2. Academic Validation
  3. Synthesis, antiproliferative activities, and computational evaluation of novel isocoumarin and 3,4-dihydroisocoumarin derivatives

Synthesis, antiproliferative activities, and computational evaluation of novel isocoumarin and 3,4-dihydroisocoumarin derivatives

  • Eur J Med Chem. 2016 Mar 23:111:103-13. doi: 10.1016/j.ejmech.2016.01.051.
Keller G Guimarães 1,  Rossimiriam P de Freitas 1,  Ana L T G Ruiz 2,  Giovanna F Fiorito 2,  João E de Carvalho 2,  Elaine F F da Cunha 3,  Teodorico C Ramalho 3,  Rosemeire B Alves 4
Affiliations

Affiliations

  • 1 Laboratório de Síntese Orgânica (Labsinto), Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
  • 2 Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), Universidade Estadual de Campinas, Campinas, SP, CP 6171, 13083-970, Brazil.
  • 3 Laboratório de Química Computacional, Departamento de Química, Universidade Federal de Lavras, CP 3037, 37200-000, Lavras, MG, Brazil.
  • 4 Laboratório de Síntese Orgânica (Labsinto), Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil. Electronic address: rosebrondi@yahoo.com.br.
PMID: 26859070 DOI: 10.1016/j.ejmech.2016.01.051
Abstract

A series of novel isocoumarin derivatives were synthesized using Castro-Stephens cross-coupling. Moreover, novel 3,4-dihydroisocoumarin derivatives were obtained by catalytic hydrogenation of the corresponding isocoumarin precursors. The antiproliferative activity of all compounds was evaluated in vitro in different tumor cells. Furthermore, docking calculations were performed for the Kallikrein 5 (KLK5) active site to predict the possible mechanism of action of this series of compounds. Theoretical findings indicate that the 3,4-dihydroisocoumarin derivative 10a forms hydrogen bonds with Ser190 and Gln192 residues of KLK5. This derivative was the most active compound in the series with potent antiproliferative activity and high selectivity index (SI > 378.79) against breast Cancer cells (MCF-7, GI50 = 0.66 μg mL(-1)). This compound represents a promising matrix for developing new antiproliferative agents.

Keywords

3,4-Dihydroisocoumarin; Antiproliferative; Castro–Stephens reaction; Isocoumarin.

Figures