2. Academic Validation
  3. Methylsulfanylpyridine based diheteroaryl isocombretastatin analogs as potent anti-proliferative agents

Methylsulfanylpyridine based diheteroaryl isocombretastatin analogs as potent anti-proliferative agents

  • Eur J Med Chem. 2021 Jan 1:209:112933. doi: 10.1016/j.ejmech.2020.112933.
Raquel Álvarez 1,  Laura Aramburu 2,  Consuelo Gajate 3,  Alba Vicente-Blázquez 4,  Faustino Mollinedo 5,  Manuel Medarde 6,  Rafael Peláez 7
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 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: lauramvil@usal.es.
  • 3 Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain. Electronic address: cgajate@cib.csic.es.
  • 4 Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, 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: avicenteblazquez@usal.es.
  • 5 Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain. Electronic address: fmollin@cib.csic.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: medarde@usal.es.
  • 7 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: 33328100 DOI: 10.1016/j.ejmech.2020.112933
Abstract

Isocombretastatins are the not isomerizable 1,1-diarylethene isomers of combretastatins. Both families of antimitotics are poorly soluble and new analogs with improved water solubility are needed. The ubiquitous 3,4,5-trimethoxyphenyl ring and most of its replacements contribute to the solubility problem. 39 new compounds belonging to two series of isocombretastatin analogs with 2-chloro-6-methylsulfanyl-4-pyridinyl or 2,6-bis(methylsulfanyl)-4-pyridinyl moieties replacing the 3,4,5-trimethoxyphenyl have been synthesized and their antimitotic activity and aqueous solubility have been studied. We show here that 2-chloro-6-methylsulfanylpyridines are more successful replacements than 2,6-bis(methylsulfanyl)pyridines, giving highly potent tubulin inhibitors and cytotoxic compounds with improved water solubilities. The optimal combination is with indole rings carrying polar substitutions at the three position. The resulting diheteroaryl isocombretastatin analogs showed potent cytotoxic activity against human Cancer cell lines caused by tubulin inhibition, as shown by in vitro tubulin polymerization inhibitory assays, cell cycle analysis, and confocal microscopy studies. Cell cycle analysis also showed apoptotic responses following G2/M arrest after treatment. Conformational analysis and docking studies were applied to propose binding modes of the compounds at the colchicine site of tubulin and were in good agreement with the observed SAR. 2-Chloro-6-methylsulfanylpyridines represent a new and successful trimethoxyphenyl ring substitution for the development of improved colchicine site ligands.

Keywords

Docking; G(2)/M arrest and apoptosis; Isocombretastatins and phenstatin oximes; Pyridine analogs; Solubility improvement; Tubulin polymerization inhibition.

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