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

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.