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Merck

Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: hints for collateral sensitivity.

ChemMedChem (2013-10-10)
Mauro Niso, Carmen Abate, Marialessandra Contino, Savina Ferorelli, Amalia Azzariti, Roberto Perrone, Nicola Antonio Colabufo, Francesco Berardi
RESUMEN

With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3,4-tetrahydroisoquinoline (15) and 9-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-9H-carbazole (25) showing exceptional selectivity for the σ2 subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin-resistant MCF7adr cell line. Surprisingly, a few compounds, including 25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug-resistant tumors. All of the compounds showed interaction with P-glycoprotein (P-gp), and 15 and 25, with the greatest activity, were able to revert P-gp-mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug- resistant cancers.

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Sigma-Aldrich
Tetrahidrofuran, anhydrous, contains 250 ppm BHT as inhibitor, ≥99.9%
Sigma-Aldrich
Palladium on activated charcoal, 10% Pd basis
Sigma-Aldrich
Bromocyclopropane, 99%
Sigma-Aldrich
Paladio sobre carbono, sulfided, extent of labeling: 5 wt. % loading (dry basis), matrix activated carbon, wet support, (wet)