Abstract:
It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis-1,3-diaminocyclohexane (cis-1,3-DACH) upon formation, stability, and stereochemistry of the (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5\'- and 3\'-guanosine monophosphate; d(GpG) = deoxyguanosil(3\'-5\')deoxyguanosine). A peculiar feature of the cis-1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (cis-1,3-DACH)Pt(5\'GMP)2 and (cis-1,3-DACH)Pt(3\'GMP)2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis-1,3-DACH derivatives with respect to the analogous cis-(NH3)2 species could be a consequence of the greater bite angle of the cis-1,3-DACH carrier ligand with respect to cis-(NH3)2. Finally, the (cis-1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3\'-G base flipped with respect to the 5\'-G residue.
摘要:
人们普遍认为,DNA中相邻的鸟嘌呤残基是铂抗肿瘤药物的主要靶标,并且Pt-DNA加合物的构象差异可能在其抗肿瘤活性中起作用。在这项研究中,我们研究了载体配体顺式-1,3-二氨基环己烷(顺式-1,3-DACH)对形成的影响,稳定性,和(顺式-1,3-DACH)PtG2和(顺式-1,3-DACH)Pt(d(GpG))加合物的立体化学(G=9-乙基鸟嘌呤,鸟苷,5'-和3'-一磷酸鸟苷;d(GpG)=脱氧鸟苷(3'-5')脱氧鸟苷)。顺式-1,3-DACH载体配体的独特特征是二胺的空间体积,相对于Pt配位平面是不对称的。(顺式-1,3-DACH)Pt(5'GMP)2和(顺式-1,3-DACH)Pt(3'GMP)2加合物显示出对ΛHT和ΔHT构象的偏好,分别(HT代表头对尾)。此外,相对于类似的顺式-(NH3)2物种,顺式-1,3-DACH衍生物中的圆二色性信号强度的增加可能是顺式-1,3-DACH载体配体相对于顺式-(NH3)2的更大咬合角的结果。最后,(顺式-1,3-DACH)Pt(d(GpG))加合物以两种异构形式存在,每个给出一对由NOE交叉峰连接的H8共振。两种异构体的形成量相当,并且在HH构象异构体中占主导地位,但ΔHT构象与HH构象有关,ΔHT构象与5'-G残基的3'-G碱基翻转有关。