Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines.

  1. William J Legge,
  2. Yuna Shimadate,
  3. Mahdi Ghorbani,
  4. Jennette SakoffORCID Logo,
  5. Todd A HoustonORCID Logo,
  6. Atsushi KatoORCID Logo,
  7. Paul Bernhardt and
  8. Michela I. SimoneORCID Logo

Submitting author affiliation: University of Newcastle, Callaghan, Australia

Beilstein Arch. 2021, 20214.

Published 22 Jan 2021

  • Preprint


Three cinnamate derivatives bearing a boronate pinacol ester group para, meta and ortho to the a,b-unsaturated ester group have been synthesized via a solventless, expedited Wittig protocol in the best stereoisomeric ratios yet reported, purified by recrystallization, characterized and analyzed by X-ray crystallography. These are valuable building blocks to biologically active derivatives and are themselves biologically active drug leads, displaying excellent selectivities as glycosidase modulators and for future testing as boron neutron capture therapy (BNCT) agents. In a panel of 15 glycosidases, IC50 values of 351 mM and 374 mM were shown for para 2 against almond b-glucosidase and bovine liver b-galactosidase, respectively. For meta 2 the selectivity profile is improved with only inhibition of bovine liver b-galactosidase with an IC50 of 780 mM. These borylated derivatives also possess the capability to be used as BNCT agents. This occurs via irradiation with slow neutrons, thus granting them a switch-on/switch-off toxicity. This is an important new capability imbued into anticancer drugs, too many of which are too toxic in their therapeutic window. BNCT drugs bearing the organic boron pharmacophore have the potential to fine-tune the timing of toxicity delivery.

Keywords: Cinnamate, pinacol boronate ester, Wittig reaction, X-ray crystallography, glycosidase, boron neutron capture therapy, accumulation selectivity in cancer vs healthy cells

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Legge, W. J.; Shimadate, Y.; Ghorbani, M.; Sakoff, J.; Houston, T. A.; Kato, A.; Bernhardt, P.; Simone, M. I. Beilstein Arch. 2021, 20214. doi:10.3762/bxiv.2021.4.v1

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