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Pure Appl. Chem., 2006, Vol. 78, No. 7, pp. 1425-1453

Pharmacologically active boranes

Adel Jabbour1, Reem Smoum1, Khuloud Takrouri1, Eli Shalom1, Batia Zaks2, Doron Steinberg2, Abraham Rubinstein3, Israel Goldberg4, Jehoshua Katzhendler1 and Morris Srebnik1

1 Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University in Jerusalem, P.O.B. 12065, 91120, Jerusalem, Israel
2 Institute of Dental Sciences, Faculty of Dental Sciences, The Hebrew University-Hadassah, P.O.B. 12272, 91120, Jerusalem, Israel
3 Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University in Jerusalem, P.O.B. 12065, 91120, Jerusalem, Israel
4 School of Chemistry, Sackler Faculty of Exact Science, Tel-Aviv University, Ramat-Aviv, Israel

Abstract: Novel methods are described for the preparation of alkyldimethylamine cyanoboranes and β-hydroxylalkyldimethylamine cyanoboranes by C-lithiation of trimethylamine cyanoboranes followed by reaction with alkyl halides, aldehydes, and ketones. Lithiation of the monobromo derivatives of amine cyanoboranes led to the synthesis of the first examples of diborane derivatives of amine cyanoboranes. Bromo derivatives of amine cyanoboranes and amine carboxyboranes have been synthesized by new simple and efficient methods. Amine fluorocyanoboranes and amine fluorocarboxyboranes, new classes of compounds, have been prepared from the bromo precursors by fluorine/bromine exchange using fluorinating reagents such as AgF and Et3N.3HF. Eight different derivatives of oxazaborolidines were synthesized and evaluated for their affect on Streptococcus mutans viability, adhesion, and biofilm formation using 3[H]-thymidine labeled bacteria, and fluorescent stained bacteria. This is the first reported antibacterial activity of this class of compounds. The minimal inhibitory concentration (MIC) values ranged from 0.26 to 10 mM. Structure-activity relationship was observed. The B-butyl moiety of the oxazaborolidines contributed an anti-adhesion effect for all derivatives, while its effect diminished when the boron atom was incorporated in a fused heterocyclic ring. The B-phenyl group induced bacterial adhesion in all tested compounds. In a separate study for boronated saccahrides and enzymatic inhibition, the complex formation between N-butylboronic acid and a series of monosaccharides was investigated by 1H, 13C, and 11B NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS). Then, a series of boronic acid compounds with protease inhibition properties were prepared. The effect of added mono-, di-, and polysaccharides on the inhibitory activity of these compounds was studied. Potassium organotrifluoroborates were found to be reversible competitive inhibitors of α-chymotrypsin and trypsin. Based on 19F NMR, it was speculated that they inactivate the enzymes as a result of the formation of hydrogen bonds between fluorine atoms of the inhibitors and the serine protease.