Synthesis of flavonoids based novel tetrahydropyran conjugates (Prins products) and their antiproliferative activity against human cancer cell lines

•Novel flavonoids based 4-tosyloxy, 4-hydroxy and 4-cinnamoyl THPs were synthesized.•Compounds 3a, 3f, 3q, 3s and 3zb showed good to moderate cytotoxicity against the MCF-7 cells.•Compounds 3c, 3zb showed good cytotoxicity against the Hep3β cells.•Compounds 3c and 3q showed good cytotoxicity against the HeLa cells.

Following our previously reported Prins cyclization strategy, a series of novel and highly functionalized flavonoid based THPs (Prins products) were designed, synthesized and evaluated for their antiproliferative activity. Novel products were afforded in excellent yields (72–96%) within 20–90 min at 62 °C using flavonoid aldehydes, homoallylic alcohols, p-TSA·H2O (catalyst and reagent) and MS 4 Å in CHCl3. Deprotection of tosyl group was achieved with TFA (catalyst and solvent) at 140 °C to obtain 4-hydroxytetrahydropyrans and further reaction of 4-hydroxytetrahydropyrans with cinnamoyl chloride afforded 4-cinnamate tetrahydropyrans under neat condition. Synthesized compounds evaluated against human cancer cell lines (Hep3β, MCF-7 and Hela), have shown moderate to good antiproliferative activity in vivo. Compounds 3q and 3zb exhibited similar cytotoxicity (IC50 6.6 ± 1.4, 6.9 ± 1.0 μM, respectively) to the reference drug doxorubicin (IC50 7.6 ± 0.9 μM) against the MCF-7 cancer cell line. Compound 3zb was found equally active as the standard drug (IC50 4.48 ± 2.1 μM) against the Hep3β cell line and compounds 3c and 3q showed moderate cytotoxicity (IC50 10.40 ± 1.1, 12.9 ± 1.7 μM, respectively) against the HeLa cell line.

Graphical abstractFlavonoid–THP conjugates were synthesized and screened for their antiproliferative activity. Compounds 3q and 3zb have shown similar cytotoxic activity (IC50 6.6 ± 1.4, 6.9 ± 1.0 μM respectively) as doxorubicin (IC50 7.6 ± 0.9 μM) against the MCF-7. Compound 3zb showed excellent cytotoxicity against the Hep3β cells.Figure optionsDownload full-size imageDownload as PowerPoint slide