{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:06:27Z","timestamp":1784268387145,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u2013lipid 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\u201314 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\u2013lipid conjugates with optimized safety profiles for cancer therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070867","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:32:17Z","timestamp":1784266337000},"page":"867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Camptothecin-Based Lipid Conjugated with Steroids and Triterpene Acids: Enhanced Cellular Uptake and Topoismerase I Inhibition"],"prefix":"10.3390","volume":"18","author":[{"given":"Nuri M.","family":"Chobanov","sequence":"first","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin O.","family":"Vakhnin","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stepan E.","family":"Logunov","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E.","family":"Fedorov","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7048-2862","authenticated-orcid":false,"given":"Georgii V.","family":"D\u2019yakonov","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-6337","authenticated-orcid":false,"given":"Usein M.","family":"Dzhemilev","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-4746","authenticated-orcid":false,"given":"Lilya U.","family":"Dzhemileva","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-5054","authenticated-orcid":false,"given":"Vladimir A.","family":"D\u2019yakonov","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1016\/j.phytochem.2004.09.001","article-title":"Camptothecin, over four decades of surprising findings","volume":"65","author":"Lorence","year":"2004","journal-title":"Phytochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.phymed.2006.11.004","article-title":"Extraction and composition of three naturally occurring anti-cancer alkaloids in Camptotheca acuminata seed and leaf extracts","volume":"14","author":"Zhang","year":"2007","journal-title":"Phytomedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1016\/j.phymed.2016.10.018","article-title":"Combination of baicalein and 10-hydroxy camptothecin exerts remarkable synergetic anti-cancer effects","volume":"23","author":"Tang","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20506","DOI":"10.1021\/acs.jmedchem.5c01674","article-title":"A Nitroreductase-Activated Chemiluminescent Prodrug for Real-Time Monitoring of Camptothecin Release in Peritoneal Metastasis Theranostics","volume":"68","author":"Wei","year":"2025","journal-title":"J. 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