The Pathobiochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Curr Med Chem. 2010;17(4):321-33. doi: 10.2174/092986710790192703.
Compound lipophilicity connected to ADME(T)(a) has great importance in drug development and it has to be evaluated by the generally used drug developmental process. In addition to the importance of lipophilicity in ADMET, recently it has been reported that lipophilicity of small molecules correlates with their antiproliferative activity because of certain specific hydrophobic and lipophilic interactions. Due to the complexity of ADME(T) parameters an efficient and fast method is needed to characterize the many promising candidate lead molecules as a preselection in order not to be rejected from the latter phase of drug development. In the present paper we provide an overview of the importance of lipophilicity of drug candidates for biological action and for ADME(T) and describe a novel approach for drug-likeness characterization of a molecular library using correlation study between lipophilicity and biological activity. Lipophilicity and molecular characteristics have been measured, predicted and optimized for a diverse library from which the best members have been selected to describe their biological, chemical and drug-likeness properties. Molecules were selected from the family of alpha,beta-unsaturated ketones and thorough HPLC characterization for lipophilicity and morphological, antiproliferative and flow cytometric studies were carried out on them. Based on the results 17 member isochromanone library including E and Z geometric isomers were selected for further characterization. In this focused library linear correlation has been found between the calculated and measured lipophilicity and significant parabolic correlation was found between the antiproliferative effect and lipophilicity. Using our efficient and fast method, from a diverse library, we identified an outstandingly effective inhibitor of A431 tumour cell growth via a PARP(a) cleavage dependent apoptosis. In summary the optimized HPLC analyses of lipophilicity combined with the cell-culture assay, introduced above, resulted in the determination of an optimal lipophilicity range. This optimized lipophilicity range should be used in designing novel antiproliferative compounds.
化合物的亲脂性与 ADME（T）（a）密切相关，在药物开发中具有重要意义，必须通过通常使用的药物开发过程进行评估。除了亲脂性在 ADMET 中的重要性外，最近有报道称，小分子的亲脂性与其抗增殖活性相关，因为存在某些特定的疏水和亲脂相互作用。由于 ADME（T）参数的复杂性，需要一种高效快速的方法来表征许多有前途的候选先导化合物，作为预筛选，以免在药物开发的后期阶段被淘汰。在本文中，我们提供了一个概述，说明了候选药物的亲脂性对生物活性和 ADME（T）的重要性，并描述了一种使用亲脂性与生物活性之间的相关研究来描述分子文库药物相似性特征的新方法。已经测量、预测和优化了来自多样化文库的亲脂性和分子特性，从该文库中选择了最佳成员来描述它们的生物学、化学和药物相似性特性。从α，β-不饱和酮家族中选择了分子，并对其进行了彻底的 HPLC 亲脂性表征，并对其进行了形态学、抗增殖和流式细胞术研究。基于这些结果，选择了 17 个异苯并二氢吡喃酮库成员，包括 E 和 Z 几何异构体，用于进一步表征。在这个重点文库中，发现计算和亲脂性之间存在线性相关性，并且在抗增殖作用和亲脂性之间发现了显著的抛物线相关性。使用我们的高效快速方法，从一个多样化的文库中，我们通过 PARP（a）依赖性凋亡鉴定了一种对 A431 肿瘤细胞生长具有显著抑制作用的抑制剂。总之，上述优化的 HPLC 亲脂性分析与细胞培养测定相结合，确定了最佳的亲脂性范围。该最佳亲脂性范围应用于设计新型抗增殖化合物。
