Abstract

A novel 3,4-dihydroisoquinol-1-one-4-carboxamide scaffold was designed as the basis for the development of novel inhibitors of poly(ADP-ribose) polymerase (PARP). Synthesis of 3,4-dihydroisoquinol-1-one-4-carboxylic acids was achieved using the previously developed protocol based on the modified Castagnoli-Cushman reaction of homophthalic anhydrides and 1,3,5-triazinanes as formaldimine synthetic equivalents. Employment of 2,4-dimethoxy groups on the nitrogen atom of the latter allowed preparation of 2,3-unsubatituted 3,4-dihydroquinolone core building blocks. Iterative synthesis and in vitro biological testing of the amides resulting from the amidation of these carboxylic acids allowed not only drawing important structure-activity generalisations (corroborated by in silico docking simulation) but also the identification of the lead compound, 4-([1,4'-bipiperidine]-1'-carbonyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one, as the candidate for further preclinical development. The lead compound as well as its des-fluoro analog were compared to the approved PARP1 inhibitor, anticancer drug Olaparib, in terms of their molecular characteristics defining druglikeness as well as experimentally determined ADME parameters. The newly developed series demonstrated clear advantages over Olaparib in terms of molecular weight, hydrophilicity, human liver microsomal and plasma stability as well as plasma protein binding. Further preclinical investigation of the lead compound is highly warranted.

摘要

一种新型 3,4-二氢异羟基喹啉-1-one-4-carboxamide 支架被设计为开发新型聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂的基础。3,4-二氢异喹啉-1-one-4-羧酸的合成是使用先前开发的协议实现的，该协议基于同邻苯二甲酸酐和 1,3,5-三嗪烷作为甲醛亚胺合成等价物的改良 Castagnoli-Cushman 反应。在后者的氮原子上使用 2,4-二甲氧基允许制备 2,3-未取代的 3,4-二氢喹诺酮核心构件。由这些羧酸的酰胺化产生的酰胺的迭代合成和体外生物测试不仅允许绘制重要的结构-活性概括（由in silico证实）对接模拟）以及先导化合物 4-([1,4'-bipiperidine]-1'-carbonyl)-7-fluoro-3,4-dihydroisoquinolin-1(2 H )-one的鉴定，作为进一步临床前开发的候选者。先导化合物及其脱氟类似物与获批的 PARP1 抑制剂、抗癌药物奥拉帕尼（Olaparib）进行了比较，比较了它们定义药物相似性的分子特征以及实验确定的 ADME 参数。新开发的系列在分子量、亲水性、人肝微粒体和血浆稳定性以及血浆蛋白结合方面表现出优于 Olaparib 的明显优势。非常有必要对先导化合物进行进一步的临床前研究。