Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity

Abstract

Despite a recent publication describing boronic acids as a "novel class of bacterial mutagen," process and analytical chemists may not be aware of the potential worker exposure hazards, or of the need to assess boron compounds as potential genotoxic impurities (GTIs) per ICH M7. This publication provides new Ames data for 44 commercially available boronic acids, boronic acid derivatives, and boron containing reagents. Trends in the Ames data are discussed from a structure-activity perspective. Common reagents such as bis(pinacolato)diboron and bisboronic acid were shown to be mutagenic in the Ames assay. Currently available in silico computational models were found to provide little value in predicting the outcome of the Ames assay for boronic acids and derivatives. We propose oxygen mediated oxidation of boron compounds to generate organic radicals as a potential mechanism for mutagenicity. It is hoped that this paper will result in increased awareness of this class of GTIs, and prompt publication of additional Ames data for boronic acids and their derivatives that will lead to improved (Q)SAR models, and an understanding of the mechanism of mutagenicity.KEY WORDS GTI, mutagen, Ames, boron, boronic acid, (Q)SAR

Current data regarding the structure-toxicity relationship of boron-containing compounds

“…However, much work remains to be done in this field. Some other results suggest that oxidation of boron compounds can generate organic radicals as a potential mechanism for mutagenicity (Hansen, 2015).…”

“…Considering the doses employed, the results of several studies strongly suggest that these compounds do not produce toxic effects in humans (SorianoUrsúa, 2014a;Sanjoh, 2014;Fu, 2014). Moreover, it is known that they have a low mutagenic or cytotoxic effect (O'Donovan, 2011;Hansen, 2015;Pellizzaro, 2015;Scott, 2015). O'Donovan et al (2011) reported that a number of aryl boronic acids have low or null mutagenic effects.…”

“…Recent studies have been trying to find strategies to identify highly toxic BCCs by employing analytical chemistry, the quantitative structure-activity relationship (Endo, 2003;Dembitsky, 2004;Zhang, 2014;Hansen, 2015;Pellizzaro, 2015), and/or computational predictive assays (Ciani, 2012;Kehlert, 2013;Bakri, 2014). Most of these studies have suggested that specific moieties in aryl or alkyl boronic acids are likely to be responsible for inducing cytotoxicity or mutagenicity (Pellizzaro, 2015).…”

“…Whatever the case, BCCs are often 'score-punished' for the sole reason of having a boron atom in their structure (Hansen, 2015), which is probably the case for other non-organic atoms as well. In fact, the theoretical approach for biological assessment of BCCs is only weakly related to experimental results, and the former has shown a bias to exaggerating the toxic effect of BCCs (Ciani, 2012).…”

Why You Really Should Consider Using Palladium-Catalyzed Cross-Coupling of Silanols and Silanolates

“…4 These results are further strengthened by a recent study that discloses the mutagenicity associated with a large number of boronic acids, esters, MIDA boronates, potassium trifluoroborates, as well as their precursors bis(pinacolato)diboron and bis-boronic acid. 5 The newly-assessed genotoxicity of boron compounds naturally poses some serious limitations to their applications in medicinal and process chemistry, both in terms of worker exposure hazards and more stringent standards of purity to avoid the persistence of genotoxic impurities. It is foreseeable that these findings will stress the necessity of a paradigm shift and prompt the organic synthetic community to appreciate the advantages and potentials of other classes of donors in cross-coupling processes, including silicon.…”