Model platinum nucleobase and nucleoside complexes and antitumor activity:: X-ray crystal structure of [PtIV(trans-1 R,2R-diaminocyclohexane) trans-(acetate)2(9-ethylguanine)Cl]NO3 • H2O
Model platinum nucleobase and nucleoside complexes and antitumor activity:: X-ray crystal structure of [PtIV(trans-1 R,2R-diaminocyclohexane) trans-(acetate)2(9-ethylguanine)Cl]NO3 • H2O
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DOI：
10.1016/j.jinorgbio.2004.12.015
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发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
Khokhar, AR
中科院分区：
文献类型：
--
作者：
Ali, MS;Khan, SRA;Khokhar, AR
A series of platinum(II) and (IV) monoadducts of the type [Pt-II(DACH)LCl]NO3 and [Pt-IV(DACH)trans-(X)(2)LCl]NO3 (where DACH = trans-1R,2R-diaminocyclohexane, L = adenine, guanine, hypoxanthine, cytosine, adenosine, guanosine, inosine, cytidine, 9-ethylguanine (9-EtGua), or 1-methylcytosine and X = hydroxo or acetato ligand) have been synthesized and characterized by elemental analysis and by H-1 and Pt-195 nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the model nucleobase complex [Pt-IV(trans-1R,2R-diaminocyclohexane)trans-(acetate)(2)(9-EtGua)Cl]NO3 (.) H2O was determined using a single crystal X-ray diffraction method. The compound crystallized in the monoclinic space group P2(1), with a = 10.446(2) Angstrom, b = 22.906(5) Angstrom, c = 10.978(2) Angstrom, Z = 4, and R = 0.0718, based upon the total of 11,724 collected reflections. In this complex, platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogen of DACH, whereas, the other two equatorial positions occupied by chloride ion and 9-ethylguanine. The remaining two axial positions were occupied by the oxygen atoms of acetato ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. Some of these synthesized models of DACH-Pt-DNA adducts have good in vitro cytotoxic activity against the cisplatin-sensitive human cancer ovarian A2780 cell line (IC50 = 1-8 muM). Interestingly, a substituted nucleobase (9-ethylguanine) adduct was over 6-fold more potent than regular adducts. The cross-resistance factor against the 44-fold cisplatin-resistant 2780CP/clone 16 cells was about 3-9: thus, the cytotoxicity of adducts was indicative of low potency, but the resistance factors were also substantially low. These results suggest that DNA adducts of DACH-Pt are cytotoxic with low cross-resistance. (C) 2004 Elsevier Inc. All rights reserved.
