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首页> 外文期刊>Chemistry: A European journal >The trans influence in the modulation of platinum anticancer agent biology: The effect of nitrite leaving group on aquation, reactions with S-nucleophiles and DNA binding of dinuclear and trinuclear compounds
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The trans influence in the modulation of platinum anticancer agent biology: The effect of nitrite leaving group on aquation, reactions with S-nucleophiles and DNA binding of dinuclear and trinuclear compounds

机译：反式调节铂抗癌剂生物学的影响：亚硝酸盐离去基团对水合，与S-亲核试剂反应以及双核和三核化合物与DNA结合的影响

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摘要

To examine the effect of leaving group and trans influence on the general reactivity of polynuclear platinum antitumor agents we investigated substitution of the chloride leaving groups with nitrite ion, which forms strong bonds to Pt. It was of interest to explore whether nitrite could be used to modulate biological properties of these agents, in particular the deactivating reactions that occur on reaction with S-nucleophiles, involving loss of the linking diamine under the trans influence of sulfur. Reported herein is a study of the synthesis, aquation, DNA binding and reactions with glutathione (GSH), methionine (Met) and acetylmethione (AcMet) of nitrito derivatives of di-and trinuclear platinum antitumor compounds: [{trans-PtNO_2-(NH _3)_2}_2(μ-NH_2(CH _2)6NH_2)](NO_3)_2 (1-NO_2) and [{trans-PtNO_2(NH_3)_2}_2(μ- trans-Pt(NH_3)_2{NH_2(CH_2) _6NH_2}_2)]-(NO_3)_4 (1'-NO_2). {~1H,~(15)N}-HSQC NMR studies revealed that 1-NO_2 is inert to aquation reactions, even after prolonged incubation at physiological pH. Monitoring of the interaction of 1-NO _2 with the duplex 5'-d(ATATGTA-CATAT)_2 (I) showed only unreacted complex, consistent with activation by aquation being a requirement for covalent DNA binding. The reaction of 1-NO_2 with GSH was studied by~1H,~(195)Pt,~(15)N and {~1H, ~(15)N}-HSQC NMR spectroscopy. For the parent dichlorido compounds (1 and 1') substitution of chloride by GS- leads to drug degradation involving liberation of the diamine linker. While the same final products trans-[Pt(SG)_2(NH_3)_2] (5) and trans-[{Pt(SG)(NH_3)_2}_2-μ-SG] (6) are formed, different mechanisms are involved, consistent with the trans influence NO _2- > Cl-; the half-life is slightly longer for 1-NO_2 (1.8 h) compared with 1 (1.3 h). Identification of the intermediate trans-[Pt(NH_3)_2(NO_2)(SG)] (4) shows that the nitrito group remains coordinated while the linker amine is substituted by coordination of GS-, and then trans labilization of the nitrito group occurs leading to 5 and 6. Reaction of the trinuclear 1'-NO_2 with GSH follows essentially the same reaction pathway. Reaction of 1-NO_2 with Met and AcMet is much slower and only 20% liberated amine was observed after reaction with Met for 24 h at 37 °C. The final product from reaction with AcMet is trans-[Pt(NH_3) _2(NO_2)-(AcMet)], as in this case coordination of the S-nucleophile does not lead to trans labilization of the nitrito group
机译：为了研究离去基团和反式对多核铂抗肿瘤剂总体反应活性的影响，我们研究了亚硝酸根离子取代氯化物离去基团，该亚硝酸根离子与Pt形成牢固的键。有趣的是探索亚硝酸盐是否可用于调节这些试剂的生物学特性，特别是与S-亲核试剂反应时发生的失活反应，包括在硫的反式影响下连接二胺的丢失。本文报道了二核和三核铂抗肿瘤化合物的亚硝基衍生物的合成，水合，DNA结合以及与谷胱甘肽（GSH），蛋氨酸（Met）和乙酰甲硫基（AcMet）反应的研究：[{trans-PtNO_2-（NH _3）_2} _2（μ-NH_2（CH _2）6NH_2）]（NO_3）_2（1-NO_2）和[{trans-PtNO_2（NH_3）_2} _2（μ-trans-Pt（NH_3）_2 {NH_2（ CH_2）_6NH_2} _2）]-（NO_3）_4（1'-NO_2）。 {〜1H，〜（15）N} -HSQC NMR研究表明，即使在生理pH下长时间孵育后，1-NO_2对水合反应也是惰性的。监测1-NO _2与双链体5'-d（ATATGTA-CATAT）_2（I）的相互作用仅显示出未反应的复合物，这与水合激活是共价DNA结合所必需的。用〜1H，〜（195）Pt，〜（15）N和{〜1H，〜（15）N} -HSQC NMR光谱研究了1-NO_2与GSH的反应。对于母体二氯代化合物（1和1'），GS-取代氯会导致药物降解，包括二胺连接基的释放。虽然形成了相同的最终产物反式[[Pt（SG）_2（NH_3）_2]（5）和反式[{{Pt（SG）（NH_3）_2}_2-μ-SG]（6），但形成的机理不同与反式影响NO _2-> Cl-一致; 1-NO_2（1.8 h）的半衰期略长于1（1.3 h）。中间体反式-[Pt（NH_3）_2（NO_2）（SG）]（4）的鉴定表明，亚硝基基团保持配位，而连接胺被GS-配位取代，然后发生亚硝基基团的反式化导致5和6。三核1'-NO_2与GSH的反应基本遵循相同的反应路径。 1-NO_2与Met和AcMet的反应要慢得多，在37°C下与Met反应24小时后，仅观察到20％的游离胺。与AcMet反应的最终产物是反式[Pt（NH_3）_2（NO_2）-（AcMet）]，因为在这种情况下，S-亲核试剂的配位不会导致亚硝基的反式

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