2. Academic Validation
  3. Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents

Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents

  • Eur J Med Chem. 2015 Sep 18:102:648-60. doi: 10.1016/j.ejmech.2015.08.009.
Andrea Spallarossa 1,  Chiara Caneva 2,  Matteo Caviglia 2,  Silvana Alfei 2,  Stefania Butini 3,  Giuseppe Campiani 3,  Sandra Gemma 3,  Margherita Brindisi 3,  Daniela M Zisterer 4,  Sandra A Bright 4,  Clive D Williams 4,  Emmanuele Crespan 5,  Giovanni Maga 5,  Giuseppina Sanna 6,  Ilenia Delogu 6,  Gabriella Collu 6,  Roberta Loddo 6
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. Electronic address: andrea.spallarossa@unige.it.
  • 2 Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
  • 3 European Research Centre for Drug Discovery & Development, Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
  • 4 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
  • 5 Institute of Molecular Genetics IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
  • 6 Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, s.p. 8, Km 0.700, I-09042 Monserrato, Cagliari, Italy.
PMID: 26320088 DOI: 10.1016/j.ejmech.2015.08.009
Abstract

A new series of indole-based analogues were recently identified as potential Anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal Cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce Apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b.

Keywords

Antiproliferative agents; Indoles; Pro-apoptotic agents; Tubulin immunostaining.

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