Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC₅₀, 67.0 nM) and 19b (IC₅₀, 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.

氟化是在药物开发项目的前期优化阶段提高生物活性分子生物利用度的众所周知的策略。为了提高喜树碱（CPT）的抗肿瘤活性，设计，合成并评估了新型10-氟-CPT衍生物对五种人类癌细胞系的细胞毒性（A-549，MDA-MB-231，KB，​​KB- VIN和MCF-7）。与临床CPT衍生药物伊立替康相比，所有这些衍生物对被测试的肿瘤细胞系均显示出更强的体外细胞毒性活性，并且大多数都表现出与拓扑替康相当或更高的效价。值得注意的是，化合物16B（IC ₅₀，nM的67.0）和19B（IC ₅₀，99.2 nM）对多药耐药（MDR）KB-VIN细胞系表现出最高的细胞毒性，作为治疗包括MDR表型在内的癌症的临床前候选药物，值得进一步发展。我们的研究表明，将氟原子掺入CPT的10位是发现新的有效CPT衍生物的有效方法。