Synthesis, conformational analysis and SAR research of OSW-1 analogues

A series of novel OSW-1 analogues were synthesized by coupling disaccharides (2-O-4-methoxylbenzoyl-β-d-xylopyranosyl-(1→3)-2-O-acetyl-α-l-arabinopyranosyl) or (2-O-4-(E)-cinnamoyl-β-d-xylopyranosyl-(1→3)-2-O-acetyl-α-l-arabinopyranosyl) and their 1→4 linked analogues [(2-O-4-methoxylbenzoyl-β-d-xylopyranosyl-(1→4)-2-O-acetyl-α-l-arabinopyranosyl) or (2-O-4-(E)-cinnamoyl-β-d-xylopyranosyl-(1→4)-2-O-acetyl-α-l-arabinopyranosyl)] with three different steroidal sapogenins at 16β-hydroxy. Their conformation was analyzed with NMR spectroscopy and molecule simulation. The arabinose moiety of 1-3 linked analogues was in chair conformation and 1-4 linked analogues was in boat conformation. 1-3 linked analogues exhibited potent anti-proliferation activity against a panel of human tumor cells at nanomolar concentration level, while 1-4 linked analogues did not show antitumor activity. This work should provide an evidence that the conformation plays an important role in the antitumor activity.

Graphical abstractDownload high-res image (133KB)Download full-size imageThe highest antiproliferative activity was displayed by compounds containing 1-3 linked disaccharide which had convergent structures at nanomolar concentrations level. 1-4 linked analogues which had divergent structures showed a lower activity. The key role of triangular molecular shape of 1-3 linked OSW-1 analogues for the high activity was confirmed.