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

Colorectal cancer typically begins from a nonmalignant polyp formation in the large intestine that, over time, develops into colorectal cancer. The growth of benign polyps can be checked if detected in the early stages of the disease. Doctors usually recommend colonoscopy to average and high-risk individuals for colorectal cancer screening. Elevated carcinoembryonic antigen (CEA) is a broadly used biomarker for colorectal cancer. The genetic and epigenetic alteration of genes such as p53, BRAF, APC, and PIK3CA is also correlated with colorectal cancer in various clinical studies. In general, tissue biopsy is most frequently used for colorectal cancer diagnosis, but the whole tumor heterogeneity cannot be accessed by this technique. Furthermore, such a highly invasive technique is not suitable for repeated testing. Recently, extracellular vesicles (EVs), lipid bilayer enclosed sacs secreted from colorectal cancer cells, are emerging as a diagnostic tool for colon cancer detection. The major advantages of using EVs for colon cancer diagnosis are (i) EVs can be isolated in a noninvasive manner from the body fluid and (ii) EV incorporated cargoes (mostly RNAs) reveal various aspects of colorectal cancer. EV-RNAs are also implicated in tumor invasion and influence the immune system for the further spread of tumors. However, due to the lack of standardized EV detection strategies, diagnostic applicability is limited. Herein, we review the recent literature on the pathobiological dependence of colorectal cancer on EV-RNAs. Further, we present the advantages of identification and characterization of EV-RNAs to explore the connection between differential expression of extracellular vesicle incorporated RNAs and colorectal cancer. How this approach may potentially translate into point of care colorectal cancer diagnostics is also discussed. © 2022 by the Author(s).

World University root node

(SoNS) School of Natural Sciences

ACS Bio and Med Chem Au

Importance of Extracellular Vesicle Derived RNAs as Critical Colorectal Cancer Biomarkers

In the presence of eosin Y, a visible light-induced one-step procedure (isolated yield of ≥75%) for thiolation of substituted 1,4-naphthoquinones using various aromatic and aliphatic thiols at room temperature is described herein. The rate-determining step of the reaction is thiyl radical generation, and the radical was characterized by high-resolution mass spectrometry. Cost effectiveness, operational simplicity, a short reaction time, high atom economy, and a very good yield make this photoredox-mediated process a useful alternative to the transition metal (e.g., Cu, Ag, and Pd)-catalyzed coupling reaction of quinones with thiols or disulfides. © 2022 American Chemical Society. All rights reserved.

Journal of Organic Chemistry

Visible Light-Mediated Thiolation of Substituted 1,4-Naphthoquinones Using Eosin y as a Photoredox Catalyst

Cytochrome P450 peroxygenases use hydrogen peroxide to hydroxylate long-chain fatty acids by bypassing the use of O2 and a redox partner. Among the peroxygenases, P450OleT uniquely performs decarboxylation of fatty acids and production of terminal olefins. This route taken by P450OleT is intriguing, and its importance is augmented by the practical importance of olefin production. As such, this mechanistic choice merits elucidation. To address this puzzle, we use hybrid QM/MM calculations and MD simulations for the OleT enzyme as well as for the structurally analogous enzyme, P450BSβ. The study of P450OleT reveals that the protonated His85 in the wild-type P450OleT plays a crucial role in steering decarboxylation activity by stabilizing the corresponding hydroxoiron(IV) intermediate (Cpd II). In contrast, for P450BSβ in which Q85 replaces H85, the respective Cpd II species is unstable and it reacts readily with the substrate radical by rebound, producing hydroxylation products. As shown, this single-site difference creates in P450OleT a local electric field (LEF), which is significantly higher than that in P450BSβ. In turn, these LEF differences are responsible for the different stabilities of the respective Cpd II/radical intermediates and hence for different functions of the two enzymes. P450BSβ uses the common rebound mechanism and leads to hydroxylation, whereas P450OleT proceeds via decarboxylation and generates terminal olefins. Olefin production projects the power of a single residue to alter the LEF and the enzyme’s function. © 2022 American Chemical Society

Journal of Chemical Information and Modeling

Local Electric Fields Dictate Function: The Different Product Selectivities Observed for Fatty Acid Oxidation by Two Deceptively Very Similar P450-Peroxygenases OleT and BSβ

Ni(ii)-tetradentate amido-quinoline complexes effectively catalysed C-H chlorination of a series of hydrocarbons in the presence of NaOCl and acetic acid. The bond dissociation energy of the C(sp3)-H bond of the substrates varies from 99.3 kcal mol−1 (cyclohexane) to 87 kcal mol−1 (ethyl benzene). Exclusively chlorinated products (TON: 220 for cyclohexane) were obtained without any hydroxylated products, thus mimicking the activity of the halogenase enzyme. © 2022 The Royal Society of Chemistry

Chemical Communications

C-H bond chlorination using nickel(ii) complexes of tetradentate amido-quinoline ligands

Modeling approaches and modern simulations to investigate the biomolecular structure and function rely on various methods. Since water molecules play a crucial role in all sorts of chemistry, the accurate modeling of water molecules is vital for such simulations. In cytochrome P450 (CYP450), in particular, water molecules play a key role in forming active oxidant that ultimately performs oxidation and metabolism. In the present study, we have highlighted the behavior of the three most widely used water models TIP3P, SPC/E, and OPC for three different CYP450 enzymes CYP450BM3, CYP450OleT, and CYP450BSβ during MD simulations and QM/MM calculations. We studied the various properties, such as RMSD, RMSF, H-bond, water occupancy, and hydrogen atom transfer (HAT), using QM/MM calculations and compared them for all three water models. Our study shows that the stabilities of the enzyme complexes are well maintained in all three water models. However, the OPC water model performs well for the polar active sites, that is, in CYP450OleT and CYP450BSβ, while the TIP3P water model is superior for the hydrophobic site, such as CYP450BM3. © 2022 American Chemical Society.

Fulltext

The Performance of Different Water Models on the Structure and Function of Cytochrome P450 Enzymes

Glioblastoma multiforme (GBM) is known as the primary malignant and most devastating form of tumor found in the central nervous system of the adult population. The active pharmaceutical component in current chemotherapy regimens is mostly hydrophobic and poorly water-soluble, which hampers clinical implications. Nanodrug formulations using nanocarriers loaded with such drugs assisted in water dispersibility, improved cellular permeability, and drug efficacy at a low dose, thus adding to the overall practical value. Here, we successfully developed a water-dispersible and biocompatible nanocargo (GO-PEG) based on covalently modified graphene oxide (GO) with a 6-armed poly(ethylene glycol) amine dendrimer for effective loading of the two hydrophobic anticancer drug molecules, CPI444 and vatalanib. These drug molecules target adenosine receptor (A2AR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and type III stem cell receptor tyrosine kinase (c-KIT), which plays a crucial role in cancers. The effective cellular delivery of the drugs when loaded on GO-PEG is attributed to the increased permeability of the drug-nanoconjugate formulation. We observed that this combinatorial drug treatment with nanocargo resulted in a significant reduction in the overall cell survival as supported by reduced calcium levels and stem cell markers such as Oct4 and Nanog, which are two of the prime factors for GBM stem cell proliferation. Furthermore, reduced expression of CD24 upon treatment with nanoformulation impeded cellular migration. Cellular assays confirmed inhibition of cell proliferation, migration, and angiogenic potential of GBM treated with GO-PEG–Drug conjugates. Ultimately, GBM U87 cells assumed programmed cell death at a very low concentration due to nanocarrier-mediated drug delivery along with the chosen combination of drugs. Together, this study demonstrated the advantage of GO-PEG mediated combined delivery of CPI444 and vatalanib drugs with increased permeability, a three-pronged combinatorial strategy toward effective GBM treatment. Copyright © 2022 Mishra, Patil, Reddy and Lochab.

Frontiers in Oncology

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation

Nanodiamonds (NDs) are increasingly being assessed as potential candidates for drug delivery in cancer cells and they hold great promise in overcoming the side effects of traditional chemotherapeutics. In the current work, carboxylic acid functionalized nanodiamonds (ND-COOH) were covalently modified with poly(amidoamine) dendrimer (PAMAM) to form amine-terminated nanodiamonds (NP). Unlike ND-COOH, the chemically modified nanodiamond platform NP revealed a pH-independent aqueous dispersion stability, enhancing its potential as an effective carrier. Physical encapsulation of poorly water soluble cabazitaxel (CTX) drug on NP formed ND-PAMAM-CTX (NPC) nanoconjugates and substantially reduced the size of CTX from micrometer to nanometer. CTX was localized within the pores of nanoparticle aggregates and the cavities of the PAMAM dendrimer, thus facilitating the loaded drug's controlled and sustained release. NPC's cumulative CTX release efficiency was determined to be ∼95% at pH 4 after 96 h. A high cellular uptake of NPC both within the cytoplasm and nucleus of U87 cells is confirmed, accounting for a reduced IC50value (1 nM). Both the cell cycle and Western blot analyses confirmed enhanced cell death and suppressed tubulin protein expression in NPC-treated cells. A significantly high inhibition to cell division with early apoptosis and reduced metastasis demonstrates the effective loading of CTX dosages on the nanocarrier. The present work highlights the potential of a newly designed nanocarrier NP as an efficient nanocargo for cellular delivery applications and may provide future insights to treat one of the most aggressive tumors in neuro-oncological research, glioblastoma multiforme (GBM). © 2022 American Chemical Society. All rights reserved.

ACS Applied Bio Materials

Dendrimer-Functionalized Nanodiamonds as Safe and Efficient Drug Carriers for Cancer Therapy: Nucleus Penetrating Nanoparticles

Cytochrome P45051(CYP51) catalyzes C-C bond cleavage during the biosynthesis of the sterol, using a mechanism which is still under debate. Moreover, the mechanistic conundrum is aggravated by the experimental results, which show that the C-C bond cleavage reaction step may start either from the gem-diol or aldehyde intermediates. The present study uses hybrid QM/MM calculations (exploration of potential energy surface) supplemented by long-scale MD simulations to elucidate the mechanism of C-C bond cleavage in 14α-demethylation of lanosterol using both gem-diol and aldehyde as starting substrates for the reaction. For gem-diol, the reaction proceeds via a proton-coupled electron transfer (PCET) type pathway. However, in the aldehyde form, demethylation follows a surprising mechanism assisted by a water molecule. In both mechanisms, the active catalyst is the classical Compound I species, [(Por+•)(Scys)FeIVO]. Since the C-C cleavage plays a crucial role in the natural biosynthesis of many complex organic molecules in the biological kingdom, the present study provides a testable mechanism of this enigmatic reaction. © 2022 American Chemical Society. All rights reserved.

ACS Catalysis

Mechanistic Conundrum of C–C Bond Cleavage by CYP51

Cytochrome P450GcoAis an enzyme that catalyzes the guaiacol unit of lignin during the lignin breakdown via an aryl-O-demethylation reaction. This reaction is intriguing and is of commercial importance for its potential applications in the production of biofuel and plastic from biomass feedstock. Recently, the F169A mutation in P450GcoAelicits a promiscuous activity for syringol while maintaining the native activity for guaiacol. Using comprehensive MD simulations and hybrid QM/MM calculations, we address, herein, the origin of promiscuity in P450GcoAand its relevance to the specific activity toward lignin-derived substrates. Our study shows a crucial role of an aromatic dyad of F169 and F395 by regulating the water access to the catalytic center. The F169A mutation opens a water aqueduct and hence increases the native activity for G-lignin. We show that syringol binds very tightly to the WT enzyme, which blocks the conformational rearrangement needed for the second step of O-demethylation. The F169A creates an extra room favoring the conformational rearrangement in the 3-methoxycatechol (3MC) and second dose of the dioxygen insertion. Therefore, using MD simulations and complemented by thorough QM/MM calculations, our study shows how a single-site mutation rearchitects active site engineering for promiscuous syringol activity. © 2022 American Chemical Society. All rights reserved.

ACS Omega

Single-Site Mutation Induces Water-Mediated Promiscuity in Lignin Breaking Cytochrome P450GcoA

Five new mononuclear lanthanide complexes, [LnL2][Et3NH]·THF/H2O (Ln = Nd, Tb, Dy) (H2LCl= 2-bis(2-hydroxy-3,5-dichloro benzyl)aminomethyl]pyridine), Ln = Nd (1), Tb (2), and Dy (3), and (H2LBr= 2-bis(2-hydroxy-3,5-dibromo benzyl)aminomethyl]pyridine), Ln = Nd (4, H2O) and Tb (5), were synthesized and structurally characterized by single-crystal X-ray diffraction analyses. Being isostructural in all the five cases, the metal center is octa-coordinated with a triangular dodecahedron (D2dsymmetry) geometry, and it is independent of the halogen substitution (Cl/Br). This close similarity is due to the composite interplay of hydrogen/halogen bond interactions that control the overall crystal packing, yet notable differences in association patterns among the individual ones arise from the subtle stereo-electronic requirement of individual molecules in the three-dimensional (3D) architecture. Hirshfeld surface and density functional theory (DFT) calculations clearly vouch for the importance of the hydrogen bond and halogen bond interactions observed in the structure. Detailed magnetic measurements using direct-current and alternating-current susceptibility measurements show slow magnetic relaxation in 3, a characteristic feature of the single-molecule magnets (SMMs), which is not shown by 1 and 2. Steady-state and time-resolved photoluminescence of Tb(III) complexes shows a strong ligand-to-metal energy transfer that can be modulated by changing the substitution on phenolic ligands. The results from these analyses indicate that it may be advantageous to consider the subtle role of hydrogen bond (HB)/halogen bond (XB) intermolecular interactions judiciously for the design of SMMs and luminescent materials based on halogen-substituted ligands. © 2022 American Chemical Society. All rights reserved.

Inorganic Chemistry

Halogen Bond Mediated Self-Assembly of Mononuclear Lanthanide Complexes: Perception of Supramolecular Interactions, Slow Magnetic Relaxation, and Photoluminescence Properties