Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents

摘要: A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement noscapine’s southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing para-methoxybenzyl functionality N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase an EC50 2.7 μM MCF-7 breast-cancer cell line, 7-fold increase compared that noscapine (5). This molecule had similar activity (EC50 2.5 μM) against resistant NCI/AdrRES demonstrating its potential overcome or avert known resistance mechanisms, unlike current agents. Compound 18g found modify drug-efflux P-gp and, combination studies, potentiate antiproliferative vinblastine. These results provide insights into structural modifications will guide future development toward more potent agents are active agains...