Legendre Franck, Kozelka Jirí, Chottard Jean-Claude
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université René Descartes (Paris V), URA 400 CNRS, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Inorg Chem. 1998 Aug 10;37(16):3964-3967. doi: 10.1021/ic980008y.
The kinetics of the reactions between the diaqua form of the antitumor drug cisplatin, cis-Pt(NH(3))(2)(H(2)O)(2), and two hairpin-stabilized duplex oligonucleotides, d(TATGGTATTTTTATACCATA) (I) and d(TATAGTATTTTTATACTATA) (II), were investigated. Oligonucleotides I and II were used as models for GG and AG sequences within duplex DNA, which are known as the major sites of platinum binding. The two GG guanines of I are shown to react with similar rates (k(5)(') = 18 +/- 2 and k(3)(') = 15 +/- 1 M(-)(1) s(-)(1)), roughly twice as fast as the AG guanine of II (k(3)(') = 9 +/- 1 M(-)(1) s(-)(1)). Platination of the AG adenine of II was also observed to a minor extent (k(5)(') = 1.5 +/- 0.3 M(-)(1) s(-)(1)), whereas no other adenine of I or II was platinated to a detectable extent. The overall platination rate of I is approximately three times larger than that of II. The 3'-monoadduct of I undergoes chelation to the GG intrastrand adduct with a rate 10.5 times larger than the 5'-monoadduct (k(3)(')(c) = (1.9 +/- 0.1) x 10(-)(3) s(-)(1) and k(5)(')(c) = (0.18 +/- 0.05) x 10(-)(3) s(-)(1)). For II, the chelation rate constants of the guanine- and adenine-bound monoadducts are k(5)(')(c) = 0.3 +/- 0.1 and k(3)(')(c) = 0.08 +/- 0.01 s(-)(1), respectively. These results are discussed in relation to the platination kinetics determined for other model systems.
研究了抗肿瘤药物顺铂的二水合物形式顺式-[Pt(NH₃)₂(H₂O)₂]²⁺与两种发夹稳定的双链寡核苷酸d(TATGGTATTTTTATACCATA)（I）和d(TATAGTATTTTTATACTATA)（II）之间反应的动力学。寡核苷酸I和II被用作双链DNA中GG和AG序列的模型，已知这些序列是铂结合的主要位点。结果表明，I的两个GG鸟嘌呤以相似的速率反应（k₅' = 18 ± 2和k₃' = 15 ± 1 M⁻¹ s⁻¹），大约是II的AG鸟嘌呤反应速率（k₃' = 9 ± 1 M⁻¹ s⁻¹）的两倍。还观察到II的AG腺嘌呤有少量铂化（k₅' = 1.5 ± 0.3 M⁻¹ s⁻¹），而I或II的其他腺嘌呤没有被铂化到可检测的程度。I的总体铂化速率大约是II的三倍。I的3'-单加合物与GG链内加合物螯合的速率比5'-单加合物大10.5倍（k₃'(c) = (1.9 ± 0.1) × 10⁻³ s⁻¹和k₅'(c) = (0.18 ± 0.05) × 10⁻³ s⁻¹）。对于II，鸟嘌呤结合和腺嘌呤结合的单加合物的螯合速率常数分别为k₅'(c) = 0.3 ± 0.1和k₃'(c) = 0.08 ± 0.01 s⁻¹。结合其他模型系统确定的铂化动力学对这些结果进行了讨论。
