Yadav Mukul, Roy Nibedita, Mandal Kartik, Nagpure Mithilesh, Santra Manas K, Guchhait Sankar K
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab 160062, India.
National Centre for Cell Science, NCCS Complex, Pune University Campus Ganeshkhind, Pune, Maharastra 411007, India.
Bioorg Med Chem. 2024 Jul 15;109:117799. doi: 10.1016/j.bmc.2024.117799. Epub 2024 Jun 13.
Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.
从历史角度来看，以天然产物作为起始模板对药物开发做出了重大贡献。受抗癌天然生物碱吴茱萸次碱的结构-功能启发，研究了具有“N”原子转换（一级跳跃）和开环（二级跳跃）的吴茱萸次碱骨架跳跃无环类似物（SAAR）。开发了一种新的合成路线以有效获得这些类似物，即2-吲哚基-吡啶并[1,2-a]嘧啶酮，该路线包括制备N-Boc-N'-邻苯二甲酰色胺/美沙明溴化物和吡啶并嘧啶酮-2-基三氟甲磺酸酯，这些溴化物和三氟甲磺酸酯的镍/钯催化乌尔曼交叉偶联，邻苯二甲酰亚胺的脱保护，随后进行N-芳酰化，以及Boc-脱保护。制备了14种新型SAAR化合物，它们对各种癌细胞表现出特征性的抗增殖活性。三种活性最高的化合物（11a、11b和11c）表现出良好的抗增殖活性，对人乳腺腺癌细胞（MCF-7）、肺癌细胞（A549）和结肠癌细胞（HCT-116）的IC50为7.7 - 15.8 μM。在集落形成试验中也观察到了抗增殖特性。发现SAAR化合物11b在抗增殖活性方面比天然产物吴茱萸次碱和抗癌药物5-FU具有更高的效力，对正常乳腺上皮细胞（MCF10A）的细胞毒性相对较低，对癌细胞迁移的抑制作用明显更高。发现化合物11b具有良好的计算机模拟物理化学特性（亲脂性-MLOGP、TPSA和水溶性-ESOL等）、生物利用度评分和药代动力学性质（胃肠道吸收、血脑屏障不通透、P-糖蛋白和CYP2D6）。有趣的是，化合物11b未显示出任何PAINS和Brenk过滤器的药物化学结构警报。该研究首次成功地以吴茱萸次碱天然生物碱为起始模板发现了新的强效抗癌化学类型，并再次证实了天然产物启发的骨架跳跃技术在药物发现研究中的重要性。
