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

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