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Design, synthesis and antineoplastic activity of novel 20(S)-acylthiourea derivatives of camptothecin.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-13 , DOI: 10.1016/j.ejmech.2019.111971 Cheng-Jie Yang 1 , Bin Li 2 , Zhi-Jun Zhang 1 , Jian-Mei Gao 1 , Mei-Juan Wang 1 , Xiao-Bo Zhao 1 , Zi-Long Song 1 , Ying-Qian Liu 3 , Hu Li 1 , Yuyuan Chen 2 , Kuo-Hsiung Lee 4 , Susan L Morris-Natschke 4 , Chuanrui Xu 2
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-13 , DOI: 10.1016/j.ejmech.2019.111971 Cheng-Jie Yang 1 , Bin Li 2 , Zhi-Jun Zhang 1 , Jian-Mei Gao 1 , Mei-Juan Wang 1 , Xiao-Bo Zhao 1 , Zi-Long Song 1 , Ying-Qian Liu 3 , Hu Li 1 , Yuyuan Chen 2 , Kuo-Hsiung Lee 4 , Susan L Morris-Natschke 4 , Chuanrui Xu 2
Affiliation
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For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.
中文翻译：
喜树碱的新型20（S）-酰基硫脲衍生物的设计，合成和抗肿瘤活性。
为了促进我们对喜树碱（CPT）的各种C-20装饰的衍生物的研究，合成了46种新的CPT酰基硫脲衍生物，并在体外对其细胞毒性进行了评估。所有化合物对六种肿瘤细胞系（Hep3B，MCF7，A549，MDA-MB-231，KB和KB-vin）均显示出有希望的体外细胞毒性。其中，化合物c20具有显着的体外细胞毒性活性，并且比托泊替康更有效。从机理上讲，c20不仅诱导A549细胞的细胞周期停滞和细胞凋亡，而且以类似于拓扑替康的方式抑制细胞和无细胞系统中的Topo I活性。在异种移植和原发性HCC小鼠模型中，c20均显示出显着的体内抗癌活性，并且比托泊替康更有效。此外，急性毒性试验表明，c20对FVB / N小鼠的小鼠肝，肾和造血系统无明显毒性。综上所述，这些结果表明化合物c20可能是用于进一步临床试验的潜在抗癌候选物。
更新日期：2019-12-17
中文翻译：
喜树碱的新型20（S）-酰基硫脲衍生物的设计，合成和抗肿瘤活性。
为了促进我们对喜树碱（CPT）的各种C-20装饰的衍生物的研究，合成了46种新的CPT酰基硫脲衍生物，并在体外对其细胞毒性进行了评估。所有化合物对六种肿瘤细胞系（Hep3B，MCF7，A549，MDA-MB-231，KB和KB-vin）均显示出有希望的体外细胞毒性。其中，化合物c20具有显着的体外细胞毒性活性，并且比托泊替康更有效。从机理上讲，c20不仅诱导A549细胞的细胞周期停滞和细胞凋亡，而且以类似于拓扑替康的方式抑制细胞和无细胞系统中的Topo I活性。在异种移植和原发性HCC小鼠模型中，c20均显示出显着的体内抗癌活性，并且比托泊替康更有效。此外，急性毒性试验表明，c20对FVB / N小鼠的小鼠肝，肾和造血系统无明显毒性。综上所述，这些结果表明化合物c20可能是用于进一步临床试验的潜在抗癌候选物。
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