Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity

Natalia S Sucman; Dmitri Ya Bilan; Sergiu V Cojocari; Vsevolod S Pogrebnoi; Eugenia P Stîngaci; Vladimir A Khripach; Vladimir N Zhabinskii; Tatsiana V Tsybruk; Irina P Grabovec; Olesya V Panibrat; Leentje Persoons; Dominique Schols; Mathy Froeyen; Sergiu Shova; Steven De Jonghe; Fliur Z Macaev

doi:10.1016/j.steroids.2024.109475

Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity

Steroids. 2024 Oct:210:109475. doi: 10.1016/j.steroids.2024.109475. Epub 2024 Jul 26.

Authors

Natalia S Sucman¹, Dmitri Ya Bilan², Sergiu V Cojocari³, Vsevolod S Pogrebnoi⁴, Eugenia P Stîngaci⁵, Vladimir A Khripach⁶, Vladimir N Zhabinskii⁷, Tatsiana V Tsybruk⁸, Irina P Grabovec⁹, Olesya V Panibrat¹⁰, Leentje Persoons¹¹, Dominique Schols¹², Mathy Froeyen¹³, Sergiu Shova¹⁴, Steven De Jonghe¹⁵, Fliur Z Macaev¹⁶

Affiliations

¹ Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: natalia.sucman@sti.usm.md.
² Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: dumitru.bilan@ichem.md.
³ Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: sergiu.cojocari@sti.usm.md.
⁴ Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: vsevolod.pogrebnoi@sti.usm.md.
⁵ Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: eugenia.stingaci@sti.usm.md.
⁶ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus. Electronic address: khripach@iboch.by.
⁷ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus. Electronic address: vz@iboch.by.
⁸ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus. Electronic address: tvshkel@iboch.by.
⁹ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus.
¹⁰ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str., 5/2, 220141 Minsk, Belarus. Electronic address: panibrat@iboch.by.
¹¹ Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium. Electronic address: leentje.persoons@kuleuven.be.
¹² Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium. Electronic address: dominique.schols@kuleuven.be.
¹³ Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, P.O. Box 1030, B-3000 Leuven, Belgium. Electronic address: Mathy.froeyen@kuleuven.be.
¹⁴ Department of Inorganic Polymers, "Petru Poni" Institute of Macromolecular Chemistry, Aleea Grigore GhicaVoda 41-A, Iasi 700487, Romania. Electronic address: shova@icmpp.ro.
¹⁵ Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, P.O. Box 1043, B-3000 Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.
¹⁶ Laboratory of Organic Synthesis, Institute of Chemistry, Moldova State University, Academiei Str., 3, MD-2028 Chișinău, Moldova. Electronic address: fliur.macaev@sti.usm.md.

PMID: 39067611
DOI: 10.1016/j.steroids.2024.109475

Abstract

Nitrogen-containing steroids are known as prostate cancer therapeutics. In this work, a series of pregnane derivatives bearing an imidazolium moiety were synthesized using Δ¹⁶-20-ketones as starting material. An improved approach for the construction of the 20-keto-21-heterocycle-substituted fragment involved the rearrangement of 16,17-epoxides with HCl, followed by reaction of the formed α-chloroketone with 1-substituted imidazoles. Binding affinity analysis of the imidazolium steroids and their synthetic intermediates to human CYP17A1 showed only type I (substrate-like) interactions. The strongest affinity was observed for 16α,17α-epoxy-5α-pregnan-20-on-3β-ol (K_d = 0.66 ± 0.05 µM). The steroid derivatives have been evaluated for antitumor activity against a range of prostate cancer cells as well as against various other solid tumor and hematologic cancer cell lines. All 21-imidazolium salts were active against the hormone-dependent prostate cancer line LNCaP. The most pronounced cytotoxicity in solid tumor and hematologic cancer cell lines was observed for intermediate product, 21-chloro-5α-pregn-16-en-20-on-3β-ol. Among the imidazolium salts, the derivatives with a single bond were more cytotoxic than their unsaturated congeners.

Keywords: CYP17A1; Imidazolium salts; Prostate cancer.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology
Humans
Imidazoles* / chemical synthesis
Imidazoles* / chemistry
Imidazoles* / pharmacology
Male
Salts / chemical synthesis
Salts / chemistry
Salts / pharmacology
Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
Steroid 17-alpha-Hydroxylase / metabolism
Steroids / chemical synthesis
Steroids / chemistry
Steroids / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Imidazoles
Salts
Steroid 17-alpha-Hydroxylase
Steroids
Heterocyclic Compounds