Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy
Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy
复制标题
DOI：
10.1016/s0304-4165(97)00115-3
复制
发表时间：
1998-03-02
影响因子：
3
通讯作者：
Manfait, M
中科院分区：
文献类型：
--
作者：
Chourpa, I;Millot, JM;Manfait, M
由20-S-喜树碱（CPT）和许多衍生物表现出的有效的抗肿瘤活性是已知的失去后，这些药物的α-羟基-内酯环的开放，在中性和碱性pH值下可水解。为了量化在“真实的时间”的生理条件下的CPTs的内酯水解反应，我们已经应用了非扰动的荧光光谱法的方法。CPT及其衍生物已经研究了具有从可忽略到CPT的10倍的抗肿瘤活性的（21-内酰胺-S-CPT、10，11-（亚甲二氧基）-CPT、CPT-11、SN-38、托泊替康、三环酮-CPT）。在动力学测量之前，研究了取代、pH、分子环境的极性、通过紫外-可见吸收光谱和荧光发射光谱研究了CPTs的内酯开环（内酯-羧酸酯转变）。然后，已使用对应于各自内酯和羧酸盐形式的荧光发射光谱的测定参数来估计作为时间函数的残留内酯百分比。所获得的数据的再现性表明，光谱方法提供了一个令人满意的精度为这种测量。对于pH 7.3的CPT，内酯半衰期为29.4 +/- 1.7 min，平衡时内酯百分比为20.9 +/-0.3%。在一系列喹啉环取代的衍生物中，内酯半衰期为29 - 32 min，平衡内酯含量为15%-23%。对于每种化合物，即使pH值从7.1稍微增加到7.3或从7.3增加到7.6，逻辑上也会导致内酯半衰期和平衡内酯百分比显着降低。(C)1998年Elsevier Science B.V.
Potent antitumor activity exhibited by 20-S-camptothecin (CPT) and numerous derivatives is known to be lost upon opening of the alpha-hydroxy-lactone ring of these drugs, hydrolyzable at neutral and basic pH. To quantify in 'real time' the lactone hydrolysis reaction in CPTs under physiological conditions, we have applied a non-perturbing approach by fluorescence spectroscopy. CPT and a set of its derivatives (21-lactam-S-CPT, 10,11-(methylenedioxy)-CPT, CPT-11, SN-38, topotecan, tricyclic ketone-CPT) with antitumor activity varying from negligible to 10 times that of CPT have been studied, Prior to the kinetic measurements, the effects of substitutions, pH, polarity of molecular environment, lactone ring opening (lactone-carboxylate transition) have been investigated in terms of the UV-visible absorption and fluorescence emission spectra of CPTs. Then the determined parameters of the fluorescence emission spectra corresponding to the respective lactone and carboxylate forms have been used to estimate the residual lactone percentage as a function of time. The reproducibility of the obtained data demonstrates that the spectroscopic approach provides a satisfactory precision for this kind of measurements. For CPT at pH 7.3, the lactone half-life was 29.4 +/- 1.7 min and the lactone percentage at equilibrium was 20.9 +/- 0.3%, Within a series of derivatives with substitutions at quinoline rings, the lactone half-life varied from 29 to 32 min and the equilibrium lactone content varied from 15% to 23%. For each compound, even slight increase of pH from 7.1 to 7.3 or from 7.3 to 7.6 logically leads to a remarkable decrease of both lactone half-life and equilibrium lactone percentage. (C) 1998 Elsevier Science B.V.