title: 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)}.
abstract: 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)} 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 its 4R,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 than 4R,5R-optical isomer as well as the parent heptaplatin. These results imply that 4S,5S-configuration as a new drug candidate may be better than 4R,5R-counterpart.
authors.affiliation: State Key Laboratory for Platinum Group Metals, Kunming Institute of Precious Metals, 650106 Yunnan, PR China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Platinum Group Metals, Kunming Institute of Precious Metals, 650106 Yunnan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, PR China.
authors.forename: Chengying
authors.initials: C
authors.lastname: Xie
authors.affiliation: State Key Laboratory for Platinum Group Metals, Kunming Institute of Precious Metals, 650106 Yunnan, PR China.
authors.forename: Shuqian
authors.initials: S
authors.lastname: Hou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, PR China.
authors.forename: Haitian
authors.initials: H
authors.lastname: Quan
authors.affiliation: State Key Laboratory for Platinum Group Metals, Kunming Institute of Precious Metals, 650106 Yunnan, PR China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, PR China. Electronic address: liguanglou1@126.com.
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D008314:Malonates; D009944:Organoplatinum Compounds; C090717:SKI 2053R
keywords: Anticancer activity; Derivative; Heptaplatin; Platinum complexes; Toxicity