A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure–Activity Relationships

Abstract

Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivative 1 (RM-532-105) has shown strong inhibitory activity on 17β-HSD3, but needs to be improved. Herein, we describe the chemical synthesis and characterization of two series of analogues to address the impact of A- and D-ring modifications on 17β-HSD3 inhibitory activity, androgenic effect, and metabolic stability. Structure–activity relationships were generated by adding different groups at C16/C17 (D-ring diversification) or replacing the ADT backbone by a nor-androstane or an estrane backbone (A-ring diversification). D-ring derivatives were less potent inhibitors than lead compound 1, whereas steroidal backbone (A-ring) change led to identifying promising novel estrane derivatives. This culminated with potent 17β-HSD3 inhibitors 23, 27, 31, and 33 (IC50 = 0.10, 0.02, 0.13, and 0.17 μM, respectively), which did not stimulate LAPC-4 cell proliferation and displayed higher plasma concentration in mice than lead compound 1.

Induction of Endoplasmic Reticulum Stress-Mediated Apoptosis by Aminosteroid RM-581 Efficiently Blocks the Growth of PC-3 Cancer Cells and Tumors Resistant or Not to Docetaxel

“…The concentration of RM-581 was determined by liquid chromatography–mass spectrometry/mass spectrometry (LC−MS/MS) analysis using a procedure developed at the CHU de Québec-Research Center (Québec, Canada) (Bioanalytical Service) and previously published [ 52 ].…”

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

“…Moreover, treatment with specific 17b-HSD3 inhibitors may result in fewer off-target effects, compared with those following treatment with AR antagonists. The upregulation of 17b-HSD3 in prostatic tumors induces the accumulation of 17b-HSD3 inhibitors in the tumor tissues rather than in the normal tissues (Corteś-Benıtez et al, 2019).…”

Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis

“…Compound 6 inhibited the transformation of 4-dione into T in both whole LNCaP cells overexpressing 17β-HSD3 (IC 50 = 0.10 µM), as well as in a preparation of homogenized rat testes (IC 50 = 0.11 µM) (Table 3). This inhibitor also reduced the proliferation of androgen-dependent (AR+) prostate cancer LAPC-4 cells but not the proliferation of (AR-) prostate cancer PC-3 cells, suggesting an effect mediated via the reduction of the production of androgens [38]. When injected sc in mice, inhibitor 6 was found to be more abundant (4 times) in plasma than the previous lead inhibitor RM-532-105, built around a C19-steroid backbone [71,72], thus suggesting a better metabolic stability of the E1 (C18-steroid)-type 17β-HSD3 inhibitor 6.…”

“…On the other hand, amine 32 was obtained in one step by reacting 2-(trifluoromethyl)benzenesulfonyl chloride with an excess of trans-2,5-dimethylpiperazine. Finally, the formation of an amide bond between the carboxylic acid 31 and the amine 32 using hexafluorophosphate benzotriazole tetramethyl uronium (HBTU) as a coupling agent provided 17β-HSD3 inhibitor 6 [38]. Inhibitor 7: 17β-HSD12 inhibitor 7 was synthesized in four steps, as reported in Scheme 7.…”