2. Academic Validation
  3. Substitution at the indole 3 position yields highly potent indolecombretastatins against human tumor cells

Substitution at the indole 3 position yields highly potent indolecombretastatins against human tumor cells

  • Eur J Med Chem. 2018 Oct 5:158:167-183. doi: 10.1016/j.ejmech.2018.08.078.
Raquel Álvarez 1,  Consuelo Gajate 2,  Pilar Puebla 3,  Faustino Mollinedo 4,  Manuel Medarde 5,  Rafael Peláez 6
Affiliations

Affiliations

  • 1 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain. Electronic address: raquelalvarez@usal.es.
  • 2 Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain. Electronic address: cgajate@cib.csic.es.
  • 3 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain. Electronic address: puebla@usal.es.
  • 4 Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain. Electronic address: fmollin@cib.csic.es.
  • 5 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain. Electronic address: medarde@usal.es.
  • 6 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain. Electronic address: pelaez@usal.es.
PMID: 30216850 DOI: 10.1016/j.ejmech.2018.08.078
Abstract

Resistance to combretastatin A-4 is mediated by metabolic modification of the phenolic hydroxyl and ether groups of the 3-hydroxy-4-methoxyphenyl (B ring). Replacement of the B ring of combretastatin A-4 by a N-methyl-5-indolyl reduces tubulin polymerization inhibition (TPI) and cytotoxicity against human Cancer cell lines but cyano, methoxycarbonyl, formyl, and hydroxyiminomethyl substitutions at the indole 3-position restores potent TPI and cytotoxicity against sensitive human Cancer cell lines. These highly potent substituted derivatives displayed low nanomolar cytotoxicity against several human Cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies, and promoted cell killing mediated by Caspase-3 activation. Binding at the colchicine site was suggested by molecular modeling studies. Substituted combretastatins displayed higher potencies than the isomeric isocombretastatins and the highest potencies were achieved for the hydroxyiminomethyl (21) and cyano (23) groups, with TPI values in the submicromolar range and cytotoxicities in the nanomolar and subnanomolar range. Dose-response and time-course studies showed that drug concentrations as low as 1 nM (23) or 10 nM (21) led to a complete G2/M cell cycle arrest after 15 h treatment followed by a high apoptosis-like cell response after 48-72 h treatment. The P-glycoprotein antagonist verapamil increased 21 and 23 cytotoxicity to IC50 values of 10-10 M, and highly potentiated the cytotoxic activity in 100-fold of the CHO derivative (17), in A-549 human non-small cell lung Cancer cells. The cyano substituted indolecombretastatin 23 is by itself highly potent against rather resistant HT-29 and A-549 cell lines. A 3,4,5-trimethoxyphenyl ring always afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.

Keywords

3-Substituted-N-Methylindole derivatives; Caspase-3; Combretastatins; Low-nanomolar cytotoxicity; Tubulin polymerization inhibition; Verapamil.

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