Najajreh Yousef, Khazanov Elena, Jawbry Seba, Ardeli-Tzaraf Yael, Perez Jose Manuel, Kasparkova Jana, Brabec Viktor, Barenholz Yechezkel, Gibson Dan
Department of Medicinal Chemistry and Natural Products, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine.
J Med Chem. 2006 Jul 27;49(15):4665-73. doi: 10.1021/jm060237r.
A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon cancer cells were evaluated. The trans-[PtCl2(NH3)(pip-pip)] x HCl was significantly more potent than cisplatin in all the cisplatin-resistant ovarian cancer cell lines and was nearly as cytotoxic as cisplatin against colon cancer cells. In vivo studies in mice showed that the pip-pip complexes are significantly less toxic than cisplatin. Cisplatin was more efficacious than both trans-[PtCl2(NH3)(pip-pip)] x HCl and trans-[PtCl2(NBA)(pip-pip)] x HCl in the A2780 and A2780cisR tumor xenograft models, consistent with its lower IC50 values in A2780 cells but contrary to the higher IC50 values in A2780cisR cells. In the colon cancer cell studies, trans-[PtCl2(NH3)(pip-pip)] x HCl was slightly less potent than cisplatin in the in vitro studies but had efficacy comparable to that of cisplatin in the in vivo xenograft model.
制备并表征了一系列通式为trans-[PtCl2(Am)(pip-pip)]·HCl的配合物，其中pip-pip为4-哌啶基哌啶，Am为NH3、甲胺（MA）、二甲胺（DMA）、正丙胺（NPA）、异丙胺（IPA）、正丁胺（NBA）或环己胺（CHA），并评估了它们对卵巢癌细胞和结肠癌细胞的细胞毒性。在所有顺铂耐药的卵巢癌细胞系中，trans-[PtCl2(NH3)(pip-pip)]·HCl的活性明显高于顺铂，对结肠癌细胞的细胞毒性与顺铂相近。小鼠体内研究表明，pip-pip配合物的毒性明显低于顺铂。在A2780和A2780cisR肿瘤异种移植模型中，顺铂比trans-[PtCl2(NH3)(pip-pip)]·HCl和trans-[PtCl2(NBA)(pip-pip)]·HCl更有效，这与其在A2780细胞中较低的IC50值一致，但与在A2780cisR细胞中较高的IC50值相反。在结肠癌细胞研究中，trans-[PtCl2(NH3)(pip-pip)]·HCl在体外研究中的活性略低于顺铂，但在体内异种移植模型中的疗效与顺铂相当。
