SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Bioorganic & medicinal chemistry letters

28

In recent years, various biological processes have been found to be regulated by miRNA-mediated gene silencing. A small molecule that modulate the miRNA pathway will provide the biological tool for elucidating mechanisms of miRNA-mediated gene regulation, and can be the drug lead for miRNA related diseases. In this study, we demonstrated that an aminoalkoxy-substituted thioxanthone derivative interferes Dicer-mediated processing of pre-miRNA. Information about the interaction between these xanthone derivatives and pre-miRNAs will enable us to design and develop new small molecule-based inhibitors for miRNA pathway.

Concepts: DNA, Protein, Gene, Gene expression, RNA, Molecule, Drugs, Enzyme inhibitor

28

Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson’s disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.

Concepts: Parkinson's disease, Assay, Biochemistry, Inhibitor, James Parkinson, LRRK2

28

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC(50)=0.025μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson’s disease.

Concepts: Functional group, Neurology, Enzyme inhibitor, Neurotransmitter, Inhibitor, Dopamine, Monoamine oxidase, Monoamine oxidase B

28

With a view to development of novel sialidase inhibitors, mimetics of the natural inhibitor Neu5Ac2en have been prepared in which a phosphonate group replaces the sialic acid glycerol side chain. Different hex-4-en derivatives adopt half-chair conformations that place the glycosyl phosphonate in an equatorial position. For the α-L-threo-hex-4-en derivative this conformation is equivalent to that of Neu5Ac2en, and opposite to that seen for alkyl O-glycosides with the same overall stereochemistry.

Concepts: Tertiary structure, Stereochemistry, Calculus, Vector space, Derivative, Conformation, Conformational isomerism, Cyclohexane conformation

28

Two new phenolics, (3S,4R)-3,7,2',3'-tetrahydroxy-3,4-dihydro-9H-indeno[6,5-c]chromene (caesalpiniaphenol E, 1), and (3R,4S)-3,7-dihydroxy-3-(3'-methoxy-4'-hydroxyphenyl)-4-methoxychroman (caesalpiniaphenol F, 2), together with eleven known compounds (3-13), were isolated from the heartwood of Caesalpinia sappan. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW264.7 cells. Among them, compounds 10 and 13 showed strong inhibitory activities toward the LPS-induced NO production in macrophage RAW264.7 cells, with IC(50) values of 12.5 and 8.1μm, respectively. In addition, compounds 10 and 13 inhibited the inductions of iNOS mRNA in dose-dependent manners, indicating that these compounds attenuated the synthesis of these transcripts at the transcriptional level.

Concepts: DNA, Protein, Genetics, Gene expression, Mass spectrometry, Activity, Chemical structure, Caesalpinia

28

Ten azo compounds including azo-resveratrol (5) and azo-oxyresveratrol (9) were synthesized using a modified Curtius rearrangement and diazotization followed by coupling reactions with various phenolic analogs. All synthesized compounds were evaluated for their mushroom tyrosinase inhibitory activity. Compounds 4 and 5 exhibited high tyrosinase inhibitory activity (56.25% and 72.75% at 50μM, respectively). The results of mushroom tyrosinase inhibition assays indicate that the 4-hydroxyphenyl moiety is essential for high inhibition and that 3,5-dihydroxyphenyl and 3,5-dimethoxyphenyl derivatives are better for tyrosinase inhibition than 2,5-dimethoxyphenyl derivatives. Particularly, introduction of hydroxyl or methoxy group into the 4-hydroxyphenyl moiety diminished or significantly reduced mushroom tryosinase inhibition. Among the synthesized azo compounds, azo-resveratrol (5) showed the most potent mushroom tyrosinase inhibition with an IC(50) value of IC(50)=36.28±0.72μM, comparable to that of resveratrol, a well-known tyrosinase inhibitor.

Concepts: Functional group, Ether, Enzyme inhibitor, Functional groups, Inhibitor, Xanthine oxidase inhibitor, Azo compound, Azo coupling

28

We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole’s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.

Concepts: DNA, X-ray, Crystallography, Enzyme inhibitor, Drug discovery, X-ray crystallography, High-throughput screening, Lactoylglutathione lyase

28

Our earlier research has shown that N-phenyl-2,2-dichloroacetamide analogues had much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this current study, a variety of N-arylphenyl-2,2-dichloroacetamide analogues were synthesized via Suzuki coupling reaction and their anti-cancer activity was evaluated. The results showed that N-terphenyl-2,2-dichloroacetamide analogues had satisfactory anti-cancer activity. Among them, N-(3,5-bis(benzo[d][1,3]dioxol-5-yl)phenyl)-2,2-dichloroacetamide (6k) had an IC(50) of 2.40μM against KB-3-1 cells, 1.04μM against H460 cells and 1.73μM against A549 cells.

Concepts: Chemical reaction, Chemical element, Heck reaction, Suzuki reaction, Coupling reaction, Synthesis, Dichloroacetic acid

28

A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8μM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity.

Concepts: ELISA, Serum albumin, Neurotransmitter, Bovine serum albumin, Dopamine, Monoamine oxidase, Black pepper, Monoamine oxidase A

28

Apoptosis is the process of programmed cell death and plays a fundamental role in several human diseases. We have previously reported the synthesis of the perhydro-1,4-diazepine-2,5-dione and 1,4-piperazine-2,5-dione derivatives as racemic mixtures. Compounds 1 and 2 showed a potent in vitro and in cellular extracts antiapoptotic activity. In view that the chiral discrimination has been an issue in the development and use of pharmaceutical drugs, the present contribution reports the synthesis of enantiopure peptidomimetics 1 and 2. The biological evaluation of these enantiomers as apoptosis inhibitors is also reported.

Concepts: Medicine, Disease, Death, Apoptosis, Stereochemistry, Enantiomer, Programmed cell death, Racemic mixture