DNA-encoded libraries via late-stage functionalization strategies: a review.

The hit finding strategy in drug discovery has undergone a tremendous change in the past decade with the advent of DNA-encoded libraries with diverse chemical libraries. The miniaturization of the assays has enabled high-throughput screening on diverse targets to identify binders as a starting point for medicinal chemistry campaign. The diverse chemical space that can be accessed through DEL provides a unique opportunity to explore new chemistries on DNA. This review highlights the metal-mediated synthetic pathways that allow late-stage functionalisation of DNA strands to access such DEL libraries. Critical analysis of the literature and the methods employed has been done to allow readers to understand the usefulness, as well as the limitations of these protocols.

5,7-dihydroxy-2-(3-hydroxy-4, 5-dimethoxy-phenyl)-chromen-4-one-a flavone from Bruguiera gymnorrhiza displaying anti-inflammatory properties.

OBJECTIVE: Bruguiera gymnorrhiza (BRG) (L.) Lamk (Rhizophoraceae), a mangrove species, is widely distributed in the Pacific region, eastern Africa, Indian subcontinent, and subtropical Australia. The leaves of this plant are traditionally used for treating burns and inflammatory lesions. This study isolates the bioactive compound from the methanol extract of BRG leaves and evaluates the possible mechanisms of anti-inflammatory activity involved. MATERIALS AND METHODS: Bioassay-guided fractionation of BRG was performed to identify the bioactive fraction (displaying inhibition of cyclooxygenase 2 [COX2] - 5-lipoxygenase (5-LOX) activities and tumor necrosis factor-alpha (TNF-α) production at the tested concentrations of 100 and 10 µg/ml). The fractionation was performed by solvent extraction and preparative high-performance liquid chromatography. The bioactive compound was characterized by ultraviolet-visible, liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. The antioxidant potential was evaluated by electron spin resonance spectrum of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical at 250 µM. The effect of the compound was also studied on TNF-α converting enzyme and nuclear factor kappa B (NF-κB) activities at the concentrations 100, 10 and 1 µg/ml. RESULTS: Bioassay-guided purification of BRG revealed the presence of a flavone (5,7-dihydroxy-2- [3-hydroxy-4,5-dimethoxy-phenyl]-chromen-4-one) of molecular weight 330Da. It demonstrated more than 80% inhibition against COX2, 5-LOX activities and TNF-α production at 100 µg/ml. It also displayed 40% inhibition against DPPH radical at the tested concentration along with 23.1% inhibition of NF-κB activity at 100 µg/ml. CONCLUSIONS: The isolated methoxy-flavone may play a predominant role in the anti-inflammatory properties displayed by BRG leaves. Such activity may involve multiple mechanisms, namely (a) modulation of oxidative stress (b) inhibition of arachidonic acid metabolism and (c) downregulation of pro-inflammatory cytokines probably through NF-κB inhibition.

Bile acid derived PET-based cation sensors: molecular structure dependence of their sensitivity.

A number of bile acid derived photoinduced electron transfer (PET) based sensors for metal ions are prepared. A general strategy for designing the sensor with a modular nature allows for making different molecules capable of sensing different metal ions by a change in the fluorophore and receptor unit. Keeping the basic molecular structure the same, different bile acid based fluoroionophores were prepared in order to achieve the highest sensitivity toward the metal ions. The sensors showed similar binding constants for the same metal ion, but the degree of fluorescence enhancement upon addition of the metal salts were different. The sensitivities of the sensors towards a certain metal were determined from the observed fluorescence enhancement upon addition of the metal salt.

A simple and general strategy for the design of fluorescent cation sensor beads.

[Structure: see text] Chenodeoxycholic acid based PET sensors for alkali metal ions have been immobilized on Merrifield resin and on Tentagel. The fluorescence of the sensor beads is enhanced upon binding the cations. The modular nature of the sensor allows designing different sensors based on this concept.