Talukdar Dipjyoti, Panda Subhankar, Borah Rituparna, Manna Debasis
Department of Chemistry, Indian Institute of Technology , Guwahati, Assam 781039, India.
J Phys Chem B. 2014 Jul 10;118(27):7541-7553. doi: 10.1021/jp5044305. Epub 2014 Jun 26.
Protein kinase C (PKC)-C1 domain targeted regulator development is considered as a potential therapeutic strategy for the treatment of cancer and immunological and other diseases. Efforts are underway to synthesize small molecules to achieve higher specificity for the C1-domain than the natural activator, diacylglycerols (DAGs). In this regard, we conveniently synthesized 4-hydroxy-3-(hydroxymethyl) phenyl ester analogues and measured in vitro C1-domain binding properties. We also investigated different physicochemical properties of the synthesized molecules, including aggregation behavior in aqueous solution and interaction with lipid bilayers, and others with an aim for better understanding of their C1-domain binding properties. The results showed that the membrane-active compounds aggregate in aqueous solution at a reasonably lower concentration and strongly interact with the lipid bilayer. The hydrophilic part of the compounds localize at the bilayer/water interface and accessible for C1-domain binding. Biophysical studies revealed that the hydroxyl, hydroxymethyl, and carbonyl groups and acyl chain length are important for their interaction with the C1-domain. The potent compound showed more than 10-fold stronger binding affinity for the C1-domains than DAG under similar experimental conditions. Therefore, our findings reveal that these ester analogues represent an attractive group of C1-domain ligands that can be further structurally modified to improve their binding and activity.
蛋白激酶C（PKC）-C1结构域靶向调节剂的开发被认为是治疗癌症、免疫疾病及其他疾病的一种潜在治疗策略。目前正在努力合成小分子，以实现比天然激活剂二酰基甘油（DAGs）对C1结构域更高的特异性。在这方面，我们方便地合成了4-羟基-3-（羟甲基）苯基酯类似物，并测定了其体外C1结构域结合特性。我们还研究了合成分子的不同物理化学性质，包括在水溶液中的聚集行为以及与脂质双层的相互作用等，旨在更好地理解它们的C1结构域结合特性。结果表明，具有膜活性的化合物在水溶液中以相对较低的浓度聚集，并与脂质双层强烈相互作用。化合物的亲水部分定位在双层/水界面，可用于C1结构域结合。生物物理研究表明，羟基、羟甲基、羰基和酰基链长度对它们与C1结构域的相互作用很重要。在类似实验条件下，强效化合物对C1结构域的结合亲和力比DAG强10倍以上。因此，我们的研究结果表明，这些酯类似物代表了一组有吸引力的C1结构域配体，可以进一步进行结构修饰以改善其结合和活性。
