Aromatic nitroolefin with inhibition efficacy in triple-negative breast cancer cells by dual targeting RXRα and tubulins

We previously identified that 1-(2-Nitrovinyl)naphthalene (Z-10) is a ligand of retinoid x receptor alpha (RXR alpha) with a potent anti-breast cancer efficacy and revealed that nitro group is an essential pharmacophore in Z-10. In this study, we defined that the double bond of the nitrovinyl group is also vital for Z-10 to bind and activate RXR alpha. Mechanistically, the double bond has a chemical ability to mediate Z-10's covalent binding of RXR alpha via the Michael addition reaction with Cys432. By retaining the nitrovinyl group, a series of Z-10 analogues with different aromatic groups and different aromatic ring-positions of nitrovinyl group and alkoxy groups were designed and synthesized. We found that some analogues including compound 30 show stronger ability than Z10 in inhibiting TNF alpha survival signal in MDA-MB-231 breast cancer cells. Interestingly, these RXR alpha ligands also bind to tubulins likely through the similar covalent interaction and induce the degradation of tubulins and cell cycle arrest in MDA-MB-231 cells, of which 30 displays the strongest efficacy. Importantly, these analogues and TNF alpha exhibit synergistic effects in inducing breast cancer cell apoptosis, of which 30 shows greater efficacy than Z-10. Together, our study provides a theoretical basis for the RXR alpha and tubulin dual-targeting drug design for breast cancer treatment.