Remote Amide-Controlled Gold-Catalyzed Stereoselective Hydro-heteroarylation of Acrylamides: Access to Pyrido[3,4-b]indoles

Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. The amide functionality was used as a remote control for the stereoselective hydro-heteroarylation of acrylamides. This gold-catalyzed carbocyclization provides a diversity-oriented and concise route to biologically important pyrido[3,4-b]indoles. Moreover, the adverse effect of silver salts on this hydro-heteroarylation was also studied.status: publishe

Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics

Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of-10.3983 (kcal mol-1). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity

Synthesis and Biological Screening of Pyrano[3,2‑<i>c</i>]quinoline Analogues as Anti-inflammatory and Anticancer Agents

A series of pyrano­[3,2-<i>c</i>]­quinoline based structural analogues was synthesized using one-pot multicomponent condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un­(substituted) aromatic aldehydes. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxicity activity. Initially, all the compounds were evaluated for the percent inhibition of cytokine release, and cytotoxicity activity and 50% inhibitory concentrations (IC₅₀) were also determined. Based on the primary results, it was further studied for their ability to inhibit TNF-α production in the human peripheral blood mononuclear cells (hPBMC) assay. The screening results revealed that compound <b>4c</b>, <b>4f</b>, <b>4i</b>, and <b>4j</b> were found most active candidates of the series against both anti-inflammatory and anticancer activity. The structure–activity relationship is discussed and suggested that 3-substitution on the aryl ring at C4 position of the pyrano­[3,2-<i>c</i>]­quinolone structural motif seems to be an important position for both TNF-α and IL-6 inhibition and anticancer activity as well. However, structural diversity with electron withdrawing, electron donating, sterically hindered, and heteroaryl substitution sincerely affected both the inflammation and anticancer activities