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Bioorg Med Chem Lett. 2020 Jan 15;30(2):126783. doi: 10.1016/j.bmcl.2019.126783. Epub 2019 Nov 9.

Formation of 5α-dihydrotestosterone from 5α-androstane-3α,17β-diol in prostate cancer LAPC-4 cells - Identifying inhibitors of non-classical pathways producing the most potent androgen.

Author information

1
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
2
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, QC, Canada.
3
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada. Electronic address: Donald.poirier@crchul.ulaval.ca.

Abstract

5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen, following non-classical pathways. We reported the chemical synthesis of non-commercially available [4-14C]-3α-diol from [4-14C]-T, and the development of a biological assay to identify inhibitors of the 5α-DHT formation from radiolabeled 3α-diol in LAPC-4 cell PC model. We measured the inhibitory potency of 5α-androstane derivatives against the formation of 5α-DHT, and inhibition curves were obtained for the most potent compounds (IC50 = 1.2-14.1 μM). The most potent inhibitor 25 (IC50 = 1.2 μM) possesses a 4-(4-CF3-3-CH3O-benzyl)piperazinyl methyl side chain at C3β and 17β-OH/17α-CCH functionalities at C17 of a 5α-androstane core.

KEYWORDS:

Androgen; Androstane derivative; LAPC-4 cells; Prostate cancer; Steroid

PMID:
31753699
DOI:
10.1016/j.bmcl.2019.126783

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