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Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents

Authors
Journal
Bioorganic & Medicinal Chemistry
0968-0896
Publisher
Elsevier
Publication Date
Volume
14
Issue
19
Identifiers
DOI: 10.1016/j.bmc.2006.05.075
Keywords
  • Triterpenes
  • Betulinic Acid
  • Glycosides
  • Cytotoxicity
Disciplines
  • Biology
  • Pharmacology

Abstract

Abstract 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 (β- d-glucosides, α- l-rhamnosides, and α- 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-β- d-glucosidation of lupeol ( 1) improved the activity by 7- to 12-fold (IC 50 14–15.0 μM). Moreover, the results showed that cancer cell lines are 8- to 12-fold more sensitive to the 3- O-α- l-rhamnopyranoside derivative of betulinic acid (IC 50 2.6–3.9 μM, 22) than the healthy cells (IC 50 31 μM). Thus, this study indicates that 3- O-glycosides of lupane-type triterpenoids represent an interesting class of potent in vitro cytotoxic agents.

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