Synthesis, in vitro activity and in vivo toxicity of the new 2,3-dinitrobutadiene derivative (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

Maurizio Viale, Giovanni Petrillo, Cinzia Aiello, Carla Fenoglio, Cinzia Cordazzo, Maria A. Mariggiò, Amalia Cassano, Claudia Prevosto, Emanuela Ognio, Massimo Maccagno, Lara Bianchi, Rita Vaccarone, Egon Rizzato, Domenico Spinelli

Research output: Contribution to journalArticle

Abstract

Our interesting results on the antiproliferative (in vitro) and antitumour (in vivo) activities of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) have more recently induced us to design and synthesize some new 1,4-diaryl-2,3-dinitro-1,3-butadienes characterized by a common arylnitrobutadiene array but with different geometric and/or functional properties. This task was undertaken with the aim to obtain new compounds with an enhanced antiproliferative activity and, possibly, a different specificity with respect to the original (lead) compound. (1E,3E)-1,4-Bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) is one of the molecules so obtained, a structural isomer of 1-Naph-DNB provided with a different spatial arrangement. When analyzed in vitro for its inhibition of cell proliferation 2-Naph-DNB showed a remarkable activity in the range of micromolar concentrations, with significant differences, with respect to 1-Naph-DNB, against some cell lines. Furthermore, it was able to significantly trigger apoptosis, to up-regulate p53, to block cells in the G2/M phase of the cell cycle and, finally, to slightly bind to DNA forming interstrand cross-links (ISCL). 2-Naph-DNB was then analyzed for its toxic activity in vivo in CD1 mice. This allowed the determination of toxicity parameters such as the lethal doses (LD) and the maximal tolerated dose (MTD) together with the definition of the spectrum of tissue alterations due to its administration i.v. Altogether our data suggest that the idea of modifying the geometry of the lead compound 1-Naph-DNB deserves further investigation aimed at synthesizing new molecules with similar chemical functionalities but with different spatial requirements, hopefully characterized by still enhanced activities in terms of inhibition of cell proliferation and apoptosis.

Original languageEnglish
Pages (from-to)318-328
Number of pages11
JournalPharmacological Research
Volume56
Issue number4
DOIs
Publication statusPublished - Oct 2007

Keywords

  • Antiproliferative activity
  • Apoptosis
  • Naphthylnitrobutadienes
  • Toxicity

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Viale, M., Petrillo, G., Aiello, C., Fenoglio, C., Cordazzo, C., Mariggiò, M. A., Cassano, A., Prevosto, C., Ognio, E., Maccagno, M., Bianchi, L., Vaccarone, R., Rizzato, E., & Spinelli, D. (2007). Synthesis, in vitro activity and in vivo toxicity of the new 2,3-dinitrobutadiene derivative (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene. Pharmacological Research, 56(4), 318-328. https://doi.org/10.1016/j.phrs.2007.07.009