Development of new steroid-based hydrazide and (thio)semicarbazone compounds with anticancer properties

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 242; p. 106545
• Main Authors: Janković, Ðorđe D., Šestić, Tijana Lj, Bekić, Sofija S., Savić, Marina P., Ćelić, Andjelka S., Scholda, Julia, Kopp, Florian, Marinović, Maja A., Petri, Edward T., Ajduković, Jovana J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2024
• Subjects: AKR1C; Androstane; Anti-proliferative activity; Hormone receptors; Hydrazide; Semicarbazone; Hormone receptors; Semicarbazone; Anti-proliferative activity; Androstane; AKR1C; Hydrazide
• ISSN: 0960-0760; 1879-1220; 1879-1220
• DOI: 10.1016/j.jsbmb.2024.106545

Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor β, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers.
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•New androstane hydrazides and semicarbazones were synthesized.•One benzohydrazide and one hydrazine-1-carbothioamide derivative were cytotoxic.•Five compounds were identified as selective inhibitors of AKR1C3.•One acetohydrazide and one hydrazine-1-carboxamide were potent inhibitors of AKR1C4.•In silico studies support experimentally confirmed protein-ligand interactions.