Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity

•21-Imidazolium salt derivatives were prepared from 16-dehydropregnenolone acetate.•The key transformation was the rearrangement of 16,17-epoxides with HCl.•Binding affinity of synthesized compounds to CYP17A1 was evaluated.•Effects of the obtained compounds on various cancer cells were studied.•All...

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Published in:	Steroids Vol. 210; p. 109475
Main Authors:	Sucman, Natalia S., Ya. Bilan, Dmitri, Cojocari, Sergiu V., Pogrebnoi, Vsevolod S., Stîngaci, Eugenia P., Khripach, Vladimir A., Zhabinskii, Vladimir N., Tsybruk, Tatsiana V., Grabovec, Irina P., Panibrat, Olesya V., Persoons, Leentje, Schols, Dominique, Froeyen, Mathy, Shova, Sergiu, De Jonghe, Steven, Macaev, Fliur Z.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-10-2024
Subjects:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects CYP17A1 Drug Screening Assays, Antitumor Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Imidazolium salts Male Prostate cancer 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 Imidazolium salts Prostate cancer CYP17A1
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Summary:	•21-Imidazolium salt derivatives were prepared from 16-dehydropregnenolone acetate.•The key transformation was the rearrangement of 16,17-epoxides with HCl.•Binding affinity of synthesized compounds to CYP17A1 was evaluated.•Effects of the obtained compounds on various cancer cells were studied.•All imidazolium salts were active against the hormone-dependent line LNCaP. 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 (Kd = 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0039-128X 1878-5867 1878-5867
DOI:	10.1016/j.steroids.2024.109475