Dihydrotestosterone-based A-ring-fused pyridines: Microwave-assisted synthesis and biological evaluation in prostate cancer cells compared to structurally related quinolines

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F23%3A73619589" target="_blank" >RIV/61989592:15310/23:73619589 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0960076023000705" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0960076023000705</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jsbmb.2023.106315" target="_blank" >10.1016/j.jsbmb.2023.106315</a>

Result language

angličtina

Original language name

Dihydrotestosterone-based A-ring-fused pyridines: Microwave-assisted synthesis and biological evaluation in prostate cancer cells compared to structurally related quinolines

Original language description

Dysfunction of the androgen receptor (AR) signalling axis plays a pivotal role in the development and progression of prostate cancer (PCa). Steroidal and non-steroidal AR antagonists can significantly improve the survival of PCa patients by blocking the action of the endogenous ligand through binding to the hormone receptor and preventing its activation. Herein, we report two synthetic strategies, each utilizing the advantages of microwave irradiation, to modify the A-ring of natural androgen 5α-dihydrotestosterone (DHT) with pyridine scaffolds. Treatment of DHT with appropriate Mannich salts led to 1,5-diketones, which were then converted with hydroxylamine to A-ring-fused 6′-substituted pyridines. To extend the compound library with 4′,6′-disubstituted analogues, 2-arylidene derivatives of DHT were subjected to ring closure reactions according to the Kröhnke’s pyridine synthesis. The crystal structure of a monosubstituted pyridine product was determined by single crystal X-ray diffraction. AR transcriptional activity in a reporter cell line was investigated for all novel A-ring-fused pyridines and a number of previously synthesized DHT-based quinolines were included to the biological study to obtain information about the structure-activity relationship. It was shown that several A-ring-fused quinolines acted as AR antagonists, in comparison with the dual or agonist character of the majority of A-ring-fused pyridines. Derivative 1d (A-ring-fused 6′-methoxyquinoline) was studied in detail and showed to be a low-micromolar AR antagonist (IC50 = 10.5 µM), and it suppressed the viability and proliferation of AR-positive PCa cell lines. Moreover, the candidate compound blocked the AR downstream signalling, induced moderate cell-cycle arrest and showed to bind recombinant AR and to target AR in cells. The binding mode and crucial interactions were described using molecular modelling

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30202 - Endocrinology and metabolism (including diabetes, hormones)

Project

—

Continuities

S - Specificky vyzkum na vysokych skolach

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

ISSN

0960-0760

e-ISSN

1879-1220

Volume of the periodical

231

Issue of the periodical within the volume

JUL

Country of publishing house

GB - UNITED KINGDOM

Number of pages

15

Pages from-to

"106315-1"-"106315-15"

UT code for WoS article

000989246500001

EID of the result in the Scopus database

2-s2.0-85153583509