Synthesis and cytotoxic activity of diosgenyl saponin analogues

Saponins are naturally occurring glycosides that are widely distributed in the plant kingdom and lower marine organisms. Saponins consist of a carbohydrate chain attached to either a steroid or triterpene aglycone. Diosgenyl saponins are among the most abundant steroidal saponins and have attracted much attention for a host of varying biological activities. In recent years, diosgenyl saponins have demonstrated anticancer activity in a variety of cancer cell lines. The antitumour effect of diosgenyl saponins is shown to be through apoptosis.;*Please refer to dissertation for diagrams.;Structural complexity and limited accessibility have led to a poor understanding of the mechanism of diosgenyl saponin anticancer activity. The position of attachment of moieties on the aglycone and the variety of the side chains are all factors that contribute to the complexity of a structure activity relationship study. Monosaccharide diosgenyl analogues bearing a 2-amino-2-deoxy-beta- D-glucopyranose containing a variety of substituents replacing the alpha- L-rhamnose residue have been designed and synthesized. This rhamnose residue is usually found at the 2-0-position of the inner glucose moiety for most diosgenyl saponins. Moderate cytotoxic activity is found for most analogues against neuroblastoma SK-N-SH cells, breast cancer MCF-7 cells, and cervical cancer HeLa cells. Mechanistically, diosgenyl saponin analogue A with R = Bz was able to induce cell cycle arrest at G1 phase in SK-N-SH cells, while, in contrast, induced cell cycle arrest at G2 phase in MCF-7 cells. Disaccharide diosgenyl analogues B bearing an alpha-L-rhamnopyranosyl moiety attached to the 4-OH of the 2-amino-2-deoxy-beta-D-glucopyranose residue containing a variety of substituents at the amino group have also been synthesized. The biological investigation of disaccharide analogues B is still underway.*...