| This thesis describes the chemical synthesis and the in vitro evaluation of the anticancer and haemolytic activities of natural and non-natural lupane-type triterpenoid saponins. On the one hand, two naturally occurring betulinic acid saponins isolated from Chinese medicinal plants bearing an alpha-L-rhamnopyranosyl-(1→2)-alpha- L-arabinopyranose moiety, a library of eight bidesmosidic saponins with betulin and betulinic acid as aglycones as well as five lupane- and germanicane-type chacotriosidic derivatives have been synthesized via the use of different glycosylation methods such as Schmidt's normal and inverse procedures and phase-transfert conditions. On the other hand, structure-activity relationship study reveals that highly polar sugar moieties at the C-3 position of the lupane skeleton have a negative impact on the anticancer activity while the activity is increased for the germanicane-type triterpenoids. Otherwise, the presence of an L-rhamnose moiety at the same position increases the cytotoxicity of lupane-type saponins such as betulin 3,28-O-bis-alpha- L-rhamnopyranoside, which exhibited a strongly potent in vitro anticancer activity against the cell lines from the most prevalent human cancers (IC50 = 1.7-1.9 mumol•L-1). Contrary to naturally occurring oleanane-type saponins, most of the lupane-type saponins and parent triterpenoids betulin and betulinic acid do not induce any haemolytic activity against sheep red blood cells (HD50 >100 mumol•L -1) independently of the nature of the sugar moieties. Also, 28- O-beta-D-glucuronide betulinic acid, which is an acyl glucuronide metabolite, has been efficiently synthesized and could be used as an anticancer prodrug according to prodrug monotherapy strategy. |
