PPh2Me-Promoted [4 + 3] Annulation for Synthesis of Quinazoline-Fused Benzothiadiazepines as Anti-Breast Cancer Agents.

A PPh2Me-promoted [4 + 3] annulation between benzo[c][1,2]dithiol-3-ones and quinazoline-derived azomethine imines for the facile synthesis of a novel quinazoline-fused benzothiadiazepine library is described. This transformation is characterized by its mild conditions and excellent functional group tolerance, affording 25 novel tetracyclic compounds in excellent yields (most >85%). The biological evaluation of the obtained tetracyclic products established the scaffold's promising preliminary anti-TNBC profile. The lead compound, 3ma, further demonstrated potent anti-migratory effects in wound healing and transwell assay, suggesting anti-metastatic potential. Preliminary mechanistic insights from molecular docking studies indicated binding affinity to the EGFR kinase active site, which provides a testable hypothesis for the mechanism of action.