Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: Structure and antimalarial and antiproliferative activity

Cholic acid-derived 1,2,4,5-tetraoxanes were synthesized in order to explor e the influence of steroid carrier on its antimalarial and antiproliferativ e activity in vitro. Starting with chiral ketones, cis and trans series of diastereomeric tetraoxanes were obtained, and the cis series was found to b e similar to 2 times as active as the trans against Plasmodium falciparum D G and W2 clones. The same tendency was observed against human melanoma (Fem -X) and human cervix carcinoma (HeLa) cell lines. The amide C(24) termini, for the first time introduced into the carrier molecule of a tetraoxane pha rmacophore, significantly enhanced both antimalarial and antiproliferative activity, as compared to the corresponding methyl esters, with cis-bis(N-pr opylamide) being most efficient against the chloroquine-susceptible D6 clon e (IC50 = 9.29 nM). cis- and trans-bis(N-propylamides) were also screened a gainst PBMC, and PRA-stimulated PBMC, showing a cytotoxicity/antimalarial p otency ratio of 1/10 000.