Metal-free functionalization of tyrosine residues in short peptides and study of the morphological alterations.

An efficient functionalization of tyrosine residues in phenolic regions is achieved under metal-free conditions. The strategy involves the conversion of a tyrosine residue to 4-amino phenylalanine or 4-amino-3-methoxy phenylalanine in short peptides through a controlled oxidative dearomatization. This transformation is achieved in one pot with good yields and excellent regioselectivity. Consequently, the self-assembly of the peptide compounds has been studied at the nanoscopic level before and after functionalization. The results suggest that the peptide derivatives comprising amide groups promote intermolecular H-bonding interactions and the difference in -OH and -NH2 functional groups is found to be responsible for the morphological changes. Morphological transitions from 1D nanowires to 2D nanosheets were observed during functional group modification.

6-Strand to Stable 10/12 Helix Conformational Switch by Incorporating Flexible ß-hGly in the Homooligomers of Camphor Derived ß-Amino Acid: NMR and X-Ray Crystallographic Evidence.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel ß-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible ß-hGly spacer at alternate positions (1 : 1 ß-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing ß-amino acids of either alternate chirality or alternate ß2/ß3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[ß-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions.

Therapeutic Potential of Benzimidazoisoquinoline Derivatives in Alleviating Murine Hepatic Fibrosis.

Short Title: Benzimidazoisoquinoline derivatives as potent antifibrotics Hepatic fibrosis is a pathological condition of liver disease with an increasing number of cases worldwide. Therapeutic strategies are warranted to target the activated hepatic stellate cells (HSCs), the collagen-producing cells, an effective strategy for controlling the disease progression. Benzimidazoisoquinoline derivatives were synthesized as hybrid molecules by the combination of benzimidazoles and isoquinolines to evaluate their anti-fibrotic potential using an in-vitro and in-vivo model of hepatic fibrosis. A small library of benzimidazoisoquinoline derivatives (1-17 and 18-21) was synthesized from 2-aryl benzimidazole and acetylene functionalities through C-H and N-H activation. Compounds (10 and its recently synthesized derivatives 18-21) depicted a significant decrease in PDGF-BB and/or TGFß-induced proliferation (1.7-1.9 -fold), migration (3.5-5.0 -fold), and fibrosis-related gene expressions in HSCs. These compounds could revert the hepatic damage caused by chronic exposure to hepatotoxicants, ethanol, and/or carbon tetrachloride as evident from the histological, biochemical, and molecular analysis. Anti-fibrotic effect of the compounds was supported by the decrease in the malondialdehyde level, collagen deposition, and gene expression levels of fibrosis-related markers such as α-SMA, COL1α1, PDGFRß, and TGFRIIß in the preclinical models of hepatic fibrosis. In conclusion, the synthesized benzimidazoisoquinoline derivatives (compounds 18, 19, 20, and 21) possess anti-fibrotic therapeutic potential against liver fibrosis.

Anticancer effect and apoptosis induction by azaflavanone derivative in human prostate cancer cells.

Polyphenols are naturally occurring organic compounds with varying structures represented by four major groups: flavonoids, phenolic acids, lignans and stilbenes. Several studies suggested that these secondary metabolites have health benefits due to its anti-tumorigenic effect. Therefore, substantial effort has been put forward to isolate and characterize these natural compounds and synthesize analogues that may serve as potential anti-cancer therapeutics. This present study is aimed at designing and synthesis of azaflavanone derivative and in understanding its mechanism of action in vitro and in vivo. Molecular docking studies predicted that the compound can potentially bind strongly to the Cyclin E1-Cdk2 complex which is a key mediator of the cell cycle progression indicating a biological interference in aggressive prostate cancer. Further downstream studies to understand its cytotoxicity and mechanism of action showed this azaflavanone derivative markedly inhibits viability of prostate cancer cells (DU145) showing an IC50 value of 0.4 µM compared to other cancer cells. The pharmacological ROS insult using the azaflavanone derivative increases the oxidative damage leading to high expression of apoptotic markers with increasing concentration. On compound treatment, the cells lose the metabolic flexibility accompanied by mitochondrial dysfunction leading to cell cycle arrest and apoptosis. Further, no compound mediated toxicity was observed in xenograft mouse model of prostate cancer at a concentration as high as 5 mg/kg. The tumor burden was reduced to 60% rendering the azaflavanone derivative a potential candidate in cancer therapeutics. Collectively, the compound triggers cell cycle arrest and ROS mediated oxidative stress sensitizing the cancerous cells towards apoptosis.

"Click" reaction based synthesis of nimbolide derivatives and study of their insect antifeedant activity against Spodoptera litura Larvae.

A series of Nimbolide-triazole conjugates were synthesized through copper(I)- catalyzed azide-alkyne "click" chemistry approach and these derivatives (2-4, 2a-2l) were characterized using modern spectroscopic techniques. Antifeedant activities of these derivatives were studied on Tobacco Caterpillar, Spodoptera litura (F.) using no-choice leaf disk bioassay. Interestingly, the synthesized derivatives were more effective in reducing feedancy by insect species when compared to the parent nimbolide. Among the tested compounds, 2a, 2c, and 2d showed potent antifeedancy with ED50 values of 0.49, 0.95 and 0.97mg/cm2 against S. litura. Several of the analogs were also toxic or caused developmental abnormalities following leaf disc assay.

LC-HRMS determination of piperine on rat dried blood spots: A pharmacokinetic study.

A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed and validated for the determination of piperine (PPR) on dried blood spots (DBS). DBS samples were prepared by spiking the whole blood with analyte to produce 30 µL of blood spots on specimen collection cards. Chromatographic separation was achieved on an Atlantis dC18 column using acetonitrile and water (0.1% formic acid) (85:15, v/v) as mobile phase in an isocratic mode of elution at a flow rate of 0.75 mL/min. MS detection was carried out in electrospray positive ion mode for the target ions and monitored at m/z 286.1465 for PPR and 272.1303 for the internal standard (IS). The developed method exhibited a linear dynamic range over 0.01-2000 ng/mL for PPR on DBS. The overall extraction recovery of PPR from DBS was 92.5%. Influence of hematocrit and spot volume on DBS was also evaluated and found to be well within the acceptable limits. The method was successfully applied to pharmacokinetic studies of PPR in rats.