Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents.
The weak hydrosolubility of betulinic acid (3) hampers the clinical development of this natural anticancer agent. In order to circumvent this problem and to enhance the pharmacological properties of betulinic acid (3) and the lupane-type triterpenes lupeol (1), betulin (2), and methyl betulinate (7), glycosides (beta-D-glucosides, alpha-L-rhamnosides, and alpha-D-arabinosides) were synthesized and in vitro tested for cytotoxicity against three cancerous (A-549, DLD-1, and B16-F1) and one healthy (WS1) cell lines. The addition of a sugar moiety at the C-3 or C-28 position of betulin (2) resulted in a loss of cytotoxicity. In contrast, the 3-O-beta-D-glucosidation of lupeol (1) improved the activity by 7- to 12-fold (IC50 14-15.0 microM). Moreover, the results showed that cancer cell lines are 8- to 12-fold more sensitive to the 3-O-alpha-L-rhamnopyranoside derivative of betulinic acid (IC50 2.6-3.9 microM, 22) than the healthy cells (IC50 31 microM). Thus, this study indicates that 3-O-glycosides of lupane-type triterpenoids represent an interesting class of potent in vitro cytotoxic agents.
Gauthier
Charles
C
Laboratoire LASEVE, Département des Sciences Fondamentales, UQAC, Chicoutimi, Québec, Canada G7H 2B1.
Legault
Jean
J
Lebrun
Maxime
M
Dufour
Philippe
P
Pichette
André
A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D029662:Betula / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D051379:Mice; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000094062:Betulinic Acid; D000094042:Lupanes
D000972:Antineoplastic Agents, Phytogenic; D006027:Glycosides; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid; C480546:lupane; C002503:betulin; C010480:lupeol; D000094042:Lupanes