- Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
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Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
- Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
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p. 3720 - 3746
(2021/05/04)
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- Design, synthesis, and biological studies of novel 3-benzamidobenzoic acid derivatives as farnesoid X receptor partial agonist
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Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, regulates the metabolism of bile acid and lipids as well as maintains the stability of internal environment. FXR was considered as a therapeutic target of liver disorders, such as drug-induced liver injury, fatty liver and cholestasis. The previous reported FXR partial agonist 6 was a suitable lead compound in terms of its high potent and low molecular size, while the docking study of compound 6 suggested a large unoccupied hydrophobic pocket, which might be provided more possibility of structure-activity relationship (SAR) study. In this study, we have performed comprehensive SAR and molecular modeling studies based on lead compound 6. All of these efforts resulted in the identification of a novel series of FXR partial agonists. In this series, compound 41 revealed the best activity and strong interaction with binding pocket of FXR. Moreover, compound 41 protected mice against acetaminophen-induced hepatotoxicity by the regulation of FXR-related gene expression and improving antioxidant capacity. In summary, these results suggest that compound 41 is a promising FXR partial agonist suitable for further investigation.
- Hu, Lijun,Ren, Qiang,Deng, Liming,Zhou, Zongtao,Cai, Zongyu,Wang, Bin,Li, Zheng
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- AMINO ACID DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISEASES
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The present disclosure provides certain amino acid derivatives that inhibit NF-kB activation and are therefore useful for the treatment of inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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- Loss of benzene to generate an enolate anion by a site-specific double-hydrogen transfer during CID fragmentation of o-alkyl ethers of ortho-hydroxybenzoic acids
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Collision-induced dissociation of anions derived from orffco- alkyloxybenzoic acids provides a facile way of producing gaseous enolate anions. The alkyloxyphenyl anion produced after an initial loss of CO2 undergoes elimination of a benzene molecule by a double-hydrogen transfer mechanism, unique to the ortho isomer, to form an enolate anion. Deuterium labeling studies confirmed that the two hydrogen atoms transferred in the benzene loss originate from positions 1 and 2 of the alkyl chain. An initial transfer of a hydrogen atom from the C-l position forms a phenyl anion and a carbonyl compound, both of which remain closely associated as an ion/neutral complex. The complex breaks either directly to give the phenyl anion by eliminating the neutral carbonyl compound, or to form an enolate anion by transferring a hydrogen atom from the C-2 position and eliminating a benzene molecule in the process. The pronounced primary kinetic isotope effect observed when a deuterium atom is transferred from the C-l position, compared to the weak effect seen for the transfer from the C-2 position, indicates that the first transfer is the rate determining step. Quantum mechanical calculations showed that the neutral loss of benzene is a thermodynamically favorable process. Under the conditions used, only the spectra from ortho isomers showed peaks at mlz 77 for the phenyl anion and mlz 93 for the phenoxyl anion, in addition to that for the ortho-specific enolate anion. Under high collision energy, the ortho isomers also produce a peak at mlz 137 for an alkene loss. The spectra of meta and para compounds show a peak at mlz 92 for the distonic anion produced by the homolysis of the O-C bond. Moreover, a small peak at mlz 136 for a distonic anion originating from an alkyl radical loss allows the differentiation of para compounds from meta isomers. Copyright
- Attygalle, Athula B.,Bialecki, Jason B.,Nishshanka, Upul,Weisbecker, Carl S.,Ruzicka, Josef
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experimental part
p. 1224 - 1234
(2009/09/29)
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- Design and synthesis of low molecular weight compounds with complement inhibition activity
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An attempt was made to synthesize a series of non-cytotoxic low molecular weight compounds of varying substitutions and functionalities having pharmacophore activity like carbonyl compounds, carboxylic acid and bioisosteres like tetrazole and phenyl acrylic acid. The in vitro assay of these analogues for the inhibition of complement activity revealed significant inhibitory activity for varying substituents and, particularly, for bioisosteres, that is, tetrazole and phenyl acrylic acid derivatives.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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p. 4891 - 4899
(2007/10/03)
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- Synthesis of low molecular weight compounds with complement inhibition activity
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An attempt was made to synthesize a series of non-cytotoxic low molecular weight meta-substituted aromatic ethers (2-4, 5-7) and some of their bioisosteres (14-16) and to evaluate their activity on the activation of human complement (classical pathway) and their intrinsic hemolytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis by these analogues indicate that the aldehydic meta substituted aromatic ethers show inhibitory potency, while carboxylic acid meta substituted aromatic ethers show hemolytic activity. Some of the bioisosteres exhibit both inhibitory as well as hemolytic property.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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p. 1249 - 1251
(2007/10/03)
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- Synthesis and structure-activity relationships of analogs of 2'-deoxy-2'- (3-methoxybenzamido)adenosine, a selective inhibitor of trypanosognal glycosomal glyceraldehyde-3-phosphate dehydrogenase
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In continuation of a project aimed at the structure-based design of drugs against sleeping sickness, analogs of 2'-deoxy-2'-(3- methoxybenzamido)adenosine (1) were synthesized and tested to establish structure-activity relationships for inhibiting glycosomal glyceraldehyde-3- phosphate dehydrogenase (GAPDH). Compound 1 was recently designed using the NAD: GAPDH complexes of the human enzyme and that of Trypanosoma brucei, the causative agent of sleeping sickness. In an effort to exploit an extra hydrophobic domain due to Val 207 of the parasite enzyme, several new 2'- amido-2'-deoxyadenosines were synthesized. Some of them displayed an interesting improvement in inhibitory activity compared to 1. Carbocyclic or acyclic analogs showed marked loss of activity, illustrating the importance of the typical (C-2'-endo) puckering of the ribose moiety. We also describe the synthesis of a pair of compounds that combine the beneficial effects of a 2- and 8-substituted adenine moiety on potency with the beneficial effect of a 2'-amide moiety on selectivity. Unfortunately, in both cases, IC50 values demonstrate the incompatibility of these combined modifications. Finally, introduction of a hydrophobic 5'-amide group on 5'-deoxyadenosine enhances the inhibition of the protozoan enzyme significantly, although the gain in selectivity is mediocre.
- Van Calenbergh,Verlinde,Seehens,De Bruyn,Callens,Blaton,Peeters,Rozenski,Hol,Herdewijn
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p. 3838 - 3849
(2007/10/02)
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- Chemistry of Fruit Flies: Composition of the Male Rectal Gland Secretions of some Species of South-East Asian Dacinae. Re-examination of Dacus Cucurbitae (Melon Fly)
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The major components of the rectal glandular secretions of male Dacus (Bactrocera) umbrosus (jack fruit fly), D. (Bactrocera) nigrotibialis, D. (Bactrocera) albistrigatus, D. (Zeugodacus) tau and D. (Zeugodacus) sp. (taxonomically similar to D. tau) have been identified.Alcohols, spiroacetals, and amides are the dominant components.The major component in the rectal gland secretion of Dacus (Zeugodacus) cucurbitae (melon fly) is shown to be ethyl 4-hydroxybenzoate and not 2-ethoxybenzoic acid.
- Perkins, Michael V.,Kitching, William,Drew, Richard A. I.,Moore, Christopher J.,Koenig, Wilfried A.
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p. 1111 - 1117
(2007/10/02)
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