Stereoselective synthesis of carbohydrate fused pyrano[3,2-c]pyranones as anticancer agents

Abstract

Pyrano[3,2-c]pyranone is an important structural motif present in many natural products exhibiting diverse biological activities. Two series of carbohydrate fused pyrano[3,2-c]pyranone derivatives (n = 20) were efficiently synthesized starting from 2-C-formyl galactal and 2-C-formyl glucal, reacting with various 4-hydroxycoumarins in a very short reaction time (10 min) under microwave assisted conditions. The anticancer activity of these synthesized pyrano[3,2-c]pyranones was determined in detail through cellular assays against MCF-7 (breast), MDA-MB-231 (breast) and HepG2 (liver) cancer cell lines. The newly synthesized pyrano[3,2-c]pyranones were screened for their cell-viability and anti-proliferative activity against MCF-7, MDA-MB-231 and HepG2 cell lines. Compounds 12, 13 and 14 exhibited high growth inhibitory potencies selectively against MCF-7 cells with half-maximal inhibitory concentration (IC50) values of 19.9, 14.5 and 10.9 μM respectively. Compounds 12, 13, 14, 15 and 19 inhibited the growth of MDA-MB-231 cells (breast) by 43, 44, 37, 31 and 45% respectively. However, no inhibitory effect was observed for these compounds in the human liver cancer cell line (HepG2) and normal cell lines (HEK293, human embryonic kidney cells). Mechanistic studies showed that these compounds alter the cell morphology and cause G2/M arrest in MCF-7. Further studies showed that compounds 12, 13 and 14 significantly inhibited cell migration which was accompanied by altered microtubule distribution. An enhanced accumulation of these compounds in cells was observed as compared to the 4-hydroxycoumarins precursor in the intracellular uptake assay. These findings confirm that carbohydrate fused pyrano[3,2-c]pyranones are better candidates for anticancer activity. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.