Tyrosinase-mediated cytotoxicity of 4-substituted phenols: Use of QSAR to forecast reactivities of thiols towards the derived ortho-quinones
Tyrosinase-mediated cytotoxicity of 4-substituted phenols: Use of QSAR to forecast reactivities of thiols towards the derived ortho-quinones
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DOI：
10.1002/qsar.19960150606
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发表时间：
1996-12-01
期刊：
影响因子：
--
通讯作者：
Riley, PA
中科院分区：
文献类型：
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作者：
Cooksey, CJ;Land, EJ;Riley, PA
某些4-取代的酚类可以表现为酪氨酸类似物，并经过酪氨酸酶催化氧化成细胞毒性的邻醌，后者与关键的细胞硫醇反应。这些酚类物质是恶性黑色素瘤化疗的潜在黑色素生成特异性前药。在此之前（Cooksey et al.（1995）抗癌药物设计，10,119），我们在有或没有巯基的情况下，通过在氧化条件下脉冲辐射分解相应的稳定儿茶酚，我们发现10个4-取代的邻醌的谷胱甘肽和半胱氨酸的反应活性与相应取代基的Hammett sigma(p)常数具有良好的相关性。从相应的儿茶酚开始，其中一种以前没有被描述过，我们现在研究了另外六种4取代的邻醌，包括两种取代基σ (p)值高于先前研究的邻醌。早期定量构效关系（QSAR）的外推正确地预测了这两种分别具有OCF3和CH2NH3+取代基的邻醌对硫醇的高反应活性。所有16种4-取代邻苯醌的数据，以及邻苯醌本身的数据，已经结合起来，提供了最新的，统计上显着的Hammett和Swain-Lupton相关性，包括使用这两种硫醇数据的多变量回归。这些关系表明，取代的邻醌与巯基反应时，速率常数随着取代基吸电子能力的增加而增加，这主要是由于共振效应，而场效应的贡献较小但也很显著。这种QSAR可能有助于设计改进的黑色素生成靶向抗黑色素瘤前药。
Certain 4-substituted phenols can behave as tyrosine analogues and undergo tyrosinase-catalysed oxidation to cytotoxic o-quinones which react with crucial cellular thiols. Such phenols are potential melanogenesis-specific pro-drugs for the chemotherapy of malignant melanoma. Previously (Cooksey et al. (1995) Anti-Cancer Drug Design, 10, 119), by pulse radiolysis under oxidative conditions of the corresponding stable catechols in the presence and absence of thiols, we showed that the glutathione and cysteine reactivities of ten 4-substituted o-quinones correlated well with the Hammett sigma(p) constants of the corresponding substituents. Starting from the corresponding catechols, one of which has not previously been described, we have now investigated six further 4-substituted o-quinones including two with substituent sigma(p) values higher than those previously studied. Extrapolation of the earlier quantitative structure - activity relationships (QSAR) correctly predicted the high reactivities of these two o-quinones, with respective substituents OCF3 and CH2NH3+, towards thiols. The data for all sixteen 4-substituted o-quinones, and for o-benzoquinone itself, have been combined to provide updated, statistically significant Hammett and Swain-Lupton correlations, including multivariate regressions using the data for both thiols. These relationships show that in reacting the substituted o-quinones with thiols, the rate constants increase with the electron withdrawing capacities of the substituent groups, this being principally due to the resonance effect, with a smaller but significant contribution attributable to the field effect. Such QSAR may facilitate the design of improved melanogenesis - targeted anti-melanoma pro-drugs.