Journal of
Medicinal Plants Research

  • Abbreviation: J. Med. Plants Res.
  • Language: English
  • ISSN: 1996-0875
  • DOI: 10.5897/JMPR
  • Start Year: 2007
  • Published Articles: 3672

Full Length Research Paper

Morelloflavone and its semisynthetic derivatives as potential novel inhibitors of cysteine and serine proteases

Vanessa Silva Gontijo
  • Vanessa Silva Gontijo
  • Department of Exact Science, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Jaqueline Pereira Januario
  • Jaqueline Pereira Januario
  • Department of Exact Science, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Wagner Alves de Souza Judice
  • Wagner Alves de Souza Judice
  • Interdisciplinary Center of Biochemical Investigation, Mogi das Cruzes University, Mogi das Cruzes, SP, Brazil.
  • Google Scholar
Alyne Alexandrino Antunes
  • Alyne Alexandrino Antunes
  • Interdisciplinary Center of Biochemical Investigation, Mogi das Cruzes University, Mogi das Cruzes, SP, Brazil.
  • Google Scholar
Ingridy Ribeiro Cabral
  • Ingridy Ribeiro Cabral
  • Department of Exact Science, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Diego Magno Assis
  • Diego Magno Assis
  • Department of Biophysics, Federal University of Sao Paulo, SP, Brazil.
  • Google Scholar
Maria Aparecida Juliano
  • Maria Aparecida Juliano
  • Department of Biophysics, Federal University of Sao Paulo, SP, Brazil.
  • Google Scholar
Ihosvany Camps
  • Ihosvany Camps
  • Department of Biological Sciences, Laboratory of Molecular Biology, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Marcos Jose Marques
  • Marcos Jose Marques
  • Department of Biological Sciences, Laboratory of Molecular Biology, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Claudio Viegas Junior
  • Claudio Viegas Junior
  • Department of Exact Science, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, MG, Brazil.
  • Google Scholar
Marcelo Henrique dos Santos*
  • Marcelo Henrique dos Santos*
  • Department of Exact Science, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, MG, Brazil.
  • Google Scholar


  •  Received: 09 October 2014
  •  Accepted: 11 March 2015
  •  Published: 03 April 2015

Abstract

This article reports the three biflavonoids isolated from the fruit pericarp of Garcinia brasiliensis Mart. (Clusiaceae): Morelloflavone-4```-glycoside (compound 1), (±)-Fukugiside (compound 2), and Morelloflavone (compound 3). Structural modifications by acylation and alkylation reactions were performed on the natural biflavonoid (±) morelloflavone to obtain three semisynthetic compounds: Morelloflavone-7,4`,7``,3```,4```-penta–O–acetyl (compound 4), Morelloflavone-7,4`,7``,3```,4```-penta-O-methyl (compound 5), and Morelloflavone-7,4`,7``,3```,4```-penta-O-butanoyl (compound 6). The inhibitory effects of these naturally isolated biflavonoid-type compounds and three semisynthetic derivatives on the activity of the cysteine proteases papain and cruzain, and on the serine protease trypsin were investigated. The potential inhibitory IC50 of natural bioflavonoids compounds 1, 2, and 3 were 11.0 ± 3.0, 23.0 ± 4.0, and 10.5 ± 0.3 µM, respectively, for papain;  0.86 ± 0.12, 106 ± 7, and 3.8 ± 0.1, 50 ± 2, 119.5 ± 5,  and 9.6 ± 1.0 µM, respectively, for cruzain. On the other hand, the semisynthetic biflavonoids compounds 4, 5, and 6 were more efficient in the inhibition of enzyme activity with IC50 values 0.60 ± 0.02 µM (papain) for biflavonoids compound 4, 1.64 ± 0.11 µM (trypsin) for biflavonoids compound 5, and 8.1 ± 0.6 µM (cruzain) for biflavonoids compound 6. Compound 4 is more active owing to the carbonyl group in the structure; perhaps, this modification could favor a higher nucleophilic attack by serine and cysteine proteases. However, the semisynthetic compound 5 (IC50 = 15.4 ± 0.7 µM for papain), which has no carbonyl group in structure, was less active in the inhibition. Interestingly, structure–activity relationships (SARs) were confirmed by flexible docking simulations. Likewise, the potential usefulness of natural compound 1 as an antioxidant compound was strengthened by our results concerning the antiproteolytic activity.

 

Key words: Garcinia brasiliensis, biflavonoids, proteases, antiproteolytic activity.

Abbreviation

r-CPB2.8, Recombinant cysteine protease type B; EOAc, ethyl acetate extract; MeOH, methanol; Z-Phe-Arg-MCA, carbobenzoxicarbonil-Phe-Arg-7-amino-4-methylcoumarin; DTT, dithiothreitol; SARs, structure–activity relationships; FT-NMR, Fourier transform nuclear magnetic resonance; Me4Si, trimethylsilane; TLCK, N-alpha-tosyl-L-lysinyl-chloromethylketone; E-64, 1-[[(Ltrans-epoxysuccinyl)-L-leucyl]amino]-4-guanidinobutane.