Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20(S)-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

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• 作者：Mei-Juan Wang ; Ying-Qian Liu ; Ling-Chu Chang ; Chih-Ya Wang ; Yong-Long Zhao ; Xiao-Bo Zhao ; Keduo Qian ; Xiang Nan ; Liu Yang ; Xiao-Ming Yang ; Hsin-Yi Hung ; Jai-Sing Yang ; Daih-Huang Kuo ; Masuo Goto ; Susan L. Morris-Natschke ; Shiow-Lin Pan ; Che-Ming Teng ; Sheng-Chu Kuo ; Tian-Shung Wu ; Yang-Chang Wu ; Kuo-Hsiung Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6008-6018
• 全文大小：620K
• ISSN：1520-4804

文摘

Twelve novel 20-sulfonylamidine derivatives (9a鈥?b>9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD₅₀ 56.2 mg/kg, i.p.) and 3 (LD₅₀ 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.