Effect of C-ring modifications on the cytotoxicity of spirostan saponins and related glycosides.
Twelve C-ring modified spirostanyl glycosides were synthesized and evaluated for their cytotoxicity against the human myeloid leukemia cell line (HL-60). With the aim of assessing the influence of the hydrophobic character, the conformational flexibility and the stereochemistry of the C-ring functionalities on the cytotoxic activity, a variety of spirostanic aglycones incorporating methylene, methoxyl, α,β-unsaturated ketone and lactone groups were subjected to a linear glycosylation strategy leading to glycosides derived from the 3,6-dipivaloylated β-D-glucoside and the β-chacotrioside moieties. The 3,6-dipivaloylated spirostanyl β-D-glucosides showed moderate to good cytotoxic activity against HL-60, but no significant cytotoxicity against benign blood cells. However, the cytotoxicity of spirostanyl β-chacotriosides was highly dependent on the nature of the C-ring functional groups of the steroidal aglycones. Actually, the chacotrioside-based saponins either with no functionality or bearing a hydrophobic methylene group at C-12 were the most cytotoxic ones against both HL-60 and benign blood cells. On the other hand, the incorporation of very polar functionalities and the opening of the ring C with the consequent loss of rigidity led to a significant drop in the cytotoxicity against HL-60. These results confirm that spirostanyl β-chacotriosides including very lipophilic aglycones are the most cytotoxic ones among their congeners.
Institute of Pharmacy and Food, University of Havana, San Lázaro y L, 10400 La Habana, Cuba.
Karell
K
Pérez-Labrada
Ignacio
I
Brouard
Sara
S
Estévez
María Teresa
MT
Marrero
Francisco
F
Estévez
Daniel G
DG
Rivera
D002470:Cell Survival / Q000187:drug effects; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018922:HL-60 Cells; D006801:Humans; D012503:Saponins / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013150:Spirostans / Q000737:chemistry*; D013329:Structure-Activity Relationship
D006027:Glycosides; D012503:Saponins; D013150:Spirostans