We produced (S)-4-cyano-3-(4-chlorophenyl)-butyrate by highly stereoselective biocatalyst in this study. A nitrilase-producing strain, named Gibberella intermedia WX12, was isolated by 3-(4-chlorophenyl)-glutaronitrile as substrate in the screening with phenol-sodium hypochlorite method. The fermentation conditions and catalytic properties of this strain were investigated. The preferred carbon and nitrogen sources for nitrilase production were lactose (30 g/L) and peptone (20 g/L). After being cultivated for 96 h, the cells were collected for use in biotransformation. The hydrolysis of 3-(4-chlorophenyl)-glutaronitrile was performed at 30 degrees C in phosphate buffer (pH 8.0, 50 mmol/L) for 24 h to give (S)-4-cyano-3-(4-chlorophenyl)-butyric acid with 90% yield and > 99% of ee, which can be used for the synthesis of (R)- and (S)-baclofen. The configuration of product was determined by chemically converting it to baclofen and comparison with the authentic sample by chiral HPLC analysis.
Aminohydrolases ; metabolism ; Baclofen ; chemical synthesis ; chemistry ; Biocatalysis ; Chlorophenols ; chemistry ; Gibberella ; enzymology ; Hydrolysis ; Nitriles ; chemistry ; Prodrugs ; chemical synthesis ; chemistry

The new HIV-1 NNRTI drug Etravirine (TMC125) and a promising drug candidate Rilpivirine (TMC278) in phase III clinical trial are compounds belonging to the diarylpyrimidine (DAPY) family. They are extremely high potent against both wild-type and many drug-resistant HIV-1 strains, providing new hope for HIV-infected patients who fail to use current drugs due to the emergence of drug-resistant HIV mutants. The discovery and development of DAPY derivatives as next-generation NNRTI drugs depend on multidisciplinary coordination and their success has encouraged new researches to explore more next-generation NNRTIs with new scaffolds. This review described the story of discovery and development of DAPY derivatives as next-generation NNRTIs and related progress.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Resistance, Viral ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Nitriles ; chemical synthesis ; chemistry ; pharmacology ; Pyridazines ; chemical synthesis ; chemistry ; pharmacology ; Pyrimidines ; chemical synthesis ; chemistry ; pharmacology ; Reverse Transcriptase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Rilpivirine

FK778 is a synthetic malononitrilamide (MNA) that has been demonstrated to have both both immunosuppressive and anti-proliferative activities. The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihyroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity. FK778 has been demonstrated to prevent acute allograft rejection in multiple experimental transplant models in rodents, dogs and primates and to be effective in the rat model of chronic renal allograft rejection. In addition, FK778 has been shown to prevent vascular remodeling after mechanical intimal injury via a mechanism which may be related to tyrosine kinase inhibitory activity in vascular smooth muscle cells. Another intriguing activity of the MNA family is the ability to block replication of members of the Herpes virus family with in vitro evidence that of efficacy against cytomegalovirus (CMV) and polyoma virus, important pathogens in the transplant recipient. FK778 is currently being explored in a number of trials in solid organ transplant recipients.
Animals ; Clinical Trials, Phase I ; Humans ; Immunosuppressive Agents/*therapeutic use ; Isoxazoles/*therapeutic use ; Nitriles/chemical synthesis ; *Organ Transplantation ; Randomized Controlled Trials ; Treatment Outcome

Optically active form of alpha-cyano-3-phenoxybenzyl (CPB) alcohol, building block of pyrethroid insecticides, was synthesized as its acetate by the combination of anion-exchange resin (D301)-catalyzed transcyanation between m-phenoxybenzaldehyde (m-PBA) and acetone cyanohydrin (AC), and lipase (from Alcaligenes sp.)-catalyzed enantioselective transesterification of the resulting cyanohydrin with vinyl acetate. Through optimizing technological conditions, the catalyzing efficiency was improved considerably compared to methods previously reported. Concentrations of CPB acetate were determined by gas chromatograph. The enantio excess (e.e.) values of CPB acetate were measured by NMR (nuclear magnetic resonance) method. Effects of solvents and temperatures on this reaction were studied. Cyclohexane was shown to be the best solvent among the three tested solvents. 55 degrees C was the optimal temperature for higher degree of conversion. External diffusion limitation was excluded by raising the rotational speed to 220 r/min. However, internal diffusion could not be ignored, since the catalyst (lipase) was an immobilized enzyme and its particle dimension was not made small enough. The reaction rate was substantially accelerated when the reactant (m-PBA) concentration was as high as 249 mmol/L, but decreased when the initial concentration of m-PBA reached to 277 mmol/L. It was also found that the catalyzing capability of recovered lipase was high enough to use several batches. Study of the mole ratio of AC to m-PBA showed that 2:1 was the best choice. The strategy of adding base catalyst D301 was found to be an important factor in improving the degree of conversion of the reaction from 20% to 80%. The highest degree of conversion of the reaction has reached up to 80%.
Alcaligenes ; enzymology ; Benzaldehydes ; chemistry ; Combinatorial Chemistry Techniques ; methods ; Lipase ; chemistry ; Nitriles ; chemistry ; Organic Chemicals ; chemistry ; Phenyl Ethers ; chemical synthesis ; Technology, Pharmaceutical ; methods

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.
Antifungal Agents ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Fungi ; drug effects ; Heterocyclic Compounds ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Lipopeptides ; chemistry ; pharmacology ; therapeutic use ; Molecular Structure ; Mycoses ; drug therapy ; Nitriles ; chemistry ; pharmacology ; therapeutic use ; Plant Extracts ; chemical synthesis ; chemistry ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Pyridines ; chemistry ; pharmacology ; therapeutic use ; Quinazolines ; chemistry ; pharmacology ; therapeutic use ; Quinones ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Thiazoles ; chemistry ; pharmacology ; therapeutic use ; Triazoles ; chemistry ; pharmacology ; therapeutic use