Chemistry

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Shiv Nadar University

The study uses MD simulations and QM/MM calculations to address the preparatory half of the catalytic cycle for two cytochrome P450 (CYP450) enzymes, CYP450CAM and CYP450BM3. We focus on two unexplored/"gray"events: (a) the O2 entrance and binding to form the oxyferrous species as a function of the O2 concentration/pressure and (b) the protonation steps that eventually lead to the formation of the ultimate active species, compound I (cf. 7). Two fundamental and paradigm-shifting findings emerge: (a) the O2 concentration/pressure required for O2 binding must be neither high nor low. The binding is ushered by substrate choreography, which is guided by the moderate O2 pressure and strategic protein residues (Arg112 and Phe87) that block the substrate approach to the heme, thus enabling O2 accumulation near iron. (b) The formation of water channels, which elicit that the protonation steps are different for 5 → 6 and 6 → 7. The process 5 → 6, generating the ferric hydroperoxide, occurs via the channels that are formed by breakage of the salt bridges holding the propionate side chains of the porphyrin, while the formation of compound I, 6 → 7, transpires via the traditional acid-alcohol pairs (Asp251/Thr252 in CAM; Glu267/Thr268 in BM3). The location of acidic ammonium groups (Lys69 in CYP450BM3 and Arg299 in CYP450CAM) near the propionate side chains is generally conserved in the CYP450 family. Therefore, our study highlights the evolutionary need for at least two alternative water channels to tune the P450 nanomachine, so it can complete the two steps of the protonation and form ultimately compound I. Copyright © 2020 American Chemical Society.

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(SoNS) School of Natural Sciences

ACS Catalysis

A Paradigm Shift in the Catalytic Cycle of P450: The Preparatory Choreography during O2Binding and Origins of the Necessity for Two Protonation Pathways

Lithium-sulfur (Li–S) batteries are among the most promising candidates for the next-generation rechargeable batteries due to their high energy density, cost-effectiveness, environmental friendliness and being on the verge of commercialization. However, considering the cathode part, low conductivity of sulfur, large volume expansion, dissolution of polysulfides in the electrolyte and their unfavorable shuttle behavior lead to low cell capacity and poor cycle life. More importantly, the high flammability of sulfur causes safety concerns that might hinder the large-scale application of lithium-sulfur batteries in electric vehicles, especially in tropical countries. Herein, we report a covalently linked sulfur (~83\% w/w) flame retarding sustainable copolymer as a suitable and safe cathode material for the practical application of Li–S batteries in tropical region. A remarkable intrinsic flame-retardant property with appreciable specific capacity and excellent capacity retention provide an alternative strategy for designing cathode materials for safe and sustainable Li–S batteries. © 2020

Energy Storage Materials

Halogen-free flame-retardant sulfur copolymers with stable Li–S battery performance

A mild strategy for consecutive diazenylation and amination of indole moieties has been demonstrated. The functionalization occurs at C3 and C2 carbon atoms, respectively, at the indole scaffold in the presence of catalytic iodine and air at 40 °C in the 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) solvent. It is noteworthy that the aromatic amines are generated in situ by the reaction of aryl hydrazine with iodine. In general, bright red products are obtained in moderate to good yield. Control reactions are conducted to establish the reaction mechanism. Copyright © 2020 American Chemical Society.

Journal of Organic Chemistry

Iodine-Catalyzed Aerobic Diazenylation-Amination of Indole Derivatives

Arylated building blocks or heterocycles are key to myriad applications, including pharmaceutical drug discovery, materials sciences, and many more. Herein, we have reported a mild and efficient strategy for generation of aryl radicals by reacting appropriate aryl hydrazines with catalytic iodine in open air. The aryl radicals were quenched by diversely substituted 1,4-napthoquinones present in the reaction mixture to afford diversely substituted 2,3-napthoquinones in moderate to excellent yield. Control experiments provided insights into the putative reaction mechanism. Copyright © 2020 American Chemical Society.

Fulltext

ACS Omega

Generation of Aryl Radicals from Aryl Hydrazines via Catalytic Iodine in Air: Arylation of Substituted 1,4-Naphthoquinones

Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite’s death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite. © 2019, The Author(s).

Scientific Reports

Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death

Pure organic white light emitters with an afterglow (AG) feature have unique advantages and various potential applications. However, the studies of single-component organic white light emitters with AG and visible light excitation (VLE)-dependent efficient room-temperature phosphorescence (RTP) features remain a challenging area of research in photophysics. Herein, we synthesize three terephthalonitriles in which 2,3,5,6-positions are covalently attached to 2-fluoro-phenoxy (TOF), 2-chloro-phenoxy (TOC), and 2-methoxy-phenoxy groups (TOM) to give twisted geometries. We observed that powder samples of both TOC and TOM show white light emission with CIE coordinates of (0.32, 0.38) and (0.26, 0.33), respectively, while TOM gives VLE-dependent efficient RTP under ambient conditions. In addition, both TOC and TOF exhibit a dim AG feature. Spectroscopic studies reveal that dual emission of these chromophores originates via radiative decay of monomeric excited states (singlet, triplet), dimer-like excited states (DLES) (singlet, triplet), and aggregated triplet states. Detailed spectroscopic and X-ray analyses reveal the signature of DLES that is formed via conformational reorganization of the phenoxy donors in the excited states. Single-crystal X-ray diffraction analysis shows that the multiple lp(O)···π(CN)/C=C, Cl/F···π, and hydrogen-bonding interactions in the X-ray structures play a significant role in facilitating intersystem crossing, stabilizing multiple triplet states, and suppressing nonradiative decay, thereby triggering dim afterglow under ambient conditions. We found that TOC and TOF exhibit persistent RTP (PRTP) with lifetimes of 139 and 736 ms, respectively, when they are embedded in the polyvinyl alcohol matrix. Given the PRTP feature, invisible security ink application is developed. These results provide a guidance to design white light-emitting materials with afterglow and visible light-activated efficient RTP features. Copyright © 2019 American Chemical Society.

Journal of Physical Chemistry C

Use of Dimeric Excited States of the Donors in D4-A Systems for Accessing White Light Emission, Afterglow, and Invisible Security Ink

Polybenzoxazines (PBzs) are emerging as a highly promising and superior class of thermoset polymers for a variety of applications. However, it remains a significant challenge to substantially lower the ring-opening polymerization (ROP) temperature with an ease in processability. On the other hand, biomacromolecule chitosan (CS) is explored extensively, but its practical applications have been precluded by poor thermal and mechanical properties. Here, we developed a fully biobased copolymer of vanillin benzoxazine (V-fa) monomer with CS, which is effective in providing mutual benefits, effective lowering in ROP temperature of benzoxazine (70 °C), and an enhanced thermal stability of CS (by 85 °C, and with char yield of â32\%). To understand this unusual lowering in ROP temperature, we investigated the structural interaction mechanism between solvated CS and V-fa using in situ NMR studies. The analysis of fully intercalated co-structure demonstrated that there is a strong preference for ROP over Schiff base reaction. It is anticipated that benzoxazine molecules move within the interplanar distance of CS as supported by powder X-ray diffraction studies. An increase in V-fa content in feed ratio led to a placement of V-fa units from random to a systematic and hierarchical arrangement within the CS framework followed by its subsequent polymerization. The synergistic interactions were further supported by Fourier transform infrared, differential scanning calorimetry, scanning electron micrsocopy, thermogravimetric analysis, and tensile studies. Current work represents preparation of CS benzoxazine copolymers using a low-cost, efficient, and sustainable approach to assist metal-free ROP reaction of Bz to afford low curable temperature processable films. A new strategy is devised for the utility of CS-PBzs copolymers, enabling their extension to innovative applications in cross-domains. © 2019 American Chemical Society.

ACS Sustainable Chemistry and Engineering

Sustainable Framework of Chitosan-Benzoxazine with Mutual Benefits: Low Curing Temperature and Improved Thermal and Mechanical Properties

The first manganese-catalyzed cyclopropanation of indoles is reported in moderate to excellent yield with methyl-2-diazo-2-arylacetates. This new strategy involved acetyl (COCH 3 ) as the directing group and exhibited exceptional functional group tolerance. In the absence of stereodirecting groups the desired products were obtained as a mixture of diastereomers (7:3 → 8:2). Control experiments and DFT studies elucidated the probable pathway for the formation of cyclopropane-fused indole product. Deacetylation of the final products afforded both C3-substituted NH-indoles. © 2019 American Chemical Society.

Organic Letters

Directing-group-assisted manganese-catalyzed cyclopropanation of indoles

The C-branched pentose sugar d-apiose is important for plant cell wall development. Its biosynthesis as urdine diphosphate-d-apiose (UDP-d-apiose) involves decarboxylation of the UDP-d-glucuronic acid precursor coupled with pyranosyl-to-furanosyl sugar ring contraction. This unusual multistep reaction is catalysed in a single active site by UDP-d-apiose/UDP-d-xylose synthase (UAXS). Here we decipher the UAXS catalytic mechanism on the basis of crystal structures of the enzyme (which is from Arabidopsis thaliana), molecular dynamics simulations that are expanded by hybrid quantum mechanics/molecular mechanics calculations and mutational mechanistic analyses. Our studies show how UAXS uniquely integrates a classical catalytic cycle of oxidation and reduction by a tightly bound nicotinamide co-enzyme with retroaldol/aldol chemistry for the sugar ring contraction. We further demonstrate that decarboxylation occurs only after the sugar ring opening and identify that the thiol group of Cys100 steers the sugar skeleton rearrangement by proton transfer to and from C3′. The mechanistic features of UAXS highlight the evolutionary expansion of the basic catalytic apparatus of short-chain dehydrogenases/reductases for functional versatility in sugar biosynthesis. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Nature Catalysis

Deciphering the enzymatic mechanism of sugar ring contraction in UDP-apiose biosynthesis

In this chapter, we provide a brief overview of the current status, challenges and scope for charge density analysis in proteins. The approach, basic requirements, available tools for performing protein charge density analysis are discussed here. A brief review of reported charge density studies on six protein systems ranging from 4.7 to 55 kDa and with resolutions ranging from 0.78 to 0.48 Å, and the key outcomes, which were inaccessible from the routine structural studies, are highlighted. The use of neutron diffraction data and its joint refinement with X-ray diffraction data for quantifying interactions involving water molecules themselves and with the protein residues is also discussed for a lone reported protein complex. Further, we perform a topological analysis of main-chain N-HO=C hydrogen bonds both in α-helices and β-sheets of a high-resolution (0.66 Å) protein structure of hAR based on electron densities from the ELMAM2 database. The quantitative characterizations reveal that the N-HO=C type hydrogen bonds in proteins follow the same trend as those in small molecules. Furthermore, both the electrostatic and dissociation energies of H-bonds are estimated based on the electron densities and electrostatic potentials. The electrostatic energies are comparable with the experimental values. The energies were also found to correlate well with the topological properties of N-HO=C hydrogen bonds. © The Royal Society of Chemistry 2019.