142005-11-6Relevant academic research and scientific papers
N-Cinnamoylanthranilates as human TRPA1 modulators: Structure-activity relationships and channel binding sites
Chandrabalan, Arundhasa,McPhillie, Martin J.,Morice, Alyn H.,Boa, Andrew N.,Sadofsky, Laura R.
supporting information, p. 141 - 156 (2019/03/17)
The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel, which detects noxious stimuli leading to pain, itch and cough. However, the mechanism(s) of channel modulation by many of the known, non-reactive modulators has not been fully elucidated. N-Cinnamoylanthranilic acid derivatives (CADs) contain structural elements from the TRPA1 modulators cinnamaldehyde and flufenamic acid, so it was hypothesized that specific modulators could be found amongst them and more could be learnt about modulation of TRPA1 with these compounds. A series of CADs was therefore screened for agonism and antagonism in HEK293 cells stably transfected with WT-human (h)TRPA1, or C621A, F909A or F944A mutant hTRPA1. Derivatives with electron-withdrawing and/or electron-donating substituents were found to possess different activities. CADs with inductive electron-withdrawing groups were agonists with desensitising effects, and CADs with electron-donating groups were either partial agonists or antagonists. Site-directed mutagenesis revealed that the CADs do not undergo conjugate addition reaction with TRPA1, and that F944 is a key residue involved in the non-covalent modulation of TRPA1 by CADs, as well as many other structurally distinct non-reactive TRPA1 ligands already reported.
Precursor-directed combinatorial biosynthesis of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates in saccharomyces cerevisiae
Eudes, Aymerick,Benites, Veronica Teixeira,Wang, George,Baidoo, Edward E.K.,Lee, Taek Soon,Keasling, Jay D.,Loqué, Dominique
, (2015/11/24)
Biological synthesis of pharmaceuticals and biochemicals offers an environmentally friendly alternative to conventional chemical synthesis. These alternative methods require the design of metabolic pathways and the identification of enzymes exhibiting ade
Anthranilamides: New antimicroalgal active substances from a marine Streptomyces sp
Farooq Biabani,Baake, Matthias,Lovisetto, Barbara,Laatsch, Hartmut,Helmke, Elisabeth,Weyland, Horst
, p. 333 - 340 (2007/10/03)
2-[Methyl-(3-phenylpropionyl)amino]-benzoic acid (1e) was isolated from a culture of marine Stretomyces sp. strain B7747. Analogous compounds have potential importance as phytotoxic substances, hence compound 1e and the analogues 1a-1d and 1f-3a were synthesised. Antimicroalgal activity of the anthranilamide analogues showed that esters 1b, 1f and 2b were more active than the free acids. The minimum inhibitory concentration (MIC) against Chlorella vulgaris, Chlorella solokiniana, Chlorella salina and Scenedesmus subspicatus ranged from 20 to 107 μg/ml. All anthranilamides were inactive against Staphylococcus aureus, Escherichia coli, and Mucor miehei.
Synthesis and X-ray crystallographic analysis of quinazolinone cholecystokinin/gastrin receptor ligands
Yu,McCowan,Mason,Deeter,Mendelsohn
, p. 2534 - 2542 (2007/10/02)
Compounds exemplified by 2-[2-(5-bromo-1H-indol-3-yl)ethyl]-3-[3-(1- methylethoxy)phenyl]-4(3H)-quinazolinone (3, IC50 = 0.0093 μM using mouse brain membranes) represent a structurally novel series of non-peptide cholecystokinin B receptor ligands. Since asperlicin, a selective CCK-A receptor antagonist, may be regarded as a conformationally constrained 2- substituted-3-phenyl-4(3H)-quinazolinone, the progenitor of compound 3 (compound 2, 2-[2-(1H-indol-3-yl)ethyl]-3-phenyl-4(3H)-quinazolinone) might therefore represent a conformationally flexible pharmacophore of the natural product. To probe possible conformational preferences for this class of receptor ligands, in particular the spatial relationship between the indole and quinazolinone rings, we prepared a series of analogues with methyl substituents on the ethylene bridge as well as congeners with different linkers. The X-ray crystal structure conformation for compound 22 (2-[2-(1H- indol-3-yl)ethyl]-3-]-3-(1-methylethoxy)phenyl]-4(3H)-quinazolinone, IC50 = 0.026 μM) is extended with the two heteroaromatic rings adopting an antiperiplanar arrangement around the central σ bond of the ethane linker, whereas the solid-state conformation for a less active analogue 19 (2-[2-(1H- indol-3-yl)-1-methylethyl]-3-[3-(1-methylethoxyphenyl]-4(3H)-quinazolinone, IC50 = 9.1 μM) is folded with the two heteroaromatic systems adopting a synclinal orientation. However, MM2 force field calculations (MacroModel, v 3.0) suggest that the energy difference between the folded and extended conformation is small. Thus, other factors such as unfavorable steric interactions may account for the difference in receptor affinity. For derivatives with one to three methylene units separating the indole and quinazolinone rings, maximal receptor binding activity was found when the distance separating the two heteroaromatic systems is defined by an ethyl group. Introducing unsaturation into the ethylene bridge of compound 3 limited the conformational flexibility of the molecule and decreased its receptor affinity greater than 2 orders of magnitude.
