Cytotoxicity of Atropisomeric [1,1′-Binaphthalene]-2,2′-Diamines (BINAM) and Analogs in Human Cancer Cells: Enantioselectivity, Structure–Activity Relationships, and Mechanism

Binaphthyls usually serve as key chiral ligands in catalysts for asymmetric syntheses, having been reported in thousands of published reactions. Herein, the discovery that atropisomeric (R)-[1,1′-binaphthalene]-2,2′-diamine (R-BINAM, 1(R)) is a moderately potent spindle poison, causing antiproliferation, depolymerization of microtubules, multipolar spindles, pericentriolar material (PCM) fragmentation, mitotic catastrophe, multinucleated cells, and apoptosis in cancer and normal human cell lines, is reported. Furthermore, the resulting abnormalities resemble those induced by microtubule-depolymerizing agents (MDAs) such as colchicine. In contrast, the enantiomer S-BINAM (1(S)) was inactive in all biological assays. Additionally, the structure–activity relationships of a selection of R- and S-BINAM derivatives with key structural differences have been studied; these studies show the same enantiomeric trend as with R-BINAM and provide insight into the structural requirements for the antiproliferative activity of this compound class. These findings should be useful for the development of more selective spindle poisons, especially due to the natural rigidity of binaphthyls and their scaffold that allows for various modifications.