Synthesis and structure–activity relationship study of cytotoxic germanicane- and lupane-type 3β-O-monodesmosidic saponins starting from betulin

Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydrosolubility and pharmacokinetics properties. In order to overcome this major problem, we synthesized and studied the in vitro anticancer activity of a series of 3β-O-monodesmosidic saponins derived from betulin (14–16), betulinic acid (20–22), allobetulin (23–28) and 28-oxoallobetulin (29–34) based on six different natural sugar residues (d-glucose, l-rhamnose, d-arabinose, d-galactose, d-mannose and d-xylose). This structure–activity relationship study confirmed that betulinic acid saponins are generally better in vitro anticancer agents than those derived from betulin with the exception of betulin 3β-O-α-d-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC50 ranging from 7.3 to 10.1 μmol/L. Furthermore, although the synthesis of novel germanicane-type saponins was carried out with success, the bioactivity measured for these glycosides was not as high as we anticipated since only the 3β-O-β-d-glucopyranoside and 3β-O-β-d-galactopyranoside of allobetulin (23, 24) showed moderate anticancer activity (IC50 30–40 μmol/L).

Starting from betulin (1) isolated from the outer bark of Betula papyrifera, we successfully synthesized a library of 3-O-monodesmosidic saponins (11–34) in order to enhance the hydrosolubility and the cytotoxicity of germanicane- and lupane-type triterpenes.Figure optionsDownload as PowerPoint slide