Chemistry

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Although multifunctional upconversion imaging probes have recently attracted considerable interest in biomedical research, there are currently few methods for stabilizing these luminescent nanoprobes with oligonucleotides in biological systems. Herein, a method to robustly disperse upconversion nanoprobes in physiological buffers based on rational design and synthesis of nanoconjugates comprising hairpin-DNA-modified gold nanoparticles is presented. This approach imparts the upconversion nanoprobes with excellent biocompatibility and circumvents the problem of particle agglomeration. By combining single-band anti-Stokes near-infrared emission and the photothermal effect mediated by the coupling of gold to upconversion nanoparticles, a simple, versatile nanoparticulate system for simultaneous deep-tissue imaging and drug molecule release in vivo is demonstrated. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

World University root node

(SoNS) School of Natural Sciences

Advanced Materials

Gold and Hairpin DNA Functionalization of Upconversion Nanocrystals for Imaging and In Vivo Drug Delivery

α-glucosidase is an essential enzyme located at the brush border of intestines. It is an important therapeutic target for type II diabetes. Herein we have designed a library of novel α-arylketones as inhibitors of α-glucosidase (yeast origin) via scaffold hopping and bioisosteric modification of known inhibitors of α-glucosidase. The design was validated through molecular docking that revealed strong binding interactions of the newly designed compounds against α-glucosidase. A library comprising of 15 compounds was synthesized in a combinatorial fashion, where the advanced amide intermediates were accessed through "shot gun" synthesis. The final compounds were characterized by 1H, 13C-NMR and with high resolution mass spectroscopy. In vitro screening of the compounds against yeast α-glucosidase revealed substantial inhibition with IC50s in the range of 4-10 μM (the standard drug acarbose inhibits α-glucosidase with an IC50 of 9.95 μM). Reaction kinetics suggested mixed type inhibition. Finally, in vivo studies of the most active compound 3c against Streptozotocin induced male albino Wistar rats revealed that its administration in the rats for about 4 weeks lead to a highly significant (P &lt; 0.001) decrease in the fasting blood glucose (FBG) compared to the untreated diabetic rats. Moreover, lower dose of 3c had better control over FBG in contrast to high-dose. © 2017 The Author(s).

Fulltext

Scientific Reports

A novel library of -arylketones as potential inhibitors of α-glucosidase: Their design, synthesis, in vitro and in vivo studies

Two different scoring functions, Hirshfeld fingerprint-based scoring (HFBS) and molecular operating environment (MOE), and the kernel energy method (KEM) along with counterpoise (CP)-corrected approach were used to estimate the binding energies of protein–ligand complexes and tested against a series of inhibitors of human aldose reductase enzyme. The new scoring function, HFBS, is based on Hirshfeld fingerprints, which are 2D histogram plots of the distances from the molecular Hirshfeld surface to the nearest atomic nuclei inside versus outside the surface and are highly sensitive to the immediate environment of the molecule. The Hirshfeld surface plotted over the ligand molecule helped to visualize the contacts with the active site residues and solvents, which were then taken into account for interaction energy calculations. Application of KEM-assisted CP-corrected approach facilitated an efficient way of calculating interaction energies in protein complex systems. Interaction energies calculated using MP2/6-31G(d) level of theory allowed us to rank the ligands by potency. We find that both the KEM-assisted CP-corrected interaction energies and the scoring functions used here predict comparable rankings for the strength of binding of the series of ligands as docked to the active site of the protein, which are also in good agreement with the experimental binding affinities in this case. © 2017, Springer Science+Business Media, LLC.

Structural Chemistry

Exploring potent ligand for proteins: insights from knowledge-based scoring functions and molecular interaction energies

It is a long-standing mechanistic consensus that the mutation of the proton-shuttle mediator Threonine (T) in Cytochrome P450 enzymes severs the water channel and thereby quenches the formation of the active species: the high-valent iron(iv)-oxo porphyrin π-cation radical species, compound I (Cpd I). Using MD simulations and hybrid QM/MM calculations of P450BM3 we demonstrate that this is not the case. Thus, while the original water channel is disrupted in the T268A mutant of the enzyme, a new channel is formed that generates Cpd I. With this new understanding, we address the puzzling regiochemical and kinetic-isotope effect (KIE) results (Volz et al., J. Am. Chem. Soc., 2002, 124, 9724-9725) on the sulfoxidation and N-dealkylation of dimethyl-(4-methylsulfanyl-phenyl)-amine by wild type (WT) P450BM3 and its T268A vs. F87A mutants. We show that the observed variable ratio of S/Me oxidation for these enzymes, vis-à-vis the constant KIE, originates from Cpd I being the sole oxidant. Thus, while the conserved KIE probes the conserved nature of the transition state, the variable regiochemical S/Me ratio reflects the active-site reorganization in the mutants: the shifted location of the new water channel in T268A tightens the binding of the S-end by Cpd I and increases the S/Me ratio, whereas the absence of π-interaction with the S-end in F87A creates a looser binding that lowers the S/Me ratio. Our results match the experimental findings. As such, this study sheds light on puzzling experimental results, and may shift a central paradigm in P450 research. The broader implication on enzymatic research is that a single-site mutation is not a localised alteration but one that may lead to a profound change in the active site, sufficiently so as to change the chemoselectivity of catalyzed reactions. © 2017 The Royal Society of Chemistry.

Chemical Science

MD simulations and QM/MM calculations show that single-site mutations of cytochrome P450BM3 alter the active site's complexity and the chemoselectivity of oxidation without changing the active species

Alumina nanoparticles were incorporated in blends of benzoxazine monomers synthesized from bio- and petrobased phenols, cardanol and bisphenol A, respectively, by way of a one-pot solventless methodology. The structures of the monomers were characterized by proton (1H) nuclear magnetic resonance and Fourier transform infrared spectroscopy. Thermal characterization was performed using differential scanning calorimetry and thermogravimetry. The size of bare alumina nanoparticles and those in the polymer nanocomposite was analyzed by powder X-ray diffraction. Blending of alumina particles resulted in lowering of curing temperature of benzoxazine monomer. The effect of nanoparticle incorporation was reflected in the curing behavior and adhesive properties. The adhesive strength is found to be dependent on whether solution or solventless processing is used and on the weight percent of the nanoparticles in the monomer blend. The replacement of 75\% bisphenol A content with cardanol in the benzoxazine resulted in a copolymer which showed a better or comparable adhesive strength. The adhesion was found to improve further with the incorporation of alumina nanoparticles. The lower viscosity of cardanol-based benzoxazine allowed both solventless synthesis and application of monomers, which is a way forward toward greener chemistry and low volatile organic compound processing strategies. © 2017 ICE Publishing. All rights reserved.

Green Materials

Nanoparticles as curing and adhesive aid for biobased and petrobased polybenzoxazines

Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates. © 2017, Springer Science+Business Media New York.

Life Sciences

Molecular and Cellular Biochemistry

A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton

The reactivity of dichloro-(1,10-phenanthroline)gold(III) chloride towards sulfite has been studied spectrophotometrically in phen-phenH+ buffer medium in the temperature range of 288 K to 303 K. The reaction between [Au(phen)Cl2]+ and HSO3- in phen-phenH+ buffer medium shows 1:1 stoichiometry. The reaction exhibits first order dependence on [{Au(phen)Cl2}Cl] and less than unit order dependence on [HSO3-]. Phenanthroline has a retarding effect on the reaction rate. The variation in H+ concentration did not affect the rate of the reaction significantly. The reaction obeys the following rate expression.The pseudo-first order rate constant decreases with the increase in ionic strength, while the reaction rate increases with the decrease in dielectric constant of the medium. The reaction possibly involved a one step two electron transfer process to produce AuCl2- and SO42- as the reaction products of the respective reactants. A probable mechanism in conformity with the experimental observations has been suggested. The thermodynamic and the activation parameters were calculated with respect to the equilibrium step and the slow step of the reaction mechanism respectively. © 2017 Scientific Publishers.All rights reserved.

Journal of the Indian Chemical Society

Reactivity of dichloro-(1,10-phenanthroline) gold (III) chloride towards sulfite in phen-phenH+ buffer medium

This chapter explores the utility of cardanol as a potential feedstock for the synthesis of benzoxazine monomers and polymers. Cardanol is a renewable phenolic compound obtained from the plant Anacardium occidentale L. Commercially it is produced as cashew nut shell liquid (CNSL) as a byproduct of cashew nut processing. It is currently under exploration as a valuable phenolic reagent in benzoxazine monomers and polymers. Cardanol-based benzoxazines are attractive monomers due to their sustainable aspect, opportunities for solventless synthesis, and processing. To date, Cardanol monomers have primarily been utilized for adhesive and composite applications, but they are ideal candidates for a variety of other applications, which need further exploration. © 2017 Elsevier Inc. All rights reserved.

Advanced and Emerging Polybenzoxazine Science and Technology

Cardanol-Based Benzoxazines and Their Applications

Carbonyl-carbonyl n→πinteractions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the πorbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n→πand π→πelectron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding. © 2017 The Author(s).

Nature Communications

Reciprocal carbonyl-carbonyl interactions in small molecules and proteins

Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and synthesized three C2-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C3, BBZ-ARO, and BBZ-AROCH2, which stabilize human telomeric G-quadruplex DNA with high affinity. Herein, we have studied the binding affinities and thermodynamic contributions of each of these molecules with G-quadruplex DNA and compared the same to those of the parent NDI analogue, BMSG-SH-3. Results of fluorescence resonance energy transfer and surface plasmon resonance demonstrate that these ligands have a higher affinity for G4-DNA over duplex DNA and induce the formation of a G-quadruplex. The binding equilibrium constants obtained from the microcalorimetry studies of BBZ-ARO, ALI-C3, and BBZ-AROCH2 were 8.47, 6.35, and 3.41 μM, respectively, with h-telo 22-mer quadruplex. These showed 10 and 100 times lower binding affinity with h-telo 12-mer and duplex DNA quadruplexes, respectively. Analysis of the thermodynamic parameters obtained from the microcalorimetry study suggests that interactions were most favorable for BBZ-ARO among all of the synthesized compounds. The ΔGfree obtained from molecular mechanics Poisson-Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that BBZ-ARO interacted strongly with G4-DNA. MD simulation results showed the highest hydrogen bond occupancy and van der Waals interactions were between the side chains of BBZ-ARO and the DNA grooves. A significant inhibition of telomerase activity (IC50 = 4.56 μM) and induced apoptosis in cancer cell lines by BBZ-ARO suggest that this molecule has the potential to be developed as an anticancer agent. © 2017 American Chemical Society.