The introduction of Bortezomib (Velcade), a proteasome inhibitor approved for the treatment of multiple myeloma, a growing number of additional boron-based drugs are under investigation. Considering that the boron moiety in these agents typically retains an electrophilic character, it is possible to interfere with other molecules that are taken at the same time either as part of the diet or for medicinal purposes. Indeed, our earlier studies revealed that green tea polyphenols such as epigallocatechin (EGCG) suppress the cytotoxicity of bortezomib. In order to further understand the mechanism behind such inactivating interactions we employed several NMR-based methods, including 1H-NMR, 13C-NMR, 11B-NMR, and 19F-NMR for the purpose of characterizing the adducts of bortezomib EGCG and related polyphenols. By monitoring and quantifying a single peak we were able to evaluate the likely inactivation of the boron group. Using a 11B-NMR-based SAR study, it was determined that bortezomib has the ability to form a boronate adduct with EGCG as well as other polyphenols of variable structures. These results were further validated with cell-based assays that produced analogous results. Overall, this approach may offer a simple and novel method for screening food-drug and drug-drug interactions of boron-containing drugs.

NMR-based methods for screening inactivating molecular interactions of boron-based drugs

247th National Meeting (2014)

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