Potent Antiglioblastoma Agents by Hybridizing the Onium-Alkyloxy-Stilbene Based Structures of an α7-nAChR, α9-nAChR Antagonist and of a Pro-Oxidant Mitocan
Potent Antiglioblastoma Agents by Hybridizing the Onium-Alkyloxy-Stilbene Based Structures of an α7-nAChR, α9-nAChR Antagonist and of a Pro-Oxidant Mitocan
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DOI：
10.1021/acs.jmedchem.8b01052
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发表时间：
2018-12-13
影响因子：
7.3
通讯作者：
Pallavicini, Marco
中科院分区：
文献类型：
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作者：
Bavo, Francesco;Pucci, Susanna;Pallavicini, Marco
腺癌和胶质母细胞瘤细胞系表达含α 7和α 9 α 10的烟碱乙酰胆碱受体（nAChR），其活化促进肿瘤细胞生长。在这些细胞上，已知的α 7和α 9 α 10 nAChR的选择性拮抗剂4-芪酚MG 624的三乙基铵甲基醚具有抗增殖活性。MG 624与mitocan RDM-4 'BTPI（蝶芪的三苯基膦丁基醚）的结构相似性表明，它们的三个亚结构（芪氧基残基、亚烷基连接基和末端鎓）之间的分子杂交和亚烷基连接基的延伸可能导致具有更高效力和选择性的新型抗肿瘤剂。我们发现，延长三乙铵衍生物中的乙烯桥导致对腺癌和胶质母细胞瘤细胞更有效和选择性的毒性，这是通过增加α 7和α 9 α 10 nAChR拮抗作用和提高减少线粒体ATP产生的能力来实现的。亚烷基接头的延伸对于三苯基磷衍生物也是有利的，导致抗肿瘤活性的普遍增强，与有丝分裂毒性的增加相关。
Adenocarcinoma and glioblastoma cell lines express alpha 7- and alpha 9 alpha 10-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 alpha 7 and alpha 9 alpha 10 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 alpha 7 and alpha 9 alpha 10 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.