title: Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin.
abstract: 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 3beta-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 3beta-O-alpha-d-mannopyranoside (15) which exerted a potent cytotoxic activity against lung carcinoma (A-549) and colorectal adenocarcinoma (DLD-1) human cell lines with IC(50) ranging from 7.3 to 10.1mumol/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 3beta-O-beta-d-glucopyranoside and 3beta-O-beta-d-galactopyranoside of allobetulin (23,24) showed moderate anticancer activity (IC(50) 30-40 micromol/L).
authors.affiliation: Laboratoire d'Analyse et de Séparation des Essences Végétales, Département des Sciences Fondamentales, Université du Québec à Chicoutimi, 555 boul. de l'Université, Chicoutimi, Québec, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Thibeault
authors.forename: Charles
authors.initials: C
authors.lastname: Gauthier
authors.forename: Jean
authors.initials: J
authors.lastname: Legault
authors.forename: Jimmy
authors.initials: J
authors.lastname: Bouchard
authors.forename: Philippe
authors.initials: P
authors.lastname: Dufour
authors.forename: André
authors.initials: A
authors.lastname: Pichette
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D029662:Betula / Q000737:chemistry; D002478:Cells, Cultured / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D012503:Saponins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry*; D053978:Pentacyclic Triterpenes; D000094062:Betulinic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012503:Saponins; D014315:Triterpenes; C480546:lupane; D053978:Pentacyclic Triterpenes; C002503:betulin; D000094062:Betulinic Acid