Synthesis and structure-activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid.
Chemical transformation studies were conducted on betulin and betulinic acid, common plant-derived lupane-type triterpenes. The concise synthesis, via a stepwise approach, of betulin and betulinic acid carbamate and N-acylheterocyclic containing derivatives is described. All new compounds, as well as betulinic acid were tested in vitro for their cytotoxic activity. Most of the compounds have shown a better cytotoxic profile than betulinic acid, including the synthesized betulin derivatives. Compounds 25 and 32 were the most promising derivatives, being up to 12-fold more potent than betulinic acid against human PC-3 cell lines (IC(50) values of 1.1 and 1.8 microM, respectively).
Santos
Rita C
RC
Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
Salvador
Jorge A R
JA
Marín
Silvia
S
Cascante
Marta
M
Moreira
João N
JN
Dinis
Teresa C P
TC
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D053978:Pentacyclic Triterpenes; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D000094062:Betulinic Acid
C552766:2-hydroxy-28-(1H-triazol-1-yl)-lup-1,20(29)-dien-3,28-dione; C552765:28-(1H-triazol-1-yl)-28-oxo-lup-20(29)-en-3-yl-1H-triazole-1-carboxylate; D000970:Antineoplastic Agents; D002219:Carbamates; D006571:Heterocyclic Compounds; D053978:Pentacyclic Triterpenes; D059004:Topoisomerase I Inhibitors; D014230:Triazoles; D014315:Triterpenes; C002503:betulin; D004264:DNA Topoisomerases, Type I; D000094062:Betulinic Acid