Multiple targeted actions of CYP17 inhibitors on prostate cancer cells

Vânia M. Moreira, Jorge A. R. Salvador

Research output: Contribution to journalConference Contribution

Abstract

Cytochrome P450 17a-hydroxylase, c17-20-lyase (CYP17) is one of the enzymes involved in androgen biosynthesis in the human body. Its inhibition has traditionally been recognized as an important strategy for PC treatment as a way to lower androgen levels and thus stop disease progression Ketoconazole, a non steroidal antifungal compound which was reported to cause gynecomastia in male patients, was the first to be used clinically for PC treatment. After ketoconazole, a series of compounds, both steroidal and non steroidal, have been synthesized and evaluated as CP17 inhibitors in the hope of finding more potent molecules with a better side effects' profile.
Pre-clinical evaluation of several compounds designed as CYP17 inhibitors has shown that some of these compounds were able to interact with other molecular targets concomitantly, such as the androgen receptor (AR) which is involved in disease progression, and might therefore bear additional interest as promiscuous agents for PC treatment. This communication will describe our efforts and results in the synthesis of two series of novel androstane derivatives, generally designated as indazole derivatives and C17 2'-methylimidazole derived carbamates. Some of these compounds were found to inhibit CYP17 and also bind to the AR, blocking AR mediated transcription. Moreover, they inhibited the proliferation of the most common PC cell line models, namely LNCaP, PC-3 and LAPC4 cells.
LanguageEnglish
Article numberOC-26
Pages46
Number of pages1
JournalRevista Portuguesa de Farmacia
VolumeLII
Issue number3 Suppl.
Publication statusPublished - 18 Nov 2008
Event1st National Meeting on Medicinal Chemistry: 1 Encontro Nacional de Quimica Terapeutica - Porto, Portugal
Duration: 13 Nov 200815 Nov 2008

Fingerprint

Lyases
Androgen Receptors
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Prostatic Neoplasms
Ketoconazole
Cells
Androgens
Disease Progression
Hope
Indazoles
Derivatives
Gynecomastia
Carbamates
Biosynthesis
Transcription
Human Body
Therapeutics
Cell Line
Molecules

Keywords

  • prostrate cancer cells
  • CYP17
  • CYP17 inhibitors

Cite this

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title = "Multiple targeted actions of CYP17 inhibitors on prostate cancer cells",
abstract = "Cytochrome P450 17a-hydroxylase, c17-20-lyase (CYP17) is one of the enzymes involved in androgen biosynthesis in the human body. Its inhibition has traditionally been recognized as an important strategy for PC treatment as a way to lower androgen levels and thus stop disease progression Ketoconazole, a non steroidal antifungal compound which was reported to cause gynecomastia in male patients, was the first to be used clinically for PC treatment. After ketoconazole, a series of compounds, both steroidal and non steroidal, have been synthesized and evaluated as CP17 inhibitors in the hope of finding more potent molecules with a better side effects' profile.Pre-clinical evaluation of several compounds designed as CYP17 inhibitors has shown that some of these compounds were able to interact with other molecular targets concomitantly, such as the androgen receptor (AR) which is involved in disease progression, and might therefore bear additional interest as promiscuous agents for PC treatment. This communication will describe our efforts and results in the synthesis of two series of novel androstane derivatives, generally designated as indazole derivatives and C17 2'-methylimidazole derived carbamates. Some of these compounds were found to inhibit CYP17 and also bind to the AR, blocking AR mediated transcription. Moreover, they inhibited the proliferation of the most common PC cell line models, namely LNCaP, PC-3 and LAPC4 cells.",
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Multiple targeted actions of CYP17 inhibitors on prostate cancer cells. / Moreira, Vânia M.; Salvador, Jorge A. R.

In: Revista Portuguesa de Farmacia, Vol. LII, No. 3 Suppl., OC-26, 18.11.2008, p. 46.

Research output: Contribution to journalConference Contribution

TY - JOUR

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AU - Salvador, Jorge A. R.

PY - 2008/11/18

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AB - Cytochrome P450 17a-hydroxylase, c17-20-lyase (CYP17) is one of the enzymes involved in androgen biosynthesis in the human body. Its inhibition has traditionally been recognized as an important strategy for PC treatment as a way to lower androgen levels and thus stop disease progression Ketoconazole, a non steroidal antifungal compound which was reported to cause gynecomastia in male patients, was the first to be used clinically for PC treatment. After ketoconazole, a series of compounds, both steroidal and non steroidal, have been synthesized and evaluated as CP17 inhibitors in the hope of finding more potent molecules with a better side effects' profile.Pre-clinical evaluation of several compounds designed as CYP17 inhibitors has shown that some of these compounds were able to interact with other molecular targets concomitantly, such as the androgen receptor (AR) which is involved in disease progression, and might therefore bear additional interest as promiscuous agents for PC treatment. This communication will describe our efforts and results in the synthesis of two series of novel androstane derivatives, generally designated as indazole derivatives and C17 2'-methylimidazole derived carbamates. Some of these compounds were found to inhibit CYP17 and also bind to the AR, blocking AR mediated transcription. Moreover, they inhibited the proliferation of the most common PC cell line models, namely LNCaP, PC-3 and LAPC4 cells.

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