Abstract β-Nitrostyrene, an important intermediate in chemical industry, shows relevant anti-proliferative and pro-apoptotic potential and has thus been suggested for potential use in tumor chemotherapy. If not derivatized, β-nitrostyrene is however, highly reactive and possess (geno)toxic potential. To decipher structural elements relevant for biological activity, crucial for both, chemical risk assessment and potential drug development, a panel of nine structural derivatives of β-nitrostyrene, was put together. It included structures with and without nitrovinyl moiety and was based on fingerprint similarity, QSAR-based mutagenicity alerts, and literature reports. It comprised simple structures like styrene and more complex structures such as 2-methoxy-5-(E)-2-nitroethenylphenol. In vitro experiments in human WS1 and mouse L5178/TK ± cells demonstrated that the nitrovinyl moiety of β-nitrostyrene seems vital for its cytotoxic (membrane damage, metabolic competence) and genotoxic (clastogenicity, mutagenicity) properties. The extent of adversity varied with modification of structural elements. For example 1-nitro-2-(E)-2-nitroethenylbenzene led to 2.3-fold higher mean tail intensities in the alkaline comet assay than β-nitrostyrene. Notably, all derivatives with a nitrovinyl moiety, except 5-(E)-2-nitroethenyl-1,3-benzodioxole, induced DNA double-strand breaks, as judged by γH2A.X induction. In conclusion, our study identified structural elements responsible for the cyto- and genotoxic potential of β-nitrostyrene, demonstrating that minor structural changes can significantly alter its adverse biological activity.
Sündermann et al. (Tue,) studied this question.