69888-87-5Relevant articles and documents
Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis
Aldrich, Courtney C.,Baran, Marzena,Boshoff, Helena I. M.,Fu, Peng,Grimes, Kimberly D.,Sibbald, Paul A.,Wilson, Daniel J.
, (2020/06/29)
Lipid metabolism in Mycobacterium tuberculosis (Mtb) relies on 34 fatty acid adenylating enzymes (FadDs) that can be grouped into two classes: fatty acyl-CoA ligases (FACLs) involved in lipid and cholesterol catabolism and long chain fatty acyl-AMP ligases (FAALs) involved in biosynthesis of the numerous essential and virulence-conferring lipids found in Mtb. The precise biochemical roles of many FACLs remain poorly characterized while the functionally non-redundant FAALs are much better understood. Here we describe the systematic investigation of 5′-O-[N-(alkanoyl)sulfamoyl]adenosine (alkanoyl adenosine monosulfamate, alkanoyl-AMS) analogs as potential multitarget FadD inhibitors for their antitubercular activity and biochemical selectivity towards representative FAAL and FACL enzymes. We identified several potent compounds including 12-azidododecanoyl-AMS 28, 11-phenoxyundecanoyl-AMS 32, and nonyloxyacetyl-AMS 36 with minimum inhibitory concentrations (MICs) against M. tuberculosis ranging from 0.098 to 3.13 μM. Compound 32 was notable for its impressive biochemical selectivity against FAAL28 (apparent Ki = 0.7 μM) versus FACL19 (Ki > 100 μM), and uniform activity against a panel of multidrug and extensively drug-resistant TB strains with MICs ranging from 3.13 to 12.5 μM in minimal (GAST) and rich (7H9) media. The SAR analysis provided valuable insights for further optimization of 32 and also identified limitations to overcome.
Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymer and Their Nanomicelles for Nonviral Gene Delivery Applications
Sharma, Divya,Singh, Jagdish
, p. 2772 - 2783 (2017/11/20)
The aim of this study was to synthesize and characterize fatty acid-grafted-chitosan (fatty acid-g-CS) polymer and their nanomicelles for use as carriers for gene delivery. CS was hydrophobically modified using saturated fatty acids of increasing fatty acyl chain length. Carbodiimide along with N-hydroxysuccinimide was used for coupling carboxyl group of fatty acids with amine groups of CS. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to quantify fatty acyl substitution onto CS backbone. The molecular weight distribution of the synthesized polymers was determined using size exclusion high performance liquid chromatography and was found to be in range of the parent CS polymer (～50 kDa). The critical micelle concentration (cmc) of the polymers was determined using pyrene as a fluorescent probe. The cmc was found to decrease with an increase in fatty acyl chain length. The amphiphilic fatty acid-g-CS polymers self-assembled in an aqueous environment to form nanomicelles of ～200 nm particle size and slightly positive net charge due to the cationic nature of free primary amino groups on CS molecule. These polymeric nanomicelles exhibited excellent hemo- and cytocompatibility, as evaluated by in vitro hemolysis and MTT cell viability assay, respectively, and showed superior transfection efficiency compared to unmodified chitosan and naked DNA. The surface of these nanomicelles can be further modified with ligands allowing for selective targeting, enhanced cell binding, and internalization. These nanomicelles can thus be exploited as potential nonviral gene delivery vectors for safe and efficient gene therapy.
Effect of cosolvent on the lateral order of spontaneously formed amphiphilic amide two-dimensional crystallites at the air-solution interface
Weinbach, Susan P.,Jacquemain, Didier,Leveiller, Franck,Kjaer, Kristian,Als-Nielsen, Jens,Leiserowitz, Leslie
, p. 11110 - 11118 (2007/10/02)
At low temperature (5-12 °C), uncompressed films of insoluble amphiphilic molecules C19H39X, where the head group X contains one (CONH2, 1) or two (CONHC2H4CONH2, 2) amide groups, spontaneously form two-dimensional (2D) crystalline clusters over aqueous subphases containing soluble amide or carboxylic acid molecules. These crystallites were detected and their structures were studied using grazing incidence X-ray diffraction (GID). In the presence of subphases containing carboxylic acid (RCO2H, R = H, CH2Cl) at sufficiently high concentrations, a loss of diffraction signal was observed for 1, while amide and less concentrated acid subphases did not show such a destructive effect. The effect of the subphase solute molecules was understood in terms of the different ways in which the solutes hydrogen bond to the amide head groups of the amphiphiles. Both amide and acid solute molecules can form hydrogen-bonded cyclic dimers with the amide head groups. With an amide subphase, such dimers lead to an extension of the hydrogen-bonding network of the crystallites, and thus enhance its stability, but acid molecules may also bind to the monolayer at low concentrations with less than full occupancy. At high acid concentration, and thus more extensive formation of cyclic dimers between carboxylic acid and amphiphilic amide molecules, repulsive interactions between lone pair electrons on oxygen atoms of bound acid molecules inhibit formation of ordered arrays of these dimers and lead to a lack of diffraction signal. In 2, the second amide group strengthens the crystallites to the extent that there is no decrease in crystallinity over a 1 M formic acid subphase. The shape of the intensity profiles of the Bragg rods and the specular X-ray reflectivity measurements of 2 indicate formation of molecular trilayers.
