Huq Fazlul, Daghriri Hassan, Yu Jun Qing, Tayyem Hasan, Beale Philip, Zhang M
School of Biomedical Sciences, The University of Sydney, NSW 1825, Australia.
Eur J Med Chem. 2004 Nov;39(11):947-58. doi: 10.1016/j.ejmech.2004.07.012.
The dinuclear complex: [[trans-PtCl(NH(3))(2)] [mu-(H(2)N(CH(2))(6)NH(2))] trans-PdCl(NH(3))(2)Cl (code named DHD) has been synthesized and characterized. The activity against human cancer cell lines including ovarian: A2780, A2780(cisR), cell up take, level of binding with DNA and nature of interaction of the compound with pBR322 plasmid and salmon sperm DNAs have been determined. The compound is found to exhibit significant anticancer activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R)--about two times as active as cisplatin against A2780 cell line, about five times as active as cisplatin against A2780(cisR) and A2780(ZD0473R) cell lines. The higher activity of DHD suggests that the compound is able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. DHD is believed to form a range of interstrand GG adducts with duplex DNA that induces global changes in the DNA conformation, unlike cisplatin and ZD0473 that form mainly intrastrand adducts that induces a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of DHD provides support to the idea that the interstrand binding of DHD with pBR322 plasmid DNA brings about global changes in DNA conformation.
[[反式 - 铂氯（氨）₂] [μ - （乙二胺）] [反式 - 钯氯（氨）₂]（硝酸根）氯（代号为DHD）已被合成并表征。已测定其对包括卵巢癌细胞系：A2780、A2780（顺铂耐药）在内的人类癌细胞系的活性、细胞摄取、与DNA的结合水平以及该化合物与pBR322质粒和鲑鱼精DNA的相互作用性质。发现该化合物对卵巢癌细胞系A2780、A2780（顺铂耐药）和A2780（ZD0473耐药）具有显著的抗癌活性——对A2780细胞系的活性约为顺铂的两倍，对A2780（顺铂耐药）和A2780（ZD0473耐药）细胞系的活性约为顺铂的五倍。DHD的较高活性表明该化合物能够克服在A2780（顺铂耐药）和A2780（ZD0473耐药）细胞系中起作用的多种耐药机制。据信DHD与双链DNA形成一系列链间GG加合物，从而诱导DNA构象的整体变化，这与顺铂和ZD0473不同，顺铂和ZD0473主要形成链内加合物，诱导DNA链局部扭结。随着DHD浓度的增加，对I型和II型pBR322质粒DNA的BamH1消化的抑制作用增强，这支持了DHD与pBR322质粒DNA的链间结合导致DNA构象整体变化的观点。
