Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4.

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Gram-Scale, Stereoselective Synthesis and Biological Evaluation of (+)-Armillariol C.

Natural products with heteroaromatic cores are ample and widespread in nature, with many compounds exhibiting promising therapeutic properties. (+)-Armillariol C (1a) is a furan-based natural product isolated from Armillaria species. Herein, we report the first enantioselective synthesis of (+)-armillariol C (1a, 79% overall yield), its enantiomer (1b), and four other analogues, on a gram-scale, using microwave-mediated, Suzuki-Miyaura cross-coupling and Sharpless asymmetric dihydroxylation reactions. Compounds were tested for plant- and mycelia-growth regulatory activity, with 1b, 7a, and 7b showing the strongest inhibitory properties in a lettuce assay and 7b and 9b inhibiting Flammulina velutipes.

Palladium-Catalyzed, N-(2-Aminophenyl)acetamide-Assisted Ortho-Arylation of Substituted Benzamides: Application to the Synthesis of Urolithins B, M6, and M7.

Pd-catalyzed, selective, monoarylation of ortho-C-H bonds of various benzamides with aryl/heteroaryl iodides has been realized using N-(2-aminophenyl)acetamide (APA) as a new bidentate directing group for the first time. The reaction was tolerant of a wide range of functional groups, and a variety of biaryl amide derivatives were successfully prepared in good to moderate yield. The utilization of N-(2-aminophenyl)acetamide as a novel directing group, Mn(OAc)2 as a co-oxidant (silver free reaction conditions), and absolute ortho-monoaryl selectivity are notable features of this reaction. In addition, the obtained monoarylated products could be further transformed into the bioactive natural products and human microflora metabolites of dietary ellagic acid derivatives, urolithin B, urolithin M6, and urolithin M7.

Rh-Catalyzed, Regioselective, C-H Bond Functionalization: Access to Quinoline-Branched Amines and Dimers.

Rh-catalyzed, chelation-induced, C-5 regioselective C-H functionalization of 8-amidoquinolines with a range of N-Boc aminals is reported for the first time. The addition of in situ generated imines to C(sp2)-H bonds afforded branched amines in good to excellent yields. Moreover, this transformation features good functional group compatibility, broad substrate scope, and mild reaction conditions and is suitable for gram-scale synthesis. In addition, an unprecedented, chelation-induced, site-selective, remote dimerization of quinolines led to the formation of dimer frameworks in moderate yields under Rh-catalyzed conditions.

Palladium-Catalyzed Direct Arylation of C(sp(3))-H Bonds of α-Cyano Aliphatic Amides.

Pd(OAc)2-catalyzed arylation of C(sp(3))-H bonds in α-cyano-α-methyl aliphatic amides is achieved in the presence of 8-aminoquinoline, as a removable directing group, using Mn(OAc)2 and Na2CO3. The current strategy enables the placement of an aryl/heteroaryl group at the ß-position of α-cyano aliphatic acids for the first time. Wide functional group tolerance and easily accessible starting materials provide an efficient protocol for the synthesis of arylated α-cyano amides. Furthermore, the synthetic utility of the products has been demonstrated by their efficient conversions to medicinally important α,α-dialkylated acid and ß-amino acid derivatives.

A dihydroindolizino indole derivative selectively stabilizes G-quadruplex DNA and down-regulates c-MYC expression in human cancer cells.

BACKGROUND: Telomeric and NHE III1, a c-MYC promoter region is abundant in guanine content and readily form G-quadruplex structures. Small molecules that stabilize G-quadruplex DNA were shown to reduce oncoprotein expression, initiate apoptosis and they may function as anticancer molecules. METHODS: Electrospray ionization mass spectrometry, spectroscopy, isothermal titration calorimetry, Taq DNA polymerase stop assay, real time PCR and luciferase reporter assay. Cell migration assay to find out the effect of derivatives on normal as well as cancer cell proliferation. RESULTS: Among three different dihydroindolizino indole derivatives, 4-cyanophenyl group attached derivative has shown maximum affinity, selective interaction and higher stability towards G-quadruplex DNA over dsDNA. Further, as a potential G-quadruplex DNA stabilizer, 4-cyanophenyl linked dihydroindolizino indole derivative was found to be more efficient in inhibiting in vitro DNA synthesis, c-MYC expression and cancer cell proliferation among human cancer cells. CONCLUSION: The present study reveals that dihydroindolizino indole derivative having 4-cyanophenyl group has potential to stabilize G-quadruplex DNA and exhibit anticancer activity. GENERAL SIGNIFICANCE: These studies are useful in the identification and synthesis of lead derivatives that will selectively stabilize G-quadruplex DNA and function as anticancer agents.

Studies on non-covalent interaction of coumarin attached pyrimidine and 1-methyl indole 1,2,3 triazole analogues with intermolecular telomeric G-quadruplex DNA using ESI-MS and spectroscopy.

In the present study, electrospray ionization mass spectrometry (ESI-MS) and spectroscopy have been used to evaluate the non-covalent interaction, stoichiometry, and selectivity of two synthetic coumarin-attached nucleoside and non-nucleoside 1,2,3-triazoles, namely, (1-(5-(hydroxymethyl)-4-(4-((2-oxo-2H-chromen-4-yloxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-furan-2-yl)5-methyl pyrimidine-2,4(1H,3H)-dione (Tr1) and 4-((1-((-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (Tr2) with two different human telomeric intermolecular G-quadruplex DNA structures formed by d(T2AG3) and d(T2AG3)2 sequences. ESI-MS studies indicate that Tr1 specifically interacts with four-stranded intermolecular parallel quadruplex complex, whereas Tr2 interacts with two hairpin as well as four-stranded intermolecular parallel quadruplex complexes. UV-Visible spectroscopic studies suggest that Tr1 and Tr2 interact with G-quadruplex structure and unwind them. Job plots show that stoichiometry of ligand:quadruplex DNA is 1:1. Circular dichroism (CD) studies of G-quadruplex DNA and Tr1/Tr2 ligands manifest that they unfold DNA on interaction. Fluorescence studies demonstrate that ligand molecules intercalate between the two stacks of quadruplex DNA and non-radiative energy transfer occurs between the excited ligand molecules (donor) and quadruplex DNA (acceptor), resulting in enhancement of fluorescence emission intensity. Thus, these studies suggest that nucleoside and non-nucleoside ligands efficiently interact with d(T2AG3) and d(T2AG3)2 G-quadruplex DNA but the interaction is not alike with all kinds of quadruplex DNA, this is probably due to the variation in the pharmacophores and structure of the ligand molecules.