Alvarez-Valdés Amparo, Pérez José Manuel, López-Solera Isabel, Lannegrand Raúl, Continente José Manuel, Amo-Ochoa Pilar, Camazón María José, Solans Xavier, Font-Bardía Mercè, Navarro-Ranninger Carmen
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain.
J Med Chem. 2002 Apr 25;45(9):1835-44. doi: 10.1021/jm010968l.
The reaction of Pt(dimethyl sulfoxide)(2)CBDCA (CBDCA = 1,1-cyclobutanedicarboxylate) with 1,4-diaminebutane and 1,3-diaminepropane ligands yields, under certain conditions, new [Pt(diamine)(2)]CBDCA complexes (1a,b), where the CBDCA ligand has been removed from the coordination sphere of the platinum atom by the diamine ligand, instead of forming the expected [Pt(diamine)CBDCA] complexes (1'a,b). The structure of complexes 1a and 1'b was solved by X-ray diffraction. Complex 1a crystallizes in the orthorhombic system, in the noncentrosymmetric C222 space group, with unit cell parameters: a = 20.053(2) A; b = 8.655(2) A, c = 5.711(3) A; V = 991.2(6) A(3); delta (calcd) = 1.627 mg/m(3); and R = 0.050. The Pt atom displays an unexpected distorted tetrahedral coordination with a N-Pt-N inner bond angle equal to 81(2) degrees for N atoms of the same 1,3-propanediamine ligand and a N-Pt-N bond angle for different ligands equal to 135.4(9) degrees. Complex 1'b crystallizes in the monoclinic system, in the centrosymmetric P2(1)/c space group, with unit cell parameters: a = 6.007(2) A; b = 15.336(4) A, c = 13.232(5) A; beta = 101.90(3) degrees; V = 1192.8(7) A(3); delta (calcd) = 2.369 mg/m(3); and R = 0.067. Cytotoxicity data show that of all the synthesized compounds, only complexes 1'a and 1'b exhibit remarkable cytotoxic properties. Thus, in contrast with carboplatin (cis-diammine-1,1-cyclobutane dicarboxilatoplatinum(II)), compounds 1'a and 1'b, which also contain the CBDCA ligand, are able to circumvent cisplatin (cis-diamminedichloroplatinum(II)) resistance in several tumor cells. Moreover, after 24 h of incubation of CH1cisR ovarian tumor cells with 10 microM of compounds 1'a and 1'b, the level of DNA interstrand cross-links (ICLs) induced by compounds 1'a and 1'b is 3.3 and 3.8 times higher, respectively, than that of carboplatin and 3.5 and 4.0 times higher, respectively, than that of cisplatin. Interestingly, under the same conditions, the intracellular accumulation of compounds 1'a and 1'b is similar to that of carboplatin and cisplatin. However, the extent of binding to DNA of compounds 1'a and 1'b is similar to that of cisplatin but slightly higher than that of carboplatin. We propose that circumvention of cisplatin resistance in CH1cisR cells by compounds 1'a and 1'b might be related to its higher ability to form DNA ICLs relative to carboplatin and cisplatin.
在特定条件下，二甲基亚砜合铂（II）-1,1-环丁烷二羧酸酯（CBDCA = 1,1-环丁烷二羧酸）与1,4-丁二胺和1,3-丙二胺配体反应，生成新的[Pt(二胺)₂]CBDCA配合物（1a,b），其中二胺配体将CBDCA配体从铂原子的配位球中取代，而不是形成预期的[Pt(二胺)CBDCA]配合物（1'a,b）。通过X射线衍射解析了配合物1a和1'b的结构。配合物1a在正交晶系中结晶，属于非中心对称的C222空间群，晶胞参数为：a = 20.053(2) Å；b = 8.655(2) Å，c = 5.711(3) Å；V = 991.2(6) ų；δ（计算值） = 1.627 mg/m³；R = 0.050。Pt原子呈现出意想不到的扭曲四面体配位，对于同一1,3-丙二胺配体的N原子，其N-Pt-N内键角为81(2)°，对于不同配体的N-Pt-N键角为135.4(9)°。配合物1'b在单斜晶系中结晶，属于中心对称的P2(1)/c空间群，晶胞参数为：a = 6.007(2) Å；b = 15.336(4) Å，c = 13.232(5) Å；β = 101.90(3)°；V = 1192.8(7) ų；δ（计算值） = 2.369 mg/m³；R = 0.067。细胞毒性数据表明，在所有合成化合物中，只有配合物1'a和1'b表现出显著的细胞毒性。因此，与卡铂（顺式二胺-1,1-环丁烷二羧酸铂（II））不同，同样含有CBDCA配体的化合物1'a和1'b能够在几种肿瘤细胞中规避顺铂（顺式二氯二胺铂（II））耐药性。此外，将CH1cisR卵巢肿瘤细胞与10 μM的化合物1'a和1'b孵育24小时后，化合物1'a和1'b诱导的DNA链间交联（ICL）水平分别比卡铂高3.3倍和3.8倍，比顺铂高3.5倍和4.0倍。有趣的是，在相同条件下化合物1'a和1'b的细胞内积累与卡铂和顺铂相似。然而，化合物1'a和1'b与DNA的结合程度与顺铂相似，但略高于卡铂。我们认为化合物1'a和1'b在CH1cisR细胞中规避顺铂耐药性可能与其相对于卡铂和顺铂形成DNA ICL的能力更强有关。
