Design, synthesis, and in vitro evaluation of new naphthylnitrobutadienes with potential antiproliferative activity: toward a structure/activity correlation.
On the grounds of previous encouraging results on the antitumor activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1), we have designed and synthesized two new molecules [(1E,3E)-1,4-bis(4-carboxy-1-naphthyl)-2,3-dinitro-1,3-butadiene (2) and methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (3)] characterized by a common naphthylnitrobutadiene array but with different structural properties, with the aim of approaching to some structure-activity correlation. When 2 and 3 were analyzed in vitro for their inhibition of cell proliferation and pro-apoptotic properties, the carboxyderivative 2 did not furnish appreciable results. In contrast, 3 (which contains only one of the two naphthylnitroethenyl moieties of the original compound 1) showed remarkable activities in the range of micromolar concentrations (in six over eight cell lines its IC(50)s are in the 1-3 microM range), with a significant improvement compared to 1. In particular, 3 proved able to bind to DNA, to upregulate p53, to block cells in the G2/M phase of their cycle, and to induce apoptosis. Thus, very interestingly, the performance of 3 with respect to 1 shows that a single 1-(1-naphthyl)-2-nitroethene moiety is able to ensure better (on four out of eight of the cell lines tested) or comparable levels of activity. This result suggests that the 'molecular-simplification strategy' could furnish a useful instrument for future design in our antitumor research.
Petrillo
Giovanni
G
Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, 16146 Genova, Italy.
Mariggiò
Maria A
MA
Aiello
Cinzia
C
Cordazzo
Cinzia
C
Fenoglio
Carla
C
Morganti
Stefano
S
Croce
Michela
M
Rizzato
Egon
E
Spinelli
Domenico
D
Maccagno
Massimo
M
Bianchi
Lara
L
Prevosto
Claudia
C
Tavani
Cinzia
C
Viale
Maurizio
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007399:Interphase / Q000187:drug effects; D009281:Naphthalenes; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D002070:Butadienes; D009281:Naphthalenes; D016159:Tumor Suppressor Protein p53; D004247:DNA