Adenocarcinoma and glioblastoma cell lines express α7- and α9α10-containing nicotinic acetylcholine receptors (nAChRs), whose activation promotes tumor cell growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of α7 and α9α10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM-4'BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridization among their three substructures (stilbenoxy residue, alkylene linker, and terminal onium) and elongation of the alkylene linker might result in novel antitumor agents with higher potency and selectivity. We found that lengthening the ethylene bridge in the triethylammonium derivatives results in more potent and selective toxicity toward adenocarcinoma and glioblastoma cells, which was paralleled by increased α7 and α9α10 nAChR antagonism and improved ability of reducing mitochondrial ATP production. Elongation of the alkylene linker was advantageous also for the triphenylphosphonium derivatives resulting in a generalized enhancement of antitumor activity, associated with increased mitotoxicity.

Potent Antiglioblastoma Agents by Hybridizing the Onium-Alkyloxy-Stilbene Based Structures of an α7-nAChR, α9-nAChR Antagonist and of a Pro-Oxidant Mitocan / F. Bavo, S. Pucci, F. Fasoli, C. Lammi, M. Moretti, V. Mucchietto, D. Lattuada, P. Viani, C. De Palma, R. Budriesi, I. Corradini, C. Dowell, J.M. McIntosh, F. Clementi, C. Bolchi, C. Gotti, M. Pallavicini. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:23(2018 Dec 13), pp. 10531-10544. [10.1021/acs.jmedchem.8b01052]

Potent Antiglioblastoma Agents by Hybridizing the Onium-Alkyloxy-Stilbene Based Structures of an α7-nAChR, α9-nAChR Antagonist and of a Pro-Oxidant Mitocan

F. Bavo
Co-primo
;
F. Fasoli
Co-primo
;
C. Lammi;M. Moretti;V. Mucchietto;D. Lattuada;P. Viani;C. De Palma;I. Corradini;F. Clementi;C. Bolchi
;
M. Pallavicini
Ultimo
2018

Abstract

Adenocarcinoma and glioblastoma cell lines express α7- and α9α10-containing nicotinic acetylcholine receptors (nAChRs), whose activation promotes tumor cell growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of α7 and α9α10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM-4'BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridization among their three substructures (stilbenoxy residue, alkylene linker, and terminal onium) and elongation of the alkylene linker might result in novel antitumor agents with higher potency and selectivity. We found that lengthening the ethylene bridge in the triethylammonium derivatives results in more potent and selective toxicity toward adenocarcinoma and glioblastoma cells, which was paralleled by increased α7 and α9α10 nAChR antagonism and improved ability of reducing mitochondrial ATP production. Elongation of the alkylene linker was advantageous also for the triphenylphosphonium derivatives resulting in a generalized enhancement of antitumor activity, associated with increased mitotoxicity.
nAChRs, antagonists, glioblastoma, adenocarcinoma, nicotine, cancer, mitocans, alpha7, alpha9, MG624, stilbene, resveratrol, triphenylphosphonium, triethylammonium, ROS, ATP
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
Settore BIO/10 - Biochimica
13-dic-2018
26-nov-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/632941
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