Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth

Vânia M.A. Moreira, Tadas S. Vasaitis, Zhiyong Guo, Vincent C.O. Njar, Jorge A.R. Salvador

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively.

LanguageEnglish
Pages1217-1227
Number of pages11
JournalSteroids
Volume73
Issue number12
Early online date6 Jun 2008
DOIs
Publication statusPublished - 30 Nov 2008

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Steroid 17-alpha-Hydroxylase
Carbamates
Androgen Receptors
Cell growth
Prostatic Neoplasms
Cell proliferation
Androstanes
Growth
Cell Proliferation
Lyases
Dihydrotestosterone
Transcription
Cytochromes
Mixed Function Oxygenases
Androgens
Inhibitory Concentration 50
Infrared spectroscopy
Spectrum Analysis
Nuclear magnetic resonance

Keywords

  • carbamates
  • cell division
  • cell line, tumor
  • magnetic resonance spectroscopy

Cite this

Moreira, Vânia M.A. ; Vasaitis, Tadas S. ; Guo, Zhiyong ; Njar, Vincent C.O. ; Salvador, Jorge A.R. / Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. In: Steroids. 2008 ; Vol. 73, No. 12. pp. 1217-1227.
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Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. / Moreira, Vânia M.A.; Vasaitis, Tadas S.; Guo, Zhiyong; Njar, Vincent C.O.; Salvador, Jorge A.R.

In: Steroids, Vol. 73, No. 12, 30.11.2008, p. 1217-1227.

Research output: Contribution to journalArticle

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AU - Moreira, Vânia M.A.

AU - Vasaitis, Tadas S.

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AU - Njar, Vincent C.O.

AU - Salvador, Jorge A.R.

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