Siddik Z H, al-Baker S, Thai G, Khokhar A R
Department of Clinical Investigation, University of Texas M.D. Anderson, Cancer Center, Houston 77030.
Anticancer Drug Des. 1994 Apr;9(2):139-51.
Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, platinum analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, and we have previously established that the R,R form of DACH-Pt(II) complex is in general superior. Here, we have examined if specific axial and/or equatorial ligands attached to a platinum(IV) center can modulate the antitumor activities of R,R-DACH-Pt complexes in murine tumor models in vivo. Four series of R,R-DACH-Pt complexes were synthesized, with each series consisting of one platinum(II) complex and three corresponding platinum(IV) analogs, each differing by the chemical nature of the axial ligand (chloro, hydroxo or acetato). Combination of axial chloro with equatorial chloro (Cl2Cl2), 1,1-cyclobutanedicarboxylato (Cl2CBDCA), tartronato (Cl2Tart) or methylmalonato (Cl2MeMal) gave activities which were similar to or greater than those of the corresponding platinum(II) complex in the cisplatin-sensitive L1210/0 or cisplatin-resistant L1210/DDP leukemia and solid M5076 reticulosarcoma models. The exception was the complex Cl2Cl2 in the M5076 model, which was 2-fold less sensitive to this platinum(IV) complex than to the corresponding platinum(II) analog. Axial hydroxo or acetato platinum(IV) complexes were effective in combination with equatorial chloro ([OH]2Cl2 or Ac2Cl2) or tartronato ([OH]2Tart or Ac2Tart) against L1210/0, L1210/DDP and M5076 cells, but effective only against M5076 cells when combined with equatorial 1,1-cyclobutanedicarboxylato (CBDCA) or methylmalonato. The results demonstrated a profound effect of axial and equatorial ligands on the antitumor activities of R,R-DACH-Pt(IV) complexes. Furthermore, these modulatory effects could be influenced strongly by the tumor model. The interesting finding from this structure-activity study was the emergence of R,R-DACH([OH]2Cl2)Pt(IV) complex as a 'lead' analog worthy of further exploration.
获得性耐药是顺铂用于癌症治疗的一个主要缺点；然而，含有1,2 - 二氨基环己烷（DACH）配体的铂类似物可以克服这种耐药性。DACH可以以反式 - 1R,2R、反式 - 1S,2S或顺式异构体的形式存在，我们之前已经确定DACH - Pt(II)络合物的R,R形式总体上更具优势。在此，我们研究了连接到铂(IV)中心的特定轴向和/或赤道配体是否能在体内小鼠肿瘤模型中调节R,R - DACH - Pt络合物的抗肿瘤活性。合成了四个系列的R,R - DACH - Pt络合物，每个系列由一个铂(II)络合物和三个相应的铂(IV)类似物组成，每个系列的轴向配体（氯、羟基或乙酸根）化学性质不同。轴向氯与赤道氯（Cl2Cl2）、1,1 - 环丁烷二羧酸根（Cl2CBDCA）、酒石酸根（Cl2Tart）或甲基丙二酸根（Cl2MeMal）的组合在顺铂敏感的L1210/0或顺铂耐药的L1210/DDP白血病以及实体M5076网状细胞肉瘤模型中产生的活性与相应铂(II)络合物相似或更高。在M5076模型中的例外是络合物Cl2Cl2，该铂(IV)络合物对此模型的敏感性比对相应铂(II)类似物低2倍。轴向羟基或乙酸根铂(IV)络合物与赤道氯（[OH]2Cl2或Ac2Cl2）或酒石酸根（[OH]2Tart或Ac2Tart）联合对L1210/0、L1210/DDP和M5076细胞有效，但与赤道1,1 - 环丁烷二羧酸根（CBDCA）或甲基丙二酸根联合时仅对M5076细胞有效。结果表明轴向和赤道配体对R,R - DACH - Pt(IV)络合物的抗肿瘤活性有深远影响。此外，这些调节作用可能受到肿瘤模型的强烈影响。这项构效关系研究的有趣发现是R,R - DACH([OH]2Cl2)Pt(IV)络合物成为一个值得进一步探索的“先导”类似物。
