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

      Grau, L.; Romero, M.; Privat-Contreras, C.; Presa, Daniela; Viñas, M.; Morral, J.; Pors, Klaus; Rubio-Martinez, J.; Pujol, M.D. (2020-01-01)
      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.
    • Probing cytochrome P450 bioactivation and fluorescent properties with morpholinyl-tethered anthraquinones

      Errington, R.J.; Sadiq, M.; Cosentino, L.; Wiltshire, M.; Sadiq, O.; Sini, Marcella; Lizano, E.; Pujol, M.D.; Ribeiro Morais, Goreti; Pors, Klaus (2018-05-01)
      Structural features from the anticancer prodrug nemorubicin (MMDX) and the DNA-binding molecule DRAQ5™ were used to prepare anthraquinone-based compounds, which were assessed for their potential to interrogate cytochrome P450 (CYP) functional activity and localisation. 1,4-disubstituted anthraquinone 8 was shown to be 5-fold more potent in EJ138 bladder cancer cells after CYP1A2 bioactivation. In contrast, 1,5-bis((2-morpholinoethyl)amino) substituted anthraquinone 10 was not CYP-bioactivated but was shown to be fluorescent and subsequently photo-activated by a light pulse (at a bandwidth 532–587 nm), resulting in punctuated foci accumulation in the cytoplasm. It also showed low toxicity in human osteosarcoma cells. These combined properties provide an interesting prospective approach for opto-tagging single or a sub-population of cells and seeking their location without the need for continuous monitoring.