Synthesis, anticancer activity and toxicity of a water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)}.
Synthesis, anticancer activity and toxicity of a water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)}.
复制标题
DOI：
10.1016/j.jinorgbio.2014.07.013
复制
发表时间：
2014-11
影响因子：
3.9
通讯作者：
Weiping Liu;Jing Jiang;Cheng-ying Xie;Shuqian Hou;H. Quan;Qingsong Ye;L. Lou
中科院分区：
文献类型：
--
作者：
Weiping Liu;Jing Jiang;Cheng-ying Xie;Shuqian Hou;H. Quan;Qingsong Ye;L. Lou
合成了水溶性的七铂4S,5S-衍生物cis-{Pt(II)[(4S,5S)-4,5-双(氨基甲基)-2-异丙基-1,3-二氧戊环]·(3-羟基-环丁烷-1,1-二羧酸酯)}。通过比较其与DNA的相互作用、对四种人类癌细胞系的细胞毒性、对人胃癌NCI-N87裸鼠异种移植物的抗肿瘤效率以及对大鼠的初步副作用，评估了其与临床前开发中的4R，5R光学异构体的抗癌活性和毒性。两种异构体诱导 DNA 缩合的程度相同，具有相似的细胞毒性，但表现出不同的抗肿瘤活性和毒性，可能是由于各自的药代动力学特征不同。 4S,5S-异构体似乎比 4R,5R-光学异构体以及母体七铂表现出更优异的抗肿瘤活性和更低的毒性。这些结果意味着4S,5S-构型作为新候选药物可能优于4R,5R-对应物。
A water-soluble4S,5S-derivative of heptaplatin,cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)} was synthesized. The anticancer activity and toxicity were evaluated by comparing its interaction with DNA, cytotoxicity against four human cancer cell lines, antitumor efficiency in human gastric carcinoma NCI-N87 xenografts in nude mice, and preliminary side-effects in rats to those of its4R,5R-optical isomer which is under preclinical development. Both isomers induce condensation of DNA to the same extent and have similar cytotoxicity, but show different antitumor activity and toxicity, probably owing to the difference in respective pharmacokinetic profiles.4S,5S-Isomer seems to exhibit superior antitumor activity and less toxicity than4R,5R-optical isomer as well as the parent heptaplatin. These results imply that4S,5S-configuration as a new drug candidate may be better than4R,5R-counterpart.