62 research outputs found
Small Molecule Drugs for Treatment of Alzheimerâs Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6
Alzheimerâs disease (AD) is the most common form of dementia affecting millions of people worldwide and currently, the only possible treatment is the use of symptomatic drugs. Therefore, there is a need for new and disease-modifying approaches. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of ï»żserotonin receptors the subtype 4 and 6 receptors (5-HT4R and 5-HT6R) has received increasing attention and ï»żhas become a promising target for improving cognition and limit the amyloid pathology through modulation of the neurotransmitter system. A large number of publications describing the development of ligands for these serotonin receptors have emerged, and their pharmaceutical potential is now quite evident. However, ï»ż5-HT4R and 5-HT6R functionality is much more complex than initially defined. This chapter describes recent advances in the understanding of this modulation as well as the medicinal chemistry efforts towards development of selective ï»ż5-HT4R or 5-HT6R ligands
Structural Design of Anthraquinone Bridges in Direct Electron Transfer of Fructose Dehydrogenase
Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support
The
synthetic utility and theoretical basis of a photolabile hydroxylamine-linker
are presented. The developed protocols enable the efficient synthesis
and chemoselective photolytic release of either hydroxamates or carboxamides
from solid support. The bidetachable mode of the linker unit is uniquely
dependent on the solvent. Hydroxamic acids are obtained by performing
photolysis in protic solvents, whereas photolysis in aprotic solvents
enables the selective release of carboxamides
Oxidative Modification of Tryptophan-Containing Peptides
We herein present
a broadly useful method for the chemoselective
modification of a wide range of tryptophan-containing peptides. Exposing
a tryptophan-containing peptide to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) resulted in a selective cyclodehydration between the peptide
backbone and the indole side chain of tryptophan to form a fully conjugated
indolyl-oxazole moiety. The modified peptides show a characteristic
and significant emission maximum at 425 nm, thus making the method
a useful strategy for fluorescence labeling
Photolabile Linkers for Solid-Phase Synthesis
Photolabile linkers are the subjects of intense research because they allow the release of the target molecule simply by irradiation. Photochemical release of synthesis products is often facilitated without additional reagents under mild reaction conditions, which may even be environmentally friendly and appealing in the context of greener chemistry. The mild conditions also allow for applications of released material in subsequent biological screening experiments, where contamination with cleavage reagents would be detrimental. This Review pays attention to the increasing number of photolabile linkers developed for solid-phase synthesis and release and covers: (i) o-nitrobenzyloxy linkers, (ii) o-nitrobenzylamino linkers, (iii) α-substituted o-nitrobenzyl linkers, (iv) o-nitroveratryl linkers, (v) phenacyl linkers, (vi) p-alkoxyphenacyl linkers, (vii) benzoin linkers, (viii) pivaloyl linkers, and (ix) other photolabile linkers
Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa
Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.NRF (Natl Research Foundation, Sâpore)MOE (Min. of Education, Sâpore)Published versio
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