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

J Med Chem. 2018 Dec 13;61(23):10531-10544. doi: 10.1021/acs.jmedchem.8b01052.

Francesco Bavo ¹, Susanna Pucci ² ³, Francesca Fasoli ², Carmen Lammi ¹, Milena Moretti ² ⁴, Vanessa Mucchietto ², Donatella Lattuada ⁴, Paola Viani ⁴, Clara De Palma ⁵, Roberta Budriesi ⁶, Irene Corradini ², Cheryl Dowell ⁷, J Michael McIntosh ⁷ ⁸ ⁹, Francesco Clementi ² ⁴, Cristiano Bolchi ¹, Cecilia Gotti ² ⁴, Marco Pallavicini ¹

Affiliations

1 Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Via Mangiagalli 25 , I-20133 Milano , Italy.
2 Institute of Neuroscience , CNR , Via Vanvitelli 32 , I-20129 Milano , Italy.
3 Hunimed University , Via Rita Levi-Montalcini 4 , 20090 Pieve Emanuele (MI) , Italy.
4 Department of Medical Biotechnology and Translational Medicine , Università degli Studi di Milano , Via Vanvitelli 32 , I-20129 Milano , Italy.
5 Unit of Clinical Pharmacology , University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco , Via G. B. Grassi 74 , I-20157 Milano , Italy.
6 Dipartimento di Farmacia e Biotecnologie , Università degli Studi di Bologna , Via Belmeloro 6 , I-40126 Bologna , Italy.
7 Department of Biology , University of Utah , 257S.1400 East , Salt Lake City , Utah 84112 , United States.
8 George E. Wahlen Veterans Affairs Medical Center , 500 Foothill Drive , Salt Lake City , Utah 84148 , United States.
9 Department of Psychiatry , University of Utah , 501 Chipeta Way , Salt Lake City , Utah 84108 , United States.

PMID: 30403486 DOI: 10.1021/acs.jmedchem.8b01052

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.

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