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  3. Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

  • Eur J Med Chem. 2019 Mar 15:166:514-530. doi: 10.1016/j.ejmech.2019.01.049.
Rita Morigi 1,  Alessandra Locatelli 2,  Alberto Leoni 2,  Mirella Rambaldi 2,  Roberta Bortolozzi 3,  Elena Mattiuzzo 3,  Roberto Ronca 4,  Federica Maccarinelli 4,  Ernest Hamel 5,  Ruoli Bai 5,  Andrea Brancale 6,  Giampietro Viola 7
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia e Biotecnologie Fa.Bi.T, Università di Bologna, 40100, Bologna, Italy. Electronic address: rita.morigi@unibo.it.
  • 2 Dipartimento di Farmacia e Biotecnologie Fa.Bi.T, Università di Bologna, 40100, Bologna, Italy.
  • 3 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35128, Padova, Italy.
  • 4 Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25123, Brescia, Italy.
  • 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 The Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
  • 7 Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35128, Padova, Italy. Electronic address: giampietro.viola.1@unipd.it.
PMID: 30784885 DOI: 10.1016/j.ejmech.2019.01.049
Abstract

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100-200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced Apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both Caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast Cancer cells, causing in both cases a significant reduction in tumor volume.

Keywords

3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones; Antiproliferative; Antitumor; Apoptosis; Synthesis.

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