Synthesis, 17α-hydroxylase-C17,20-lyase Inhibitory and 5AR Reductase Activity of Novel Pregnenolone Derivatives

Author(s):

Abid H. Banday*, Shameem A. Shameem, Javid A. Banday and Bashir A. Ganaie   Pages 1919 - 1926 ( 8 )

Abstract:

Background: The potential of steroids for development into lead pharmacological molecules lies in the regulation of a variety of biological processes by these molecules and also because of these being a fundamental class of signaling molecules. Steroid based scaffolds have been extensively used as active pharmaceutical agents for the treatment of various diseases including the deadly disease of cancer which despite the recent advances in the early diagnosis, prevention and therapy, remains a clinical challenge affecting millions of people world over and is one of the leading causes of death. It thus warrants the development of new drugs against this dreadful disease through exploitation of emerging molecularly defined targets. </P><P> Methods: The present study explores the effect of novel steroidal pyrazolines as presumed inhibitors of 5&#945;- reductase (5AR) and 17&#945;-hydroxylase-C17,20-lyase as a target for treatment of prostate cancer. A series of 1,5- diaryl pyrazoline pregnenolones were synthesized and screened for 5&#945;-reductase inhibitory activities. Synthesis of the analogs is multistep and proceeds in good overall yields. The key step in the synthesis of 1,5- disubstituted pyrazolinyl pregnenolones is the heterocyclization of bezylidine derivatives (3) in presence of phenylhydrazines (4) through the initial formation of the phenylhydrazones, which undergo concomitant cyclization to generate the stable pyrazoline derivatives. </P><P> Results: All the synthesised D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were screened for prostate cancer cell inhibitory, 5&#945;-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5&#945;-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active. Further, compounds 5g and 5h were found to have moderate 17&#945;-hydroxylase-C17,20-lyase inhibitory activities. </P><P> Conclusion: A series of D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were synthesized and screened for their prostate cancer cell inhibitory, 5a-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active whereas compounds 5g and 5h were found to have moderate 17α- hydroxylase-C17,20-lyase inhibitory activities.

Keywords:

Pregnenolone, benzylidines, pyrazoline, phenylhydrazones, 5&#945;-reductase inhibition.

Affiliation:

Department of Chemistry, Islamia College of Science and Commerce, Srinagar 190002, Centre of Research and Development, University of Kashmir, Hazratbal 190002, Department of Chemistry, National Institute of Technology, Hazratbal 190002, Centre of Research and Development, University of Kashmir, Hazratbal 190002

Graphical Abstract:

Read Full-Text article