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Synthesis and Biological Evaluation of 10‐Substituted Camptothecin Derivatives with Improved Water Solubility and Activity
Author(s) -
Yang XueYan,
Zhao HongYi,
Lei Hao,
Yuan Bo,
Mao Shuai,
Xin Minghang,
Zhang SanQi
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000753
Subject(s) - camptothecin , solubility , chemistry , cytotoxicity , toxicity , pharmacology , irinotecan , topoisomerase , in vitro , lead compound , apoptosis , cell growth , cell culture , combinatorial chemistry , biochemistry , biology , organic chemistry , cancer , colorectal cancer , genetics
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.