Boronic acid analog

Acetamido-2-phenylethaneboronic acid, the boronic acid analog of. V-acetylphenyl-alanine and a good inhibitor of chymotrypsin, has been prepared via a stable silylated intermediate59, 62. Coordination with boron evidently facilitated the unusual chloride displacement by sterically hindered lithium hexamethyldisilazanide. 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

Scheme8.28 Synthesis of the boronic acid analog of N-acetylpheny-lalanine.

Discovery of a boronic acid analog of chalcone as a potent anticancer proliferation agent... 

Chalcones represent a class of natural products that can be readily synthesized in efforts to improve and optimize biological activities. In this study we designed and synthesized novel boronic acid analogs of chalcones. The cytotoxicity study identified a boronic acid chalcone YK-3-237 was potent towards 16 human cancer cell lines with GI50-values in the range of 10-200 nM, and another three cell lines with GI50-values below 10 nM. Both in vitro assay and cell cycle assay excluded the involvement of this compound in either assembly or disassembly process of tubulin. Furthermore, this... 

Snyder, H. R., Reedy, A. J., and Lennarz, W. J. 1958. Synthesis of aromatic boronic acids. Aldehydo boronic acids and a boronic acid analog of tyrosinel. J. Am. Chem. Soc. 80 835-38. 

BVMOs were also reported to facilitate mild and chemoselective conversion of boronic acids to borates, which usually hydrolyze upon biotransformation conditions using isolates protein [217]. Additionally selenium oxidation has been described in analogy to sulfoxidations [218]. 

Thiazoleboronic acids are not trivial to make. Attempts to prepare 2-thiazoleboronic acid were unsuccessful [21], As a consequence, halothiazoles are chosen as the electrophilic coupling partners in the Suzuki reactions with other boronic acids. For instance, 2,5-di-(2-thienyl)thiazole (28) was installed by the union of 2,5-dibromothiazole and easily accessible 2-thiopheneboronic acid [21], Unfortunately, the yield was poor and analogous reactions of 2,5-dibromothiazole with 3-thiopheneboronic acid and 2-selenopheneboronic acid both failed. 

Lindquist, R. N. Terry, C (1974). Inhibition of Subtilisin by Boronic Acids, Potential Analogs of Tetrahedral Reaction Intermediates, Arch, Biochem. Biophvs. 160. 135-144. 

Some boronic acid-based enzyme inhibitors undergo strong yet reversible covalent attachment to a nucleophile at the enzyme s active site, while others simply act as competitive inhibitors in their borate conjugate base form. Boronic acid-based inhibition of thrombin has been achieved <93MI109>, and that of P-lactamases has been particularly effective <95TL8399, 96M1688>. When compared to other covalent transition-state analog inhibitors of P-lactamases like phos-... 

An alternate approach to the formation of pyridylboronic acids is the cross-coupling of a halopyridine with a diboronate ester (usually bis(pinacolato)diboron, 7.7.)9 The analogous reaction of 2-chloropyridine led to pyridine formation through protodeboronation. The product of the reaction, either after hydrolysis to the boronic acid or in the ester form, can be further reacted with another aryl halide to give a biaryl. In certain cases the reaction might also be carried out in a one-pot manner.10... 

A synthetic procedure 33 has been developed for the preparation of boronic acids with a protected aldehyde side chain, 2-(l,3-dioxolan-2-yl)ethyl, which is readily converted into boroOrn peptides similar to 30. Peptides containing boroLys were prepared by a series of reactions analogous to those used for the preparation of 30 except 4-bromobut-l-ene was used as starting material in place of 3-bromoprop-l -ene 36 ... 

Parrish and Buchwald30 performed couplings with a polystyrene-supported biphenyl-phosphine palladium complex between aryl halides and either amines (entry 24) or boronic acids (entry 25). The resin-bound complex is analogous to the corresponding homogeneous compound and is effective for couplings to unactivated aryl halides, including aryl chlorides. The complex is air-stable and retains activity after recovery without apparent loss of palladium. 

Assuming that the general methodology in Scheme 62 would be applicable, catechol precursors were required for the C-4 pyridone substituents of 5 and 6. This led (using analogies to the catechol cleavages illustrated in Schemes 4 and 5) to a requirement for boronic acids 178 and 179 for use in the Suzuki cross-coupling step (Scheme 64). 

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