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

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.

Borylated 2,3,4,5-Tetrachlorophthalimide and Their 2,3,4,5-Tetrachlorobenzamide Analogues: Synthesis, Their Glycosidase Inhibition and Anticancer Properties in View to Boron Neutron Capture Therapy

“…In our laboratory we are interested in glycosidase modulation [ 13 , 18 , 19 , 21 ]. Screening for selectivity, as well as potency, is of paramount importance in carbohydrate-active enzyme research.…”

“…Use of a borylated drug in BNCT would ideally require that it is non-toxic in the absence of radiation. Following a first study of synthesis, purification and toxicity of organic-boron-containing drugs for BNCT applications [ 13 ], we report here, two further families of potential BNCT agents.…”

“…In our group, we are interested in the use of organic boron as a pharmacophoric group in its boronic acid (R-B(OH) 2 ) and boronate ester (R-B(OR′) 2 ) [ 7 , 8 ] functional groups and in the development of synthetic methodologies for the installation of this pharmacophore on biologically active molecules to study and expand the palette of enzyme–drug interactions [ 9 , 10 , 11 , 12 , 13 ].…”