The chemical structures of sulfated NSGMs 43 and 44, two molecules identified in a dual-filter screening protocol as selective inhibitors/antagonists of colon cancer stem cells in HT29 and HCT116 cell lines. Molecule 43 is a dodecasulfated hexasubstituted inositol derivative whereas molecule 44 is an octasulfated flavonoid homodimer derivative. These molecules, in addition to 32, downregulated several cancer stem cell markers and self-renewal factors. A three-step molecular dynamics-based algorithm indicated that the dimeric flavonoid-based NSGM 44 mimics hexameric GAG sequences including HS06 45 in the protein-bound state which selectively inhibited cancer stem cells self-renewal and induced apoptosis in colorectal, pancreatic, and breast cancer stem cells through a specific early and sustained activation of p38α/β MAPK.