Synthesis and Biological Evaluation of 10‐Substituted Camptothecin Derivatives with Improved Water Solubility and Activity,ChemMedChem

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Synthesis and Biological Evaluation of 10‐Substituted Camptothecin Derivatives with Improved Water Solubility and Activity
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-26 , DOI: 10.1002/cmdc.202000753
Xue-Yan Yang ₁ , Hong-Yi Zhao ₁ , Hao Lei ₁ , Bo Yuan ₁ , Shuai Mao ₁ , Minghang Xin ₁ , San-Qi Zhang ₁

Affiliation

Despite remarkable clinical achievements, camptothecin (CPT) still suffers from poor solubility and severe toxicity. Therefore, it is necessary to redevelop CPT derivatives as supplementary antitumor agents with good water solubility and small side effects. In this work, 27 camptothecin derivatives were synthesized and screened for their cytotoxicity against A549 (lung) and HCT‐116 (colon) cancer cell lines. Among them, compound B7, 7‐ethyl‐10‐(2‐oxo‐2‐(4‐methylpiperidin‐1‐yl)ethoxy)camptothecin,was demonstrated in vitro to be a more potent antitumor agent than SN‐38 by comparison of their inhibitory activities against cell proliferation and colony formation and interference effect on process of cell cycle and cell apoptosis. Additionally, a molecular docking model revealed that B7 can interact with the topoisomerase I–DNA complex, and that the solubility of B7 reached 5.73 μg/mL in water. Moreover, B7 significantly inhibited tumor growth in an A549 xenograft model at dosages of 0.4 and 2.0 mg/kg, and exhibited minimum lethal doses comparable to those of irinotecan. These results indicated that B7, with improved solubility, enhanced activity and acceptable acute toxicity, can be used as a lead compound for the development of novel anticancer agents.

中文翻译：

具有改善的水溶性和活性的 10-取代的喜树碱衍生物的合成和生物学评价

尽管临床上取得了显着的成就，但喜树碱（CPT）仍然存在溶解性差和毒性严重的问题。因此，有必要重新开发CPT衍生物作为水溶性好、副作用小的辅助抗肿瘤剂。在这项工作中，合成了 27 种喜树碱衍生物并筛选了它们对 A549（肺）和 HCT-116（结肠）癌细胞系的细胞毒性。其中，化合物B7，7-乙基-10-（2-氧代-2-（4-甲基哌啶-1-基）乙氧基）喜树碱，在体外被证明是比 SN-38 更有效的抗肿瘤剂。它们对细胞增殖和集落形成的抑制活性和对细胞周期和细胞凋亡过程的干扰作用。此外，分子对接模型显示B7可以与拓扑异构酶 I-DNA 复合物相互作用，B7在水中的溶解度达到 5.73 μg/mL。此外，B7在 0.4 和 2.0 mg/kg 的剂量下显着抑制 A549 异种移植模型中的肿瘤生长，并且显示出与伊立替康相当的最小致死剂量。这些结果表明，B7具有改善的溶解性、增强的活性和可接受的急性毒性，可用作开发新型抗癌剂的先导化合物。

更新日期：2020-11-26

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