Synthesis of novel andostane-N-cyclohexyl-17-carboxamides, and their effect on the 5α-reductase isoform 2, the androgen receptor, and androgen-dependent glands

Background: Benign Prostatic Hyperplasia (BPH), and Prostate Cancer (PCa) are androgen-dependent diseases. PCa is associated with excessive signalling of the androgen receptor (AR) due to the binding of 5α-DHT and T. BPH is related to high levels of 5α-dihydrotestosterone (5α-DHT), biosynthesized from testosterone (T) by 5α-reductase (5RD5A). The inhibition of 5RD5A and the blockage of AR are targets for their treatment. In this study, the synthesis and determination of biological activity of the new N-cyclohexyl-3β-hydroxyandrosta-5,16-diene-17-carboxamide (6), N-cyclohexyl-3-oxoandrosta-4,6,16-triene-17-carboxamide (7), and N-cyclohexyl-3-oxoandrosta-4,16-diene-17-carboxamide (8) were carried out to find new drugs to improve these afflictions. Methods: The synthesis of 6 to 8 was confirmed by spectroscopic and spectrometric analyses. Competitive binding assays determined the affinity of 6 to 8 to the AR. The inhibitory activity of 5RD5A isoform 2 (5RD5A2) (IC50) was established by the conversion of [3H]-T to [3H]-5α-DHT and it was compared with finasteride (FIN). The pharmacological effect of 6 to 8 was determined on the weight of the prostate and seminal vesicles glands of castrated hamsters treated with T, and on the diameter size of their flank organs. Results: Compounds 7 and 8 bound lightly (ca. 15 %) to AR. Comparing to FIN (IC50 = 8.5 nM), 6 to 8 (IC50 = 0.169, 0.105 and 0.155 nM, respectively) showed higher potency as inhibitors of 5RD5A2. Compound 6 decreased the prostate and seminal vesicles weight, as well as the hamsters' diameter flank organs. However, 7 only decreased the diameter of flank organs. Surprisingly, 8 increased these pharmacological parameters. Conclusion: Androstane-17-caboxamide 6 is a 5RD5A2 inhibitor that reduces the weight of androgen-dependent glands such as the prostate, suggesting it could be a lead for new drugs to treat BPH and PCa.

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Androgen receptor isoforms expression in benign prostatic hyperplasia and primary prostate cancer

PLoS ONE ◽

10.1371/journal.pone.0200613 ◽

2018 ◽

Vol 13 (7) ◽

pp. e0200613 ◽

Cited By ~ 3

Author(s):

Ana Caroline Hillebrand ◽

Lolita Schneider Pizzolato ◽

Brasil Silva Neto ◽

Gisele Branchini ◽

Ilma Simoni Brum

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Benign Prostatic Hyperplasia ◽

Prostatic Hyperplasia ◽

Receptor Isoforms ◽

Primary Prostate Cancer

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Roles of Cell Cycle Regulators [p53, Cathepsin-D and Bax] in Prognostic Determination of Prostate Cancer and Benign Prostatic Hyperplasia

Journal of Carcinogenesis & Mutagenesis ◽

10.4172/2157-2518.s6-007 ◽

2013 ◽

Author(s):

Ogundele M Olalekan Ajonijebu D Chris

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Benign Prostatic Hyperplasia ◽

Cathepsin D ◽

Prostatic Hyperplasia ◽

Cell Cycle Regulators

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Determination of alpha1-antichymotrypsin-PSA complex in serum does not improve the differentiation between benign prostatic hyperplasia and prostate cancer compared with total PSA and percent free PSA

Urology ◽

10.1016/s0090-4295(99)00080-1 ◽

1999 ◽

Vol 53 (6) ◽

pp. 1160-1167 ◽

Cited By ~ 27

Author(s):

Klaus Jung ◽

Brigitte Brux ◽

Michael Lein ◽

Angela Knäbich ◽

Pranav Sinha ◽

...

Keyword(s):

Prostate Cancer ◽

Benign Prostatic Hyperplasia ◽

Prostatic Hyperplasia ◽

Free Psa ◽

Total Psa

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Androgen receptor GGC polymorphism and testosterone levels associated with high risk of prostate cancer and benign prostatic hyperplasia

Molecular Biology Reports ◽

10.1007/s11033-012-2293-5 ◽

2012 ◽

Vol 40 (3) ◽

pp. 2749-2756 ◽

Cited By ~ 6

Author(s):

Vanderlei Biolchi ◽

Brasil Silva Neto ◽

Diego Bromfman Pianta ◽

Walter José Koff ◽

Milton Berger ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Benign Prostatic Hyperplasia ◽

High Risk ◽

Prostatic Hyperplasia ◽

Testosterone Levels

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Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

Clinical Investigation ◽

10.4155/cli.14.77 ◽

2014 ◽

Vol 4 (10) ◽

pp. 935-950 ◽

Cited By ~ 16

Author(s):

Kouji Izumi ◽

Lei Li ◽

Chawnshang Chang

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Benign Prostatic Hyperplasia ◽

Prostatic Hyperplasia ◽

Immune Inflammation

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Stereological analysis of androgen receptors in prostate cancer and benign prostatic hyperplasia

Medicinski pregled ◽

10.2298/mpns1804089t ◽

2018 ◽

Vol 71 (3-4) ◽

pp. 89-95

Author(s):

Sandra Trivunic-Dajko ◽

Jovo Bogdanovic ◽

Sasa Vojinov ◽

Andrejic Visnjic

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Benign Prostatic Hyperplasia ◽

Prostatic Cancer ◽

Androgen Receptors ◽

Immunohistochemical Analysis ◽

Prostatic Hyperplasia ◽

Receptor Expression ◽

Androgen Receptor Expression ◽

Stereological Analysis

Introduction. Through androgen receptors, androgens regulate prostate cellular growth and function, proliferation, differentiation, apoptosis, lipid metabolism and secretory activity, as well as development and progression of prostate cancer. Prostate cancer, and its primary glandular tissue are influenced by hormones, and it is used for therapeutic purposes. Anti-androgen treatment is carried out in patients with metastatic prostatic cancer, in order to block effects of androgens. Immunohistochemical analysis of androgen receptors in the prostate cancer tissue may help us to assume how the tumors will react to the anti-androgen therapy, if they are androgen-positive, -negative, or hormone resistant tumors. Knowledge of the presence of androgen receptors in the tumor tissue may be a prognostic indicator in histopathological analysis. The aim of this study was stereological evaluation of androgen receptor expression in patients with benign prostatic hyperplasia and in patients with prostatic cancer, before therapy. Material and Methods. Immunohistochemical analysis was carried out using anti-human androgen receptor monoclonal antibody 441. The presence and intensity of the androgen receptors were evaluated in 195 patients: 165 with benign prostatic hyperplasia and 30 with prostatic cancer using Weibel?s multi-purpose M 42 stereological test system. Material was obtained by needle biopsy or transurethral resection of the prostate. Results. All secretory cells in patients with benign prostatic hyperplasia were androgen positive, while in patients with prostatic cancer, all tumors were mostly androgen positive, some with foci of negativity. The resulting negative correlation with Gleason score and International Society of Urological Pathology grade was not statistically significant. Conclusion. Study results of stereological analysis of androgen receptors indicate that prior the therapy prostate cancer is androgendependent, with a high level of androgen receptor expression, although slightly lower compared to benign prostatic hyperplasia.

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