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.
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.
Viale
Maurizio
M
Istituto Nazionale per la Ricerca sul Cancro, SC Terapia Immunologica, L.go R. Benzi 10, 16132 Genova, Italy. maurizio.viale@istge.it
Petrillo
Giovanni
G
Aiello
Cinzia
C
Fenoglio
Carla
C
Cordazzo
Cinzia
C
Mariggiò
Maria A
MA
Cassano
Amalia
A
Prevosto
Claudia
C
Ognio
Emanuela
E
Maccagno
Massimo
M
Bianchi
Lara
L
Vaccarone
Rita
R
Rizzato
Egon
E
Spinelli
Domenico
D
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis; D015153:Blotting, Western; D002070:Butadienes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation