Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors

Michael S. Christodoulou, Francesco Colombo, Daniele Passarella, Gabriella Ieronimo, Valentina Zuco, Michelandrea De Cesare, Franco Zunino

Research output: Contribution to journalArticle

Abstract

Since activation of p53 in response to cytotoxic stress may have proapoptotic or protective effects depending on the nature of the injury, inhibitors of p53 may have therapeutic interest as modulators of chemotherapy toxicity or efficacy. In an attempt to identify novel p53 inhibitors, a quality collection of compounds structurally related to pifithrin-β were designed and synthesized as potential inhibitors of p53. The biochemical and biological evaluations supported that compounds of the tetrahydrobenzothiazole series were inhibitors of the p53 transcriptional activity and were effective in enhancing paclitaxel-induced apoptosis. In contrast, in spite of the increased cytotoxic potency, selected compounds of the benzothiazole series were not able to modulate the transcriptional activity of p53, as indicated by lack of change of p21 expression. The therapeutic interest of the compounds of the former series in combination with taxanes was confirmed in a human tumor xenograft model.

Original languageEnglish
Pages (from-to)1649-1657
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number5
DOIs
Publication statusPublished - Mar 1 2011

Keywords

  • Analogues of pifithrin-β
  • Benzothiazole derivatives
  • Biochemical and biological evaluation
  • Combined treatment with taxanes
  • p53 Inhibitors
  • Tetrahydrobenzothiazole derivatives

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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