Anticancer metal complexes developed by adsorption to apatite as an indicator

临床抗癌铂(II)络合物如顺铂、卡铂和奥沙利铂通常由2N和2Cl或2O(羧酸盐)作为给体原子组成。这些被称为“离开基团(LG)”的氯和氧基团被认为不那么重要，因为抗癌的铂(II)药物在LG从铂(II)配位解离后攻击DNA碱基。近年来，LG作为药物传递系统(DDS)的工具已被研究。针对近年来癌症骨转移的增加，我们研究了含有类磷酸基团的阴离子铂(II)络合物及其与羟基磷灰石(HA，C&lt；10&gt；(PO_4)_6(OH)_2)的亲和力，因为HA是骨的无机成分。铂(Dach)(MDP)的晶体结构为2N(NH_2)和2O(PO_3)与铂(II)配位。这些铂(II)络合物在水中稳定，在酸性溶液中表现出较短的半衰期(t&lt；1/2)。铂(Dach)(MDP)-寡聚DNA加合物的晶体结构表明，铂(Dach)与鸟嘌呤N7呈单齿配位，MDP以lg形式脱除。这些铂(II)络合物的典型特征是对HA具有良好的吸附性能，而顺铂和卡铂表现出较低的吸附性能。吸附符合朗缪尔曲线，其吸附常数K依赖于P的个数，因此从吸附的角度区分了铂(DA)(IP6)络合物。铂(DA)(LG)表现出(1)新的与DNA的相互作用模式；(2)良好的体外测定结果；(3)良好的对HA的吸附。

Clinical anticancer Pt(II) complexes such as cisplatin, carboplatin, and oxaliplatin commonly consist of 2N and 2C1 or 2O (carboxylate) as donor atoms. These Cl and O groups called "Leaving Group (LG)" have been believed to be less important because anticancer Pt(II) drugs attack the DNA base after dissociation of LG from the Pt(II) coordination. Recently LG has been studied as a tool of drug delivery system (DDS). Focusing recent increment of cancers metastasis to bone, we studied anionic Pt(II) complexes involving phosphate like group as LG and its affinity to hydroxyapatite (HA, C_<10>(PO_4)_6(OH)_2,) because HA is inorganic component of bone.Pt(DA)(LG) complexes (DA=(NH_3)_2, dach; LG=methylenediphosphonate (MDP), pyrophosphate (PP), inositolhexakisphosphate (IP6) were prepared from corresponding Pt(DA)I_2 by treatment of Ag^+ through chelate effect. Crystal structure of Pt(dach)(MDP) showed 2N(NH_2) and 2O(PO_3) coordination to Pt(II). These Pt(II) complexes were stable for hydrolysis in water and showed short half live time (t_<1/2>) in acidic solution. The crystal structure of Pt(dach)(MDP)-oligo DNA adduct revealed the monodentate coordination of Pt(dach) to guanine N7 and removal of MDP as LG. The typical property of these Pt(II) complexes was the excellent adsorption to HA, while cisplatin and carboplatin showed low adsorption. The adsorption fits Langmuir plot and its adsorption constant K depends on the number of P, so from the view of the adsorption the Pt(DA)(IP6) complexes were distinguished.Pt(DA)(LG) exhibited (1) new interaction mode with DNA; (2) good in vitro assay results; (3) good adsorption to HA.