Chemistry

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.

Shiv Nadar University

Targeted imaging and therapy for triple-negative breast cancer (TNBC) in the perioperative period are imperative for better disease management and improved life expectancy. Still, they are not available in clinical settings, and only a few nanoparticle-based theranostic agents potentially offer these capabilities. Herein, we develop an innovative class of biocompatible triple-modality nanoprobes (TMNPs) that offer optical imaging using optoacoustic, fluorescence, and surface-enhanced Raman scattering (SERS), as well as photothermal therapy (PTT) with near-infrared (NIR) light. The TMNPs are fabricated by immobilizing positively charged NIR fluorophores on negatively charged DNA-coated gold nanorods (AuNRs), followed by silica encapsulation. The DNA-based design allows the screening of commercially available positively charged NIR fluorophores for the optimum fluorescence emission and SERS. After design optimization, we functionalize TMNPs with folate groups to target folate receptor1 (FOLR1)-overexpressing TNBC in vitro and in vivo. Our results reveal that TMNPs preferentially accumulate in FOLR1 positive tumors in TNBC patient-derived xenograft mouse models and show excellent imaging capabilities with all three imaging modalities. Selective exposure of the tumor to a NIR laser shows efficient thermal tissue ablation without causing systemic toxicity. Collectively, TMNPs hold great promise for real-time multiplexed imaging of cancer biomarkers and therapeutic capability. © 2022 American Chemical Society. All rights reserved.

World University root node

(SoNS) School of Natural Sciences

ACS Applied Nano Materials

DNA-Functionalized Gold Nanorods for Perioperative Optical Imaging and Photothermal Therapy of Triple-Negative Breast Cancer

Herein we have discussed projects related to blue LED mediated C-H and N-H insertion reaction in indoles and related heterocycles with aryl diazoesters and iodonium ylides as sources of carbenes. Blue LED effectively facilitates these conversions and was optimized from the option of numerous other LED lights. No metal catalysts were required. The reactions provide formation of differently alkylated indoles, pyrroles and furans. Control experiments and DFT calculation were used to understand the mechanism of reactions. As an application compounds bearing azepino[4, 5-b]indole and spiropiperidino indole building blocks were synthesized from the alkylated products. © 2022 Swiss Chemical Society.

Fulltext

Chimia

Blue LED Mediated C-H and N-H Insertion of Indoles into Aryldiazoesters and Iodonium Ylides

Herein we report a hitherto novel multicomponent reaction involving pyridine and its derivatives, aryl diazoesters and N-alkylmaleimides (2 equivalents), using a blue LED under neat (solvent-free) conditions and in the absence of any metal catalysts or bases at r. t. to generate densely substituted itaconimides. This environmentally sustainable strategy generated the desired products in excellent yields. The reaction involved the carbene formation of aryl diazoesters from a blue LED and a subsequent generation of pyridine ylides. The pyridine ylides underwent [3 + 2] cycloaddition with N-alkyl maleimides followed by oxidation, subsequent ring opening of the [3 + 2] adducts and finally reaction with another molecule of N-alkyl maleimides to afford the desired itaconimide derivatives. The reaction has wide functional group tolerance at the aryl moiety of the diazoesters and also on pyridine. Control experiments and DFT studies were used to elucidate the reaction mechanism. © 2022 The Royal Society of Chemistry.

Green Chemistry

Blue LED induced solvent-free multicomponent reactions among aryl diazoacetates, pyridine derivatives and maleimides: direct eco-friendly synthesis of densely functionalized itaconimides

Both mechanically and electrically rechargeable zinc-air batteries (ZABs) have received much interest due to their high energy density and suitability for mobile and stationary applications. However, their commercialization has been impeded by the lack of robust, low-cost and environmentally benign catalyst materials that can be easily scaled up. In this context, the present work introduces a new type of transition metal-free catalytic material (AlOOH/NGr) by anchoring the pseudo-boehmite phase of aluminium oxyhydroxide (AlOOH) nanosheets over nitrogen-doped graphene (NGr) via a single-step and straightforward hydrothermal process. Furthermore, density functional theory (DFT) based computation demonstrates that the nucleation of AlOOH starts from the N-sites and points towards the strong surface interaction between AlOOH and NGr via doped nitrogen. AlOOH/NGr consisting of thin layered pseudo-boehmite sheets uniformly distributed over NGr has displayed an oxygen reduction reaction onset potential of 0.83 V and a half-wave potential of 0.72 V, along with good catalytic durability in alkaline medium. With this, AlOOH/NGr, when used as an air electrode for fabricating a primary Zn-air battery, the system has exhibited an open circuit voltage of ∼1.27 V with a flat discharge profile at a current rate of 10 mA cm−2. The fabricated system delivered a specific capacity of ∼720 mA h g−1 and a high power density of 204 mW cm−2 and is comparable to the counterpart system based on the state-of-the-art Pt/C (20 wt% Pt) cathode. Additionally, the homemade battery was able to maintain its performance after 4 times of mechanical recharging of the battery, which lasted for more than 35 h at a discharge current density of 10 mA cm−2. Thus, we have uncovered the potential of an earth-abundant metal-based catalytic system for fabricating and demonstrating a robust mechanically rechargeable zinc-air battery. © 2022 The Royal Society of Chemistry

Journal of Materials Chemistry A

A pseudo-boehmite AlOOH supported NGr composite-based air electrode for mechanically rechargeable Zn-air battery applications

Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e. the “Warburg effect”), and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this ‘glutamine addiction’ of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target, and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES-class of allosteric GAC inhibitors), including CB-839, which is currently in clinal trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of action is not well understood. Here, we shed new light on the underlying basis for the differential potencies exhibited by members of the BPTES/CB-839 family of compounds, which could not previously be explained with standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 or its analogs. Using an emerging technique known as serial room temperature crystallography, we were able to observe clear differences between the binding conformations of inhibitors with significantly different potencies. We also developed a computational model to further elucidate the molecular basis of differential inhibitor potency. We then corroborated the results from our modeling efforts using recently established fluorescence assays that directly read out inhibitor binding to GAC. Together, these findings should aid in future design of more potent GAC inhibitors with better clinical outlook.

Journal of Biological Chemistry

New insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography

Frontiers in Chemistry

Editorial: Molecular Dynamics Simulations of Metalloproteins and Metalloenzymes

We review molecular dynamic (MD) simulations of catalytic cycles for two typical cytochrome P450 enzymes that oxidize organic molecules (substrates). The simulations show that P450 is an open nanomachine that exchanges molecules with the outside and functions automatically once a substrate enters the enzyme’s cavity. The rest is done by reducing partners, a few residues, and water molecules that provide timed cues for these nanomachines. Fascinating outcomes are achieved, like opening/closing of the enzyme to uptake substrates, closings/openings of water gates to shuttle protons, and gating of channels through which the oxidized products exit and provide a ‘restart’ cue. The more we analyzed the MD trajectories, the more apparent it became: the amazing features of these enzymes are rooted in the chemistry of weak interactions in tight spaces. These cues are sensed by the protein and elicit the seemingly automatic cycle that governs the regio- and enantioselectivity of the enzymes.

Trends in Chemistry

The catalytic cycle of cytochrome P450: a fascinating choreography

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer’s disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aβ). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aβ aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aβ42 (10 µM) as a toxin. Finally, Aβ-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aβ aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aβ-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives

Antioxidants

Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin:  In Vitro Comparative Structure-Activity Studies

Indoleamine-2,3-dioxygenase (IDO1) and tryptophan dioxygenases are two heme based metalloenzymes that catalyze the tryptophan oxidation reaction by inserting molecular dioxygen to cleave the pyrrole ring. The mechanism of such ring cleavage reaction is of carcinogenic importance as the malignant tumors recruit this mechanism for immune invasion. In the presence study, we have synthesized a Novel C2 aroyl indoles inhibitor, 8d, which shows significant inhibition of 180&nbsp;nM at IC50 scale. The binding and conformational changes that transpire after inhibitor binding were thoroughly studied by molecular docking and MD simulations. The subsequent QM/MM (Quantum Mechanical/Molecular Mechanical) calculations were used to proposed the mechanism of inhibition. The QM/MM calculations show that the reaction proceeds via multistep processes where the dioxygen insertion to the substrate 8a is the rate determining process. Theoretical mechanism is further supported by mass spectroscopy, and drug metabolism/pharmacokinetics study (DMPK) and metabolic stability of compound 8d was investigated in rat and human liver microsomes.

Developing C2-Aroyl Indoles as Novel Inhibitors of IDO1 and Understanding Their Mechanism of Inhibition via Mass Spectroscopy, QM/MM Calculations and Molecular Dynamics Simulation

Understanding the local triplet (3LE), charge transfer triplet (3CT), and charge transfer singlet (1CT) is of great importance in designing thermally activated delayed fluorescence (TADF) and room-temperature phosphorescence (RTP) materials for their use in organic light-emitting devices (OLEDs), sensing, and bioimaging. Herein, two phenothiazine–quinoline conjugates (PTzQ1, PTzQ2) in which the donor (PTz) and acceptor (Q1, Q2) parts are held in near-orthogonal orientation that gives rise to spatial separation of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are reported. Photophysical studies of both conjugates along with their individual components (PTz, Q1, Q2) show that TADF occurs via reverse intersystem crossing (rISC) from the upper-level local triplet (3LE) to lower-level singlet 1 CT mediated by vibronic coupling between 3LE and 3CT, whereas RTP is realized from 3LE. It is found that all three excited states are close in energy, 0.16–0.19 eV (3 LE-1CT), 0.02–0.03 eV (1CT-3CT), and 0.14–0.16 eV (3LE-3CT) with the order of 3LE &gt; 1CT &gt; 3CT. Both conjugates exhibit a high rate constant of rISC (krISC, 7.9– 9.7 105 s-1 ), resulting in external quantum efficiency (EQE) values of ~4.7% (solution processed) with emission from both RTP and TADF components.

Advanced Photonics Research

Phenothiazine–Quinoline Conjugates Realizing Intrinsic Thermally Activated Delayed Fluorescence and Room-Temperature Phosphorescence: Understanding the Mechanism and Electroluminescence Devices