Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors.
Shaun W P Rees, Tayla A Rees, Emily K Paulin, Olivia R Arnerich, Euphemia Leung, Christopher S Walker, David Barker, Lisa I Pilkington
{"title":"Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors.","authors":"Shaun W P Rees, Tayla A Rees, Emily K Paulin, Olivia R Arnerich, Euphemia Leung, Christopher S Walker, David Barker, Lisa I Pilkington","doi":"10.1039/d4md00831f","DOIUrl":null,"url":null,"abstract":"<p><p>Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5-<i>N</i>-benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the <i>N</i>-benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLC<sub>BC</sub> enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5-<i>N</i>-benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic <i>N</i>-methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734694/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1039/d4md00831f","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5-N-benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the N-benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLCBC enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5-N-benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic N-methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.
胆碱磷脂代谢失调和磷脂酰胆碱特异性磷脂酶C (PC-PLC)的过度表达与多种癌症有关。目前已知的酶抑制剂包括基于2-morpholino-5- n -苄基苯甲酸或羟肟酸支架的化合物。本研究通过对该核心结构进行修饰,合成了81个药效团化合物。具体来说,这些新化合物是由中心环取代模式、烷基杂环和n -苄基桥甲基化的变化引起的。合成的化合物对肿瘤细胞株MDA-MB-231和HCT116的抗增殖活性进行了评价。还评估了PC-PLCBC酶抑制,并使用微粒体稳定性测定法开始了药代动力学谱的开发。研究结果证实,最佳药效团是2-morpholino-5-N-benzylamino苯甲酸,或酸衍生物,支架,并且该分子家族在大鼠微粒体处理后表现出高度的稳定性。此外,苯基n甲基化化合物是最具生物活性的化合物,鼓励进一步研究药效团的这一区域。