78902-04-2

Upstream product

• 4039-32-1 lithium hexamethyldisilazane 
• 78902-03-1 1-(S)-chloro-2-phenylethylboronic acid (1S,2S,3R,5S)-(+)-pinane-2,3-glycol ester 
• 100-39-0 benzyl bromide 
• 87100-28-5 pinacol benzylboronate 
• 78922-83-5 (1-phenylmethyl)boronic acid (1S,2S,3R,5S)-(+)-2,3-pinanediol ester 

Downstream Products

• 90084-30-3 (+)-pinanediol (R)-1-[(carbobenzyloxy)amido]-2-phenylethane-1-boronate 
• 178455-03-3 (R)-2-phenyl-1-((3a5,45,65,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ethanamine hydrochloride 
• 78902-05-3 (+)-pinanediol (R)-1-acetamido-2-phenylethane-1-boronate 

Relevant academic research and scientific papers

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i)

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.

BETA-LACTAMASE INHIBITORS

Disclosed herein inter alia are Boron containing compounds and methods for treating infections related to antibiotic resistant microorganisms.

Synthesis, in vitro and in vivo biological evaluation, docking studies, and structure-activity relationship (SAR) discussion of dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids

A series of novel dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC50 value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC50 values nearly less than 5 μM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib.

Design, synthesis, biological evaluation, and Structure-Activity Relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of α-amino acid boronates

New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC50 values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC50 value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.

Synthesis of 1-amino-2-phenylethane-1-boronic acid derivatives

The boron analogue of N-acetylphenylalanine, (R)-1-acetamido-2-phenylethane-1-boronic acid (5b), has been synthesized from (+)-pinanediol phenylmethane-1-boronate (1b), which was converted by (dichloromethyl)lithium to the (S)-1-chloro-2-phenylethane-1-boronate (2b), then with N-lithiohexamethyldisilazane to the silylated 1-amino-2-phenylethane-1-boronic ester 3b, which was desilylated and acetylated in situ to (+)-pinanediol (R)-1-acetamido-2-phenylethane-1-boronate (4b) and then cleaved to the free boronic acid 5b with boron trichloride. 1-Amino-2-phenylethane-1-boronic esters (6) were found to be isolable but unstable, deboronating to 2-phenylethylamine under the influence of heat or hydroxylic solvents. 1-Amino-2-phenylethane-1-boronic acid, though not isolable, partially survives for an hour in cold aqueous solution. Attempts to synthesize the stable α-acetamido boronic esters (4) directly by reaction of lithioacetamide with 1-halo-2-phenylethane-1-boronic esters (2) have resulted in a major proportion of O-alkylation to form imino esters. Pinacol 1-acetamidino-2-phenylethane-1-boronate (8) has been obtained from the α-iodo boronic ester 2d and acetamidine.

Synthesis and properties of pinanediol α-amido boronic esters

The use of (+)-pinanediol as the chiral directing group for the synthesis of several α(R)-α-amido boronic esters and acids, which are boronic acid analogues of N-acyl-L-amino acids, has been explored. RBO2Pin (Pin = cis-pinane-2,3-diyl) was homologated to (S)-RCHClBO2Pin, which was converted to (R)-RCH-(NHAc)BO2Pin and, for R = isopropyl, to (R)-RCH(NHCOAc)B(OH)2 by previously reported methods. Where R = isobutyl, methyl, or (benzyloxy)methyl, zinc chloride catalysis was required for the homologation step. Two (S)-acetamido boronic esters (R = isopropyl, isobutyl) were made from (-)-pinanediol. Acylation of the unstable α-amino boronic ester intermediate with carbobenzyloxy chloride was accomplished in the synthesis of PhCH2CH(NHCOOCH2Ph)BO2Pin, but attempted boron trichloride cleavage of the pinanediol boronic ester to the acid also cleaved the benzyloxy group. Hydroboration of allyl halides or allyl benzyl ether with (1,2-phenyldioxy)borane has yielded γ-substituted boronic esters. These were converted to (+)-pinanediol esters and converted by the general route outlined above to α-acetamido δ-substituted boronic esters. (Pinanediyldioxy)borane has been prepared and found to be a sluggish hydroborating agent.