抗肿瘤奥沙利铂/顺铂对接双核铂配合物的制备

Preparation of antitumor oxaliplatin/cisplatin docking dinuclear platinum complex.

作者信息

Noji Masahede, Kizu Ryoichi, Takeda Yasutaka, Akiyama Nachio, Yoshizaki Iwao, Eriguchi Masazumi, Kidani Yoshinori

机构信息

Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan.

出版信息

Biomed Pharmacother. 2005 Jun;59(5):224-9. doi: 10.1016/j.biopha.2004.06.006.

DOI:10.1016/j.biopha.2004.06.006

PMID:15919175

Abstract

A new dinuclear docking Pt(II) complex, (cis-diammine) (l-1,2-cyclohexanediamine)(mu-dichloro)-diplatinum(II) oxalate was synthesized by reacting oxaliplatin(l-OHP, [Pt(oxalato)(L-dach)]), L-dach = 1R, 2R-cyclohexanediamine), with cisplatin (CDDP). Elemental analysis of the compound indicated that it was 1:1 molar ratio complex of oxaliplatin and cisplatin. A plausible chemical structure has been proposed as Cl(-) bridged dinuclear complex, judged from its yellow coloration and NMR spectral analysis. This complex can be denoted as, i.e. Pt(2)Cl(2)(NH(3))(2)(L-dach)(2) (L-OHP/CDDP). The complex showed higher cytotoxicity against L1210 than the parent complexes and low cross-resistance against L1210/CDDP and L1210/DACH. Its antitumor activity was also tested in vivo against murine leukemia L1210 cell lines. The complex showed much higher activity than the mixture(1:1 molar ratio) of oxaliplatin and cisplatin. The antitumor effect against L1210/CDDP was very high, showing collateral sensitivity, being similar to that of oxaliplatin, and against L1210/DACH it showed no cross-resistance.

摘要

通过使奥沙利铂（l-OHP，[Pt(草酸盐)(L-二氨基环己烷)]，L-二氨基环己烷 = 1R，2R-环己二胺）与顺铂（CDDP）反应，合成了一种新型双核对接铂（II）配合物，（顺二氨）（l-1,2-环己二胺）（μ-二氯）-二铂（II）草酸盐。该化合物的元素分析表明它是奥沙利铂和顺铂的1:1摩尔比配合物。从其黄色以及核磁共振光谱分析判断，已提出一种合理的化学结构为Cl(-)桥联的双核配合物。这种配合物可表示为，即Pt(2)Cl(2)(NH(3))(2)(L-二氨基环己烷)(2) （L-OHP/CDDP）。该配合物对L1210的细胞毒性高于母体配合物，对L1210/CDDP和L1210/DACH的交叉耐药性较低。还在体内对小鼠白血病L1210细胞系测试了其抗肿瘤活性。该配合物的活性比奥沙利铂和顺铂的混合物（1:1摩尔比）高得多。对L1210/CDDP的抗肿瘤作用非常高，表现出协同敏感性，与奥沙利铂相似，对L1210/DACH没有交叉耐药性。