Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
USA
Email: lddd@benthamscience.org

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Synthesis and Preliminary Screening of Novel A- and D-Ring Modified Steroids as Aromatase Inhibitors

Author(s): Mange Ram Yadav, Prafulla M. Sabale, Rajani Giridhar, Dharmendra Baria, Christina Zimmer, Rolf W. Hartmann.

Abstract:

Estrogens are responsible for the growth of hormone-dependant breast cancer. Regulation of estrogen biosynthesis is considered as a potential therapeutic strategy for the control of breast cancer. The enzyme aromatase catalyzes conversion of androgens into estrogens in the last step of estrogen biosynthesis. Inhibition of aromatase is adopted as an efficient approach for the prevention and treatment of breast cancer. Many steroidal and nonsteroidal aromatase inhibitors have been developed and are used clinically for breast cancer therapy. In this report, it has been tried to incorporate some structural features (six membered lactam ring) of nonsteroidal aromatase inhibitors like aminoglutethimide and rogletimide into the A-/D-ring of the steroid nucleus with certain additional features responsible for binding to the enzyme aromatase. Some ring-A [17β-hydroxy-4-(4-substitutedphenyl)-4-aza-5-androsten-3-one] and ring-D modified steroidal compounds [4-substituted-17a-aza-D-homo-4-androstene-3,17-dione, 4-substituted-17-aza-Dhomo- 4-androstene-3,16,17a-trione, 4-substituted-17a-methyl-17a-aza-D-homo-4-androsten-3-one] were synthesized and screened for binding to the aromatase enzyme. None of the synthesized compounds showed promising aromatase inhibiting activity leading to the conclusion that structurally the original androstane ring skeleton should not be tampered with, for obtaining good aromatase inhibiting activity.

Keywords: A-/D-Heterosteroids, Androstanes, Aromatase, Aromatase Inhibitors, Azasteroids, Breast cancer, postmenopausal breast cancer, Steroids, VEEGO, BRUKER ALPHA T FT-IR, nitrogens, preliminary screening, ketone, aromatase enzyme inhibition, nonsteroidal, heme iron, EC50, GI50

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Article Details

VOLUME: 8
ISSUE: 10
Year: 2011
Page: [943 - 950]
Pages: 8
DOI: 10.2174/157018011797655322
Price: $58