2. Academic Validation
  3. 2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition

2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition

  • Eur J Med Chem. 2018 Jan 1:143:683-698. doi: 10.1016/j.ejmech.2017.11.096.
Romeo Romagnoli 1,  Maria Kimatrai Salvador 2,  Santiago Schiaffino Ortega 2,  Pier Giovanni Baraldi 3,  Paola Oliva 3,  Stefania Baraldi 3,  Luisa Carlota Lopez-Cara 2,  Andrea Brancale 4,  Salvatore Ferla 4,  Ernest Hamel 5,  Jan Balzarini 6,  Sandra Liekens 6,  Elena Mattiuzzo 7,  Giuseppe Basso 7,  Giampietro Viola 8
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
  • 2 Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Campus de Cartuja s/n, 18071, Granada, Spain.
  • 3 Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
  • 4 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
  • 5 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
  • 6 Rega Institute for Medical Research, KU Leuven, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
  • 7 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, 35131 Padova, Italy.
  • 8 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, 35131 Padova, Italy. Electronic address: giampietro.viola.1@unipd.it.
PMID: 29220790 DOI: 10.1016/j.ejmech.2017.11.096
Abstract

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of Anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC50 values ranging from 0.13 to 0.84 μM against four different Cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC50 value of 140 nM, inhibited tubulin polymerization with an IC50 value of 1.2 μM, similar to that of CA-4 (IC50: 1.1 μM), and induced Apoptosis in HeLa cells.

Keywords

Antiproliferative agents; Colchicine site; Microtubule; Structure-activity relationship; Tubulin polymerization inhibitors.

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