2. Academic Validation
  3. Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties

Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties

  • Eur J Med Chem. 2020 Jan 1:185:111807. doi: 10.1016/j.ejmech.2019.111807.
Laura Grau 1,  Manel Romero 1,  Cristian Privat-Contreras 2,  Daniela Presa 3,  Miquel Viñas 1,  Jordi Morral 3,  Klaus Pors 3,  Jaime Rubio-Martinez 2,  Maria Dolors Pujol 4
Affiliations

Affiliations

  • 1 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
  • 2 Department of Physical Chemistry, Faculty of Chemistry, University of Barcelona, Institute de Recerca en Quimica Teòrica i Computacional (IQTCUB), E-08028, Barcelona, Spain.
  • 3 Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, BD7 1DP, West Yorkshire, UK.
  • 4 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain. Electronic address: mdpujol@ub.edu.
PMID: 31675512 DOI: 10.1016/j.ejmech.2019.111807
Abstract

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the Kras-Wnt pathway. The lactone 2a also exerted a potent inhibition of Tau Protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix α3 and α4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97.

Keywords

1,4-Benzodioxine derivatives; Antitumor compounds; Ellipticine; Tetracyclic lactones.

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