Schobert Rainer, Biersack Bernhard, Dietrich Andrea, Grotemeier Antje, Müller Thomas, Kalinowski Bernd, Knauer Sebastian, Voigt Wieland, Paschke Reinhard
Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany.
J Med Chem. 2007 Mar 22;50(6):1288-93. doi: 10.1021/jm061379o. Epub 2007 Mar 1.
(6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC90 < or = 10 microM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.
用萜烯醇酯化的（6-氨基甲基烟酸）二氯铂（II）配合物4在一组五种人类肿瘤细胞系上进行了测试。虽然它们在所有细胞系中的积累都比顺铂（CDDP）更容易，但它们的细胞毒性具有肿瘤特异性且依赖于结构。已知具有抗凋亡、影响离子通道的蛋白质水平升高或以其他方式受损的半胱天冬酶-9激活的细胞系对4的反应比对CDDP更好，例如，HL-60白血病细胞对葑基和冰片基衍生物4a、b的IC90≤10μM时反应良好。（-）-薄荷醇配合物4g在耐CDDP的1411HP男性生殖细胞肿瘤细胞中的积累远优于在同源的对CDDP敏感的H12.1细胞系中，并且更有效。4g还打破了518A2黑色素瘤细胞对CDDP的抗性。根据TUNEL和膜联蛋白V荧光测定，每种情况下的细胞死亡都是凋亡性的。一些配合物4似乎能正向调节细胞膜和封闭的线粒体阴离子通道的通透性。
