Novel Camptothecin-Based Lipid Conjugated with Steroids and Triterpene Acids: Enhanced Cellular Uptake and Topoismerase I Inhibition

Novel Camptothecin-Based Lipid Conjugated with Steroids and Triterpene Acids: Enhanced Cellular Uptake and Topoismerase I Inhibition Обзор

Журнал

Pharmaceutics
ISSN: 1999-4923

Вых. Данные

Год: 2026, Том: 18, Номер: 7, Номер статьи : 867, Страниц : DOI: 10.3390/pharmaceutics18070867

Авторы

Chobanov Nuri M. ¹ , Vakhnin Konstantin O. ² , Logunov Stepan E. ¹ , Fedorov Alexander E. ¹ , D’yakonov Georgii V. ¹ , Dzhemilev Usein M. ¹ , Dzhemileva Lilya U. ¹ , D’yakonov Vladimir A. ¹

Организации

1	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia
2	Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severniy Proezd 1, Chernogolovka 142432, Russia

Background/Objectives: The clinical application of the potent antitumor alkaloid camptothecin is severely limited by its high systemic toxicity, poor solubility, and rapid inactivation. This study aimed to design, synthesize, and evaluate a novel series of camptothecin–lipid conjugates where natural steroids and triterpenoids serve as lipophilic carriers to enhance cellular penetration and mitigate cardiotoxicity. Herein, we implemented an endogenous targeting strategy by conjugating camptothecin with natural steroids and triterpenoids, which serve as biomimetic lipophilic vectors to achieve tumor-selective intracellular delivery. Methods: Eleven novel camptothecin-based hybrids linked via succinic acid or ethylene glycol spacers were synthesized and characterized. Their in vitro cytotoxicity was evaluated against eight cancer cell lines of varied embryologic origin (Jurkat, HCT 116, A549, HL60, K562, HeLa, HEK293, and Fibroblasts). Cell cycle distribution, apoptosis induction, and topoisomerase I inhibitory activity were assessed using flow cytometry and enzyme assays. In silico pharmacokinetic profiling, including P-glycoprotein interaction and cardiotoxicity mitigation, was substantiated via ADME algorithms. Results: Among the series, compounds 12 (cholestanol conjugate) and 26 (betulin derivative) emerged as the primary lead candidates based on an optimal composite of submicromolar cytotoxicity, exceptional tumor selectivity indices (up to 7.0 for 12), and active topoisomerase I inhibition. Compounds 11–14 generally shared prominent S-phase cell cycle arrest, while the lead hybrids 12 and 26 successfully combined high apoptotic triggering with favorable in silico ADME safety profiling, including eliminated cardiotoxicity for the structural analogs. Conclusions: The integration of steroidal and triterpenoid pharmacophores via strategic spacers provides a reliable foundation for developing targeted, low-toxicity camptothecin–lipid conjugates with optimized safety profiles for cancer therapy.

Chobanov N.M. , Vakhnin K.O. , Logunov S.E. , Fedorov A.E. , D’yakonov G.V. , Dzhemilev U.M. , Dzhemileva L.U. , D’yakonov V.A.
Novel Camptothecin-Based Lipid Conjugated with Steroids and Triterpene Acids: Enhanced Cellular Uptake and Topoismerase I Inhibition
Pharmaceutics. 2026. V.18. N7. 867 . DOI: 10.3390/pharmaceutics18070867 OpenAlex

Поступила в редакцию:	30 июн. 2026 г.
Опубликована online:	17 июл. 2026 г.

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