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Publication Detail

Title: Innovative C2-symmetric testosterone and androstenedione dimers: Design, synthesis, biological evaluation on prostate cancer cell lines and binding study to recombinant CYP3A4.

Authors: Paquin, Alexis; Oufqir, Yassine; Sevrioukova, Irina F; Reyes-Moreno, Carlos; Bérubé, Gervais

Published In Eur J Med Chem, (2021 Aug 05)

Abstract: The synthesis of two isomeric testosterone dimers and an androstenedione dimer is reported. The design takes advantage of an efficient transformation of testosterone leading to the synthesis of the key diene, 7α-(buta-1,3-dienyl)-4-androsten-17β-ol-3-one, through an elimination reaction. It was found that in some instances the same reaction led to partial epimerization of the 17β-hydroxyl group into the 17α-hydroxyl group. The specific orientation of the hydroxyl function was confirmed by NMR spectroscopy. Capitalizing on this unforeseen side reaction, several dimers were assembled using an olefin metathesis reaction with Hoveyda-Grubbs catalyst. This led to the formation of two isomeric testosterone dimers with 17α-OH or 17β-OH (14α and 14β) as well as an androstenedione dimer (14). The new dimers and their respective precursors were tested on androgen-dependent (LNCaP) and androgen independent (PC3 and DU145) prostate cancer cells. It was discovered that the most active dimer was made of the natural hormone testosterone (14β) with an average IC50 of 13.3 μM. In LNCaP cells, 14β was ∼5 times more active than the antiandrogen drug cyproterone acetate (IC50 of 12.0 μM vs. 59.6 μM, respectively). At low concentrations (0.25-0.5 μM), 14α and 14β were able to completely inhibit LNCaP cell growth induced by testosterone or dihydrotestosterone. Furthermore, cross-reactivity of androgen-based dimers with sterol-metabolizing cytochrome P450 3A4 was explored and the results are disclosed herein.

PubMed ID: 33933755 Exiting the NIEHS site

MeSH Terms: Androstenedione/chemical synthesis; Androstenedione/chemistry; Androstenedione/pharmacology*; Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacology*; Cell Proliferation/drug effects; Cell Survival/drug effects; Cytochrome P-450 CYP3A/metabolism*; Dimerization; Dose-Response Relationship, Drug; Drug Design*; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; Prostatic Neoplasms/drug therapy*; Prostatic Neoplasms/metabolism; Prostatic Neoplasms/pathology; Recombinant Proteins; Structure-Activity Relationship; Testosterone/chemical synthesis; Testosterone/chemistry; Testosterone/pharmacology*; Tumor Cells, Cultured

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