2. Academic Validation
  3. Design, synthesis and biological evaluation of novel C-29 carbamate celastrol derivatives as potent and selective cytotoxic compounds

Design, synthesis and biological evaluation of novel C-29 carbamate celastrol derivatives as potent and selective cytotoxic compounds

  • Eur J Med Chem. 2017 Oct 20:139:836-848. doi: 10.1016/j.ejmech.2017.08.058.
Sandra A C Figueiredo 1,  Jorge A R Salvador 2,  Roldán Cortés 3,  Marta Cascante 4
Affiliations

Affiliations

  • 1 Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Centre for Neuroscience and Cell Biology, Coimbra, Portugal.
  • 2 Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Centre for Neuroscience and Cell Biology, Coimbra, Portugal. Electronic address: salvador@ci.uc.pt.
  • 3 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.
  • 4 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain. Electronic address: martacascante@ub.edu.
PMID: 28865279 DOI: 10.1016/j.ejmech.2017.08.058
Abstract

Celastrol and its derivatives have been reported for their potent Anticancer activity. Among Other celastrol analogues, novel carbamate derivatives were designed and synthesised, and their biological activity on the viability of human Cancer cell lines was evaluated. Additionally, a preliminary structure-activity relationship study was conducted. Derivative 18 showed the highest activity on Cancer cell viability, combined with the best selectivity between malignant cells and non-malignant fibroblasts. Preliminary mechanistic studies of its anti-tumour action indicated that compound 18 has an antiproliferative effect on SKOV-3 human ovarian Cancer cells (IC50 = 0.54 μM). The results also suggested that its potent Anticancer activity is mediated by Apoptosis, and that this process was mainly the result of the activation of the extrinsic apoptotic pathway. Moreover, our results demonstrated the potential of derivative 18 as a new agent for combinatorial drug therapy for ovarian Cancer.

Keywords

Apoptosis; Carbamates; Celastrol; Cytotoxicity; Drug synergy; Triterpenes.

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