title: Improvement of the cytotoxicity and tumor selectivity of glycyrrhetinic acid by derivatization with bifunctional amino acids.
abstract: Glycyrrhetinic acid (GA) is a major ingredient of the dried extract of licorice roots; its antitumor activity is low compared to other members of the triterpenoic family. For example, oleanolic acid, betulin or betulinic acid are more cytotoxic with a pronounced activity for tumor cells. GA, however, is easily to earn, cheap and shows apoptotic effects on tumor cells--like the other triterpenoic acids. These facts bring GA and derivatives in the focus of our scientific interest. Here we tried to improve the poor cytotoxicity of GA by simple derivatization. Thus, we selected various glutamyl and aspartyl substituents for the synthesis of C(3) esters of GA methyl ester. A short (3-5 steps) synthesis was elaborated that allowed to access more effective compounds. One compound, methyl 3β 3-(O-benzyl-L-glutamyl)-11-oxo-olean-12-en-30-oate (5), having a glutamyl substituent with a benzyl protected side chain showed up to 67-fold higher cytotoxicity and an up to 140-fold better selectivity towards tumor cells than parent GA. All compounds were evaluated by a sulforhodamine B assay as well as by a trypan blue test and extra acridine orange/ethidium bromide tests for apoptosis.
authors.affiliation: Martin-Luther-Universität Halle-Wittenberg, Bereich Organische Chemie, Halle (Saale), Germany. rene.csuk@chemie.uni-halle.de
authors.forename: René
authors.initials: R
authors.lastname: Csuk
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Ralph
authors.initials: R
authors.lastname: Kluge
authors.forename: Dieter
authors.initials: D
authors.lastname: Ströhl
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D006034:Glycyrrhetinic Acid