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

William J Legge; Yuna Shimadate; Mahdi Ghorbani; Jennette Sakoff; Todd A Houston; Atsushi Kato; Paul Bernhardt; Michela I. Simone

doi:10.3762/bxiv.2021.4.v1

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

William J Legge ,
Yuna Shimadate ,
Mahdi Ghorbani ,
Jennette Sakoff ,
Todd A Houston ,
Atsushi Kato ,
Paul Bernhardt and
Michela I. Simone

Submitting author affiliation:

University of Newcastle, Callaghan, Australia

Beilstein Arch. 2021, 20214. https://doi.org/10.3762/bxiv.2021.4.v1

Published 22 Jan 2021

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Show All Preprints Nanotechnology Organic chemistry Bioorganic chemistry / chemical biology Catalysis Chemical methods and reactions Flow and process chemistry Green and sustainable chemistry Materials chemistry Medicinal and pharmaceutical chemistry Nano- and molecular-scale electronics Nano-biomaterials and bioscience Nanomagnetics Nanomaterials, thin films and nanointerfaces Nanomedicine Nanometrology and nanomechanics Nano-optics Nanopatterning, self-assembly and nanofabrication Nanostructures for energy and sensing applications Natural products chemistry Organo main group chemistry Other nanotechnology (unclassified) Other organic chemistry (unclassified) Photochemistry and photovoltaics Physical organic chemistry Supramolecular chemistry

Abstract

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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When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information:

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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aromatic	the word “aromatic”
aromatic aldehyde	the word “aromatic” OR “aldehyde”
+aromatic +aldehyde	both words “aromatic” AND “aldehyde”
+aromatic -aldehyde	the word “aromatic” but NOT “aldehyde”
“aromatic aldehyde”	the exact phrase “aromatic aldehyde”
benz*	words which begin with “benz”, such as “benzene” or “benzyl”
benz*yl	words that begin with “benz” and end with “yl”, such as “benzyl” or “benzoyl”
benzyl~	words that are close to the word “benzyl”, such as “benzoyl” (i.e., fuzzy search)