LAUSR

A set of 41 glycosidic conjugates of pentacyclic triterpenes was synthesized in order to improve the solubility of highly cytotoxic parent compounds. Their in vitro cytotoxic activity was evaluated in 25 cancer cell lines and two non-cancer fibroblasts. Fifteen compounds had high cytotoxicity on T-lymphoblastic leukemia cell line CCRF-CEM and six of them were active in multiple cell lines of various histogenetic origin and not toxic in fibroblasts. Compound 11a had IC50 of 0.64 μM in CCRF-CEM cells, 0.60 μM in K-562 cells and 0.37 μM in PC-3 cells; compound 12a had IC50 of 0.64 μM in CCRF-CEM cells and 0.71 μM in SW620 cells; compound 17b had IC50 of 0.86 μM in HCT116 cells and 0.92 μM in PC-3 cells. Compounds 11b and 12b were slightly less active than the previously mentioned derivatives, however, their solubility was significantly better and therefore they were selected for the in vivo evaluation of the pharmacokinetic profile in mice. In both compounds, the maximum concentration in plasma was achieved very fast - the highest level in plasma was found one hour after administration (22.2 resp. 6.4 μmol/L). For compound 12b, the resorption is followed with fast elimination and 12 hours after administration, the compound was not detected in plasma. In contrast, compound 11b was being eliminated slower it was still present in plasma after 12 h but its concentration drops below the detection limit after 24 h. Elimination half-time determined for compound 11b is 2,4 h and for compound 12b just about 1.4 hour. These values are reasonable for further drug development.