C16 and C17-heterocycle bearing androstanes. CYP17 inhibition studies and multiple effects on prostate cancer cells

V.M. Moreira, J. A. R. Salvador, A. Matos Beja, José A. Paixão, T. S. Vasaitis, V. C. O. Njar

Research output: Contribution to journalConference Contribution

Abstract

Heterocycles are important features of biologically active molecules. Pyrrole, pyrimidine, indole, quinoline and purine are a few classes of heterocycles which have served as platforms for developing pharmaceutical agents for various applications (1). Many important naturally occurring steroids contain one or more heterocyclic ring(s), fused or attached to ring D, formed by modifications of the side chain (2). Moreover, attachment of heterocyclic moieties at diverse positions of the steroid core has provided novel compounds with a diverse range of biological activities including inhibition of cytochrome 17α-hydroxylase-C 17,20 -lyase (CYP17), one of the enzymes involved in androgen biosynthesis in the human body and a valuable target for prostate cancer (PC) treatment (3). Steroidal CYP17 inhibitors bearing N - containing heterocyclic moieties linked to the steroid core directly through the nitrogen atom have been shown to have antiandrogenic properties against the androgen-dependent LAPC4 human prostate tumor xenograft, actually being more effective than castration in suppressing its growth (4). We have synthesized and fully characterized C16 and C17 azole-bearing androstanes (5). Some of the C17-substituted compounds were found to inhibit CYP17, bind to the androgen receptor (AR), and block AR-mediated transcription. Moreover, they inhibited the proliferation of LNCaP, PC-3 and LAPC4 cells. The C16-substituted steroids bear privileged heterocyclic moieties attached to C16 via a methine carbon bridge, examples of which, to the best of our knowledge, are non-existent in the literature.
Original languageEnglish
Pages (from-to)43
Number of pages1
JournalEuropean Journal of Pharmaceutical Sciences
Volume44
Issue numberSuppl 1
DOIs
Publication statusPublished - 24 Sep 2011
Event4th BBBB International Conference on Pharmaceutical Sciences: New Trends in Drug Discovery, Delivery Systems and Laboratory Diagnostics - , Slovenia
Duration: 29 Sep 20111 Oct 2011
Conference number: 4th

Fingerprint

Androstanes
Steroid 17-alpha-Hydroxylase
Prostatic Neoplasms
Steroids
Androgen Receptors
Androgens
Azoles
Pyrroles
Castration
Cytochromes
Mixed Function Oxygenases
Human Body
Heterografts
Prostate
Nitrogen
Carbon
Growth
Pharmaceutical Preparations
Neoplasms

Keywords

  • CYP17
  • CYP17 inhibitors
  • prostate cancer

Cite this

Moreira, V.M. ; Salvador, J. A. R. ; Matos Beja, A. ; Paixão, José A. ; Vasaitis, T. S. ; Njar, V. C. O. / C16 and C17-heterocycle bearing androstanes. CYP17 inhibition studies and multiple effects on prostate cancer cells. In: European Journal of Pharmaceutical Sciences. 2011 ; Vol. 44, No. Suppl 1. pp. 43.
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C16 and C17-heterocycle bearing androstanes. CYP17 inhibition studies and multiple effects on prostate cancer cells. / Moreira, V.M.; Salvador, J. A. R.; Matos Beja, A.; Paixão, José A.; Vasaitis, T. S.; Njar, V. C. O.

In: European Journal of Pharmaceutical Sciences, Vol. 44, No. Suppl 1, 24.09.2011, p. 43.

Research output: Contribution to journalConference Contribution

TY - JOUR

T1 - C16 and C17-heterocycle bearing androstanes. CYP17 inhibition studies and multiple effects on prostate cancer cells

AU - Moreira, V.M.

AU - Salvador, J. A. R.

AU - Matos Beja, A.

AU - Paixão, José A.

AU - Vasaitis, T. S.

AU - Njar, V. C. O.

PY - 2011/9/24

Y1 - 2011/9/24

N2 - Heterocycles are important features of biologically active molecules. Pyrrole, pyrimidine, indole, quinoline and purine are a few classes of heterocycles which have served as platforms for developing pharmaceutical agents for various applications (1). Many important naturally occurring steroids contain one or more heterocyclic ring(s), fused or attached to ring D, formed by modifications of the side chain (2). Moreover, attachment of heterocyclic moieties at diverse positions of the steroid core has provided novel compounds with a diverse range of biological activities including inhibition of cytochrome 17α-hydroxylase-C 17,20 -lyase (CYP17), one of the enzymes involved in androgen biosynthesis in the human body and a valuable target for prostate cancer (PC) treatment (3). Steroidal CYP17 inhibitors bearing N - containing heterocyclic moieties linked to the steroid core directly through the nitrogen atom have been shown to have antiandrogenic properties against the androgen-dependent LAPC4 human prostate tumor xenograft, actually being more effective than castration in suppressing its growth (4). We have synthesized and fully characterized C16 and C17 azole-bearing androstanes (5). Some of the C17-substituted compounds were found to inhibit CYP17, bind to the androgen receptor (AR), and block AR-mediated transcription. Moreover, they inhibited the proliferation of LNCaP, PC-3 and LAPC4 cells. The C16-substituted steroids bear privileged heterocyclic moieties attached to C16 via a methine carbon bridge, examples of which, to the best of our knowledge, are non-existent in the literature.

AB - Heterocycles are important features of biologically active molecules. Pyrrole, pyrimidine, indole, quinoline and purine are a few classes of heterocycles which have served as platforms for developing pharmaceutical agents for various applications (1). Many important naturally occurring steroids contain one or more heterocyclic ring(s), fused or attached to ring D, formed by modifications of the side chain (2). Moreover, attachment of heterocyclic moieties at diverse positions of the steroid core has provided novel compounds with a diverse range of biological activities including inhibition of cytochrome 17α-hydroxylase-C 17,20 -lyase (CYP17), one of the enzymes involved in androgen biosynthesis in the human body and a valuable target for prostate cancer (PC) treatment (3). Steroidal CYP17 inhibitors bearing N - containing heterocyclic moieties linked to the steroid core directly through the nitrogen atom have been shown to have antiandrogenic properties against the androgen-dependent LAPC4 human prostate tumor xenograft, actually being more effective than castration in suppressing its growth (4). We have synthesized and fully characterized C16 and C17 azole-bearing androstanes (5). Some of the C17-substituted compounds were found to inhibit CYP17, bind to the androgen receptor (AR), and block AR-mediated transcription. Moreover, they inhibited the proliferation of LNCaP, PC-3 and LAPC4 cells. The C16-substituted steroids bear privileged heterocyclic moieties attached to C16 via a methine carbon bridge, examples of which, to the best of our knowledge, are non-existent in the literature.

KW - CYP17

KW - CYP17 inhibitors

KW - prostate cancer

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DO - 10.1016/j.ejps.2011.08.002

M3 - Conference Contribution

VL - 44

SP - 43

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

IS - Suppl 1

ER -