in the case of the 17-hydroxy-17-methyl-16-oximino derivative 2, as a result of the rearrangement, the hydrolysis product 5 of the 16-oximino group with the opposite configuration at the C-17 was obtained. By the Oppenauer oxidation and/or by dehydration of 7 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), the corresponding derivatives 12, 13, and 14 were obtained. The structures of 6 and 12 were unambiguously proved by the appropriate X-ray structural analysis. Kinetic analysis for anti-aromatase activity showed that compound 12 expressed the highest inhibition in the denucleated rat ovarian fraction in comparison to other androstene derivatives (IC 50 was 0.42 M). In comparison to aminoglutethimide (AG) activity, it was 3.5 times lower. The inhibition was competitive, with K i of 0.27 M. Introduction of additional units of unsaturation (compounds 13 and 14) in D-seco derivatives did not increase anti-aromatase activity.