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1.  Squaramide-Catalyzed Enantioselective Michael Addition of Diphenyl Phosphite to Nitroalkenes** 
Simple catalyst, high enantioselectivities. An easily prepared squaramide catalyst promotes highly enantioselective Michael addition reactions of diphenyl phosphite to a broad range of nitroalkenes, including those bearing acidic protons or sterically demanding aliphatic substituents. The methodology provides facile access to chiral β-nitro phosphonates, which are precursors to biologically active β-amino phosphonic acids.
doi:10.1002/anie.200904779
PMCID: PMC3930154  PMID: 19950156
asymmetric catalysis; hydrogen bonds; Michael addition; organocatalysis; squaramides
2.  Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis 
Objectives
New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. Targeting DNA gyrase is a clinically validated therapeutic approach using fluoroquinolone antibiotics to target the gyrase subunit A (GyrA) of the heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting the gyrase subunit B (GyrB), which has not been targeted for TB. The biological activities of two potent small-molecule inhibitors of GyrB have been characterized to validate its targeting as a therapeutic strategy for treating TB.
Materials and methods
Novobiocin and aminobenzimidazole 1 (AB-1) were tested for their activity against Mycobacterium tuberculosis (Mtb) H37Rv and other mycobacteria. AB-1 and novobiocin were also evaluated for their interaction with rifampicin and isoniazid as well as their potential for cytotoxicity. Finally, AB-1 was tested for in vivo efficacy in a murine model of TB.
Results
Novobiocin and AB-1 have both been shown to be active against Mtb with MIC values of 4 and 1 mg/L, respectively. Only AB-1 exhibited time-dependent bactericidal activity against drug-susceptible and drug-resistant mycobacteria, including a fluoroquinolone-resistant strain. AB-1 had potent activity in the low oxygen recovery assay model for non-replicating persistent Mtb. Additionally, AB-1 has no interaction with isoniazid and rifampicin, and has no cross-resistance with fluoroquinolones. In a murine model of TB, AB-1 significantly reduced lung cfu counts in a dose-dependent manner.
Conclusions
Aminobenzimidazole inhibitors of GyrB exhibit many of the characteristics required for their consideration as a potential front-line antimycobacterial therapeutic.
doi:10.1093/jac/dkr449
PMCID: PMC3254195  PMID: 22052686
non-replicating bacteria; topoisomerase; benzimidazole; drug resistance; ciprofloxacin; novobiocin; non-tuberculous mycobacteria
3.  Palladium-Catalyzed β-Allylation of 2,3-Disubstituted Indoles 
Organic Letters  2008;10(12):2381-2384.
Given the prevalence of the indole nucleus in biologically active compounds, the direct C3-functionalization of 2,3-disubstituted indoles represents an important problem. Described is a general, high-yielding method for the palladium-catalyzed β-allylation of carba- and heterocycle fused indoles, including complex natural product substrates.
doi:10.1021/ol8006277
PMCID: PMC3380807  PMID: 18491859
4.  A High-throughput Fluorescence Polarization Assay for Inhibitors of Gyrase B 
Journal of biomolecular screening  2011;16(2):230-238.
DNA gyrase, a type II topoisomerase that introduces negative supercoils into DNA, is a validated antibacterial drug target. The holoenzyme is composed of 2 subunits, gyrase A (GyrA) and gyrase B (GyrB), which form a functional A2B2 heterotetramer required for bacterial viability. A novel fluorescence polarization (FP) assay has been developed and optimized to detect inhibitors that bind to the adenosine triphosphate (ATP) binding domain of GyrB. Guided by the crystal structure of the natural product novobiocin bound to GyrB, a novel novobiocin–Texas Red probe (Novo-TRX) was designed and synthesized for use in a high-throughput FP assay. The binding kinetics of the interaction of Novo-TRX with GyrB from Francisella tularensis has been characterized, as well as the effect of common buffer additives on the interaction. The assay was developed into a 21-μL, 384-well assay format and has been validated for use in high-throughput screening against a collection of Food and Drug Administration–approved compounds. The assay performed with an average Z′ factor of 0.80 and was able to identify GyrB inhibitors from a screening library.
doi:10.1177/1087057110392038
PMCID: PMC3176662  PMID: 21245469
fluorescence polarization; gyrase; assay development; high-throughput screen; anthracycline
5.  Enantioselective α-Amination of 1,3-Dicarbonyl Compounds Using Squaramide Derivatives as Hydrogen Bonding Catalysts 
Organic letters  2010;12(9):2028-2031.
Catalytic enantioselective α-hydrazination of 1,3-dicarbonyl compounds with azodicarboxylates was investigated in the presence of our newly developed hydrogen bonding catalyst, squaramide 3j. High yields and high enantioselectivities were achieved with low catalyst loading under mild conditions.
doi:10.1021/ol1005104
PMCID: PMC2862278  PMID: 20359172
6.  Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts 
Journal of the American Chemical Society  2008;130(44):14416-14417.
Thioureas represent the dominant platform for hydrogen bond promoted asymmetric catalysts. A large number of reactions, reported in scores of publications, have been successfully promoted by chiral thioureas. The present paper reports the use of squaramides as a highly effective new scaffold for the development of chiral hydrogen bond donor catalysts. squaramide catalysts are very simple to prepare. The (-)-cinchonine modified squaramide (5), easily prepared through a two step process from methyl squarate, was shown to be an effective catalyst, even at catalyst loadings as low as 0.1 mol%, for the conjugate addition reactions of 1,3-dicarbonyl compounds to β-nitrostyrenes. The addition products were obtained in high yields and excellent enantioselectivities.
doi:10.1021/ja805693p
PMCID: PMC2701638  PMID: 18847268

Results 1-6 (6)