Synthesis and structure-activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid

Rita C Santos; Jorge A R Salvador; Silvia Marín; Marta Cascante; João N Moreira; Teresa C P Dinis

doi:10.1016/j.bmc.2010.04.085

Synthesis and structure-activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid

Bioorg Med Chem. 2010 Jun 15;18(12):4385-96. doi: 10.1016/j.bmc.2010.04.085. Epub 2010 Apr 29.

Authors

Rita C Santos¹, Jorge A R Salvador, Silvia Marín, Marta Cascante, João N Moreira, Teresa C P Dinis

Affiliation

¹ Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

PMID: 20494586
DOI: 10.1016/j.bmc.2010.04.085

Abstract

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Betulinic Acid
Carbamates / chemical synthesis
Carbamates / chemistry*
Carbamates / toxicity
Cell Line, Tumor
DNA Topoisomerases, Type I / metabolism
Drug Screening Assays, Antitumor
Heterocyclic Compounds / chemistry*
Humans
Pentacyclic Triterpenes
Structure-Activity Relationship
Topoisomerase I Inhibitors
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / toxicity
Triterpenes / chemical synthesis*
Triterpenes / chemistry*
Triterpenes / toxicity

Substances

2-hydroxy-28-(1H-triazol-1-yl)-lup-1,20(29)-dien-3,28-dione
28-(1H-triazol-1-yl)-28-oxo-lup-20(29)-en-3-yl-1H-triazole-1-carboxylate
Antineoplastic Agents
Carbamates
Heterocyclic Compounds
Pentacyclic Triterpenes
Topoisomerase I Inhibitors
Triazoles
Triterpenes
betulin
DNA Topoisomerases, Type I
Betulinic Acid