Synthesis of new chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives via domino Knoevenagel–hetero-Diels–Alder reactions and their biological evaluation towards antiproliferative activity

Abstract

A new series of chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives have been synthesized by intramolecular [4 + 2] domino Knoevenagel–hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes derived in situ from 1,3-dicarbonyls/active methylenes and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones in the presence of 20 mol% ethylenediamine diacetate (EDDA) in acetonitrile under reflux conditions in good to excellent yields. The structures were established based on spectroscopic data, and were further confirmed by X-ray diffraction analysis. These compounds were evaluated for their anti-proliferative activity using an in vitro MTT cytotoxicity assay. The results clearly demonstrated that compounds 4a, 4b, 4c, 4j, 4k, 4l, 4m and 4n exhibited significant anti-proliferative activity against human A549 lung cancer and non-cancer MRC-5 cell lines along with potent inhibitory activity against human neuroblastoma SK-N-SH cancer cell lines. Among these, compounds 4a, 4b and 4j displayed the most potent anti-proliferative activity against human lung cancer A549 cell lines, while 4a and 4b displayed against neuroblastoma SK-N-SH cancer cell lines when compared to the standard doxorubicin.