Yamashita T, Hirose J, Noji M, Saito R, Tomida H, Kidani Y
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Biol Pharm Bull. 1993 Oct;16(10):1014-8. doi: 10.1248/bpb.16.1014.
Several Pt(IV) and Pt(II) complexes containing 1R,2R-cyclohexanediamine (1R,2R-dach) as a carrier ligand were synthesized. The cytotoxicities and the uptake of the platinum complexes by leukemia L1210 cells were compared in order to study the correlation between their structures and cytotoxicities. [Pt(II)Cl2(1R,2R-dach)], [(Pt(II)(oxalato)(1R,2R-dach)], and [Pt(II)(malonato)(1R,2R-dach)], which have excellent anticancer properties, exhibited very high cytotoxicities and were easily taken up by leukemia L1210 cells. [Pt(IV)Cl4(1R,2R-dach)], trans(Cl)-[Pt(IV)Cl2(oxalato)(1R,2R-dach)], and trans(Cl)-[Pt(IV)Cl2(malonato)(1R,2R-dach)] also had high cytotoxicities. After a short incubation time, the uptake of [Pt(II)Cl2(1R,2R-dach)], [Pt(II)(oxalato)(1R,2R-dach)], and [Pt(II)(malonato)(1R,2R-dach)] by leukemia L1210 cells were respectively very similar to those of [Pt(IV)Cl4(1R,2R-dach)], trans(Cl)-[Pt(IV)Cl2(oxalato)(1R,2R-dach)], and trans(Cl)-[Pt(IV)Cl2(malonato)(1R,2R-dach)]. In addition, trans(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)] (Y2: oxalato or malonato) did not exhibit cytotoxicity towards leukemia L1210 cells, whereas trans(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)] (Y2: oxalato or malonato) were highly cytotoxic. The accumulation of trans(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)] in leukemia L1210 cells was much lower than that of trans(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)]. Platinum(IV) complexes, in which leaving groups are replaced by hydroxide groups, have decreased cytotoxic activity, because the hydroxide groups of the platinum(IV) complex reduce the uptake of platinum by the cells. trans(OH),cis(Cl)-[Pt(IV)(OH)2Cl2(1R,2R-dach)], which has hydroxide and chloride groups, was easily incorporated into the cells and exhibited the high cytotoxic activity. This behavior indicates that the chloride group apparently overcomes the ameliorating effect of the hydroxide group.
合成了几种以1R,2R-环己二胺（1R,2R-dach）作为载体配体的铂（IV）和铂（II）配合物。比较了这些铂配合物对白血病L1210细胞的细胞毒性和摄取情况，以研究它们的结构与细胞毒性之间的相关性。具有优异抗癌性能的[Pt(II)Cl2(1R,2R-dach)]、[(Pt(II)(草酸根)(1R,2R-dach)]和[Pt(II)(丙二酸根)(1R,2R-dach)]表现出非常高的细胞毒性，并且很容易被白血病L1210细胞摄取。[Pt(IV)Cl4(1R,2R-dach)]、反式(Cl)-[Pt(IV)Cl2(草酸根)(1R,2R-dach)]和反式(Cl)-[Pt(IV)Cl2(丙二酸根)(1R,2R-dach)]也具有较高的细胞毒性。在短时间孵育后，白血病L1210细胞对[Pt(II)Cl2(1R,2R-dach)]、[Pt(II)(草酸根)(1R,2R-dach)]和[Pt(II)(丙二酸根)(1R,2R-dach)]的摄取分别与对[Pt(IV)Cl4(1R,2R-dach)]、反式(Cl)-[Pt(IV)Cl2(草酸根)(1R,2R-dach)]和反式(Cl)-[Pt(IV)Cl2(丙二酸根)(1R,2R-dach)]的摄取非常相似。此外，反式(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)]（Y2：草酸根或丙二酸根）对白血病L1210细胞没有细胞毒性，而反式(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)]（Y2：草酸根或丙二酸根）具有高细胞毒性。反式(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)]在白血病L1210细胞中的积累远低于反式(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)]。离去基团被羟基取代的铂（IV）配合物的细胞毒性活性降低，因为铂（IV）配合物的羟基会减少细胞对铂的摄取。具有羟基和氯原子的反式(OH),顺式(Cl)-[Pt(IV)(OH)2Cl2(1R,2R-dach)]很容易进入细胞并表现出高细胞毒性活性。这种行为表明氯原子显然克服了羟基的改善作用。
