Chemistry

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Shiv Nadar University

Porous organic materials are an emerging class of functional nanostructures with unprecedented properties. Dynamic covalent assembly of small organic building blocks under thermodynamic control is utilized for the intriguingly simple formation of complex molecular architectures in one-pot procedures. In this Review, we aim to analyze the basic design principles that govern the formation of either covalent organic frameworks as crystalline porous polymers or covalent organic cage compounds as shape-persistent molecular objects. Common synthetic procedures and characterization techniques will be discussed as well as more advanced strategies such as postsynthetic modification or self-sorting. When appropriate, comparisons are drawn between polymeric frameworks and discrete organic cages in terms of their underlying properties. Furthermore, we highlight the potential of these materials for applications ranging from gas storage to catalysis and organic electronics.

World University root node

(SoNS) School of Natural Sciences

Angewandte Chemie - International Edition

Covalent Organic Frameworks and Cage Compounds: Design and Applications of Polymeric and Discrete Organic Scaffolds

A simple oxidative ring rearrangement of diversely substituted 1-(2-amminoaryl)-tetrahydro-β-carbolines has been developed to generate architecturally interesting tetrahydro-1H-indolo[2,3-b]pyrrolo[3,2-c]quinolones. This unique transformation involves four reaction centers (aniline, C1-carboline and C2/C3 of indole) and utilizes tert-butylhypochlorite as the reagent. The generic nature of the reaction was demonstrated by the synthesis of a wide variety of analogs 9a-j. A putative reaction mechanism was proposed. Cytotoxicity screening of these compounds against three human cancer cells (A2780 ovarian and HCT116 colorectal carcinoma cell lines and A549 lung adenocarcinoma cell line) revealed selective inhibition of proliferation of the A2780 human ovarian carcinoma cell line by one of the molecules 9a with an IC50 of 14 μM. No cytotoxic activity was observed in human normal fibroblasts for concentrations up to 100 μM. Compound 9a induced hyperpolarization of the mitochondrial membrane potential of the A2780 cell line leading to an increase of reactive oxygen species (ROS) that trigger cell death via apoptosis. Interestingly, compound 9a was also able to induce cell death via autophagy. Compounds that induce apoptosis and autophagy, thus leading to cancer cells' death, are good candidates for cancer therapy. © 2018 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Fulltext

New Journal of Chemistry

Synthesis of tetrahydro-1: H -indolo[2,3- b] pyrrolo[3,2- c] quinolones via intramolecular oxidative ring rearrangement of tetrahydro-β-carbolines and their biological evaluation

Indole derivatives bearing C-2 substituents have garnered a lot of attention due to their diverse biological activities. Various methods forthe synthesis of these compounds have been reported. Inspired by the hydrolysis of imines, an oxidative ring-opening reaction of 1-aryltetrahydro-β-carbolines with catalytic iodine in aqueous hydrogen peroxide, and also in the presence of appropriate amines, is described for the generation of 2-aroyl and arylmethanimine indole derivatives. The reaction proceeds under mild reaction conditions with ethanol as the solvent or under solvent-free conditions, respectively. This metal-free strategy facilitates the formation of the desired substituted C-2 indoles in moderate to excellent yields. The utility of this reaction is demonstrated by a facile multigram-scale synthesis of Luzindole, a selective melatonin receptor antagonist and an investigational drug against depression and disruption of the circadian rhythm. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

European Journal of Organic Chemistry

Iodine-Catalyzed Metal-Free Oxidative Ring Opening of 1-Aryltetrahydro-β-carbolines: Facile Synthesis of C-2 Aroyl and Aryl Methanimino Indole Derivatives

Fluorescent probes for simultaneous detection of multiple organelle specific analytes in cancer cells are essential for bioimaging applications. During abnormalities in cells, among other important parameters (metal ions, reactive oxygen species (ROS), enzymes, etc.) pH and Zn2+ are also altered in cells. Herein, we report the formation of nanoparticles of the fluorescent molecules based on carbazole-bipyridine conjugates (CBL1-3) and their use as nanoprobes to simultaneously detect Zn2+ and pH variations in lysosome. Upon increasing the pH from 4–6, these probes form nanoparticles with increased size and enhanced fluorescence at 510 nm. Among CBL1-3, nanoparticles of CBL2 upon Zn2+ binding, exhibit pH responsive intensity change only at lysosomal pH window at 610 nm and become silent above pH 7. Fluorescent imaging experiments on cancer cells revealed that the CBL2 nanoprobe is capable of localizing at lysosomes and facilitates the detection of endogenous Zn2+ and pH variations. Furthermore, the lysosomal Zn2+ variation with external stimuli induced programmed cell death was visualized using the nanoprobe. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemistrySelect

pH-Controlled Nanoparticles Formation and Tracking of Lysosomal Zinc Ions in Cancer Cells by Fluorescent Carbazole–Bipyridine Conjugates

Despite recent advances in polybenzoxazines (PBzs), especially of sustainable origin, the lowering of the curing temperature still remains a challenge in addressing their exploration in low-temperature processing applications. Innovative iron-based catalysts which are naturally abundant, cost-effective, and with larger surface area could demonstrate a practical, economic and facile approach for the development of iron NPs-polybenzoxazine composites. Here we propose an approach to develop a composite based on smartly-capped iron nanoparticles (NPs) and agro-waste phenolic-sourced cardanol benzoxazine monomer as a one-step solution with the benefits of lowering the curing temperature and providing superparamagnetism. NPs are smartly designed with a variation in the nature of the functionality in the capping agent and are characterized by thermogravimetry analysis (TGA), Fourier transform infrared (FTIR), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The NPs showed a spherical shape of ∼10 nm in size with appreciable magnetic characteristics. Both iron ions and available functionalities in the capping agent endow benefits in lowering the curing temperature of cardanol benzoxazine (64 °C), and enhancing its maximum thermal stability (34 °C), as determined by differential scanning calorimetry (DSC) and TGA, respectively. In addition, the nature of the chemical linkages in the polybenzoxazine network and the initial growth in the molecular weight of the polymer were found to be influenced by iron NPs, as supported by FTIR, nuclear magnetic resonance (1H-NMR), UV-visible (UV-vis) spectroscopy, and gel permeation chromatography (GPC). The capping-agent-facilitated NPs distribution in the polybenzoxazine matrix was determined by atomic force microscopy (AFM). Polymer nanocomposites even with a 5 wt\% loading of NPs showed good magnetic saturation and superparamagnetic behavior. The present work demonstrated a one-step solution with the incorporation of NPs in a benzoxazine monomer accounting for modification in the properties of polybenzoxazine composites with the benefits of magnetism. © 2018 The Royal Society of Chemistry.

Physics

Journal of Materials Chemistry A

Sustainable one-step strategy towards low temperature curable superparamagnetic composite based on smartly designed iron nanoparticles and cardanol benzoxazine

Reversibility between two concomitant polymorphs and their switching ability is demonstrated for the novel organic nonlinear optical (NLO) material Z-3-(3-methoxyphynyl)-2-(4-nitrophenyl)acrylonitrile. The appearances of their concomitant as well as exclusive polymorphic forms were discovered upon systematic crystallization experiments using various solvents. Determination of X-ray crystal structures confirmed that the polymorphs crystallize in centrosymmetric (P21/n) and non-centrosymmetric (Fdd2) space groups. A search using the Cambridge Structural Database revealed that there exist only 10 such polymorphic pairs. Reversible phase transitions and the switching ability between the polymorphs can be achieved via both heat and solvents as stimuli. Structural analysis confirmed that the polymorphs have two-dimensional similarity. Further, quantitative and qualitative analysis of interaction energies based on the UNI force field and energy frameworks indicate that they possess very similar energies, although the centrosymmetric form is slightly lower in energy. A comparably high value of second harmonic generation activity and the NLO properties as estimated based on gas-phase and in-crystal calculations suggest that the non-centrosymmetric form could be a potential NLO material. To the best of our knowledge, this study is the rarest of its kind to show the reversibility and switching ability between centrosymmetric and non-centrosymmetric polymorphic phases in an organic material, induced via both thermal and solvent stimuli. © 2017 American Chemical Society.

Crystal Growth and Design

Concomitance, Reversibility, and Switching Ability of Centrosymmetric and Non-Centrosymmetric Crystal Forms: Polymorphism in an Organic Nonlinear Optical Material

The driving force for the electron transfer (ET) step in the catalytic cycle of cytochrome P450BM3 is investigated using three sets of 1 μs molecular dynamic simulations for the resting state of P450 in complex with the flavin (FMN) in the reductase domain. These sets involve the following: (i) substrate-free (SF), (ii) substrate (N-palmitoyl glycine, i.e., NPG)-bound (SB), and (iii) SB with the semiquinone radical anion (SQ-) of FMN. Starting from the X-ray structure of the SF heme domain, we observe that the α1-helix (of the reductase) and the C-helix (of the heme) undergo reorientation to a parallel orientation, which is the thermochemically stable form. The reorientation of the helices pushes away the FMN to a distance of 18.4 Å from the heme's center. When the substrate binds it causes the I-helix of the heme domain to kink and push the C-helix toward the α1-helix, thereby locking the latter two into a stabilized perpendicular conformation, wherein the FMN-heme distance is 12 Å. The distance drops further in the SQ- form, and upon QM/MM geometry optimization the two moieties approach 8.8 Å, which enhances the ET rate (by 104-106 fold) to the heme's Fe3+ ion. These motions are driven by hydrogen bond strengthening between the C- and the α1-helices. Finally, substrate binding leads to formation of an organized water chain connecting the FMN and heme moieties. The water channel assists the ET and couples it to the proton transfer steps that should activate O2 and create the oxo-iron active species. © 2017 American Chemical Society.

Journal of the American Chemical Society

Choreography of the Reductase and P450BM3 Domains Toward Electron Transfer Is Instigated by the Substrate

A novel library of C2-substituted tryptamines (based on diverse C2-aroyl/arylimino indoles and indole-diketopiperazine hybrids) possessing antimitotic properties were designed, synthesized and screened for their inhibitory activity against tubulin polymerization, and against proliferation of A549 lung cancer, HeLa cervical cancer, MCF7 breast cancer and HePG2 liver cancer cell lines. The design of molecules were inspired from known antimitotic compounds and natural products. The molecular docking of the designed compounds indicated that they bind to the colchicin binding site of tubulin. They were synthesized by a unique iodine catalysed oxidative ring opening reaction of 1-aryltetrahydro-β-carbolines. Among the compounds synthesized quite a few compounds induced cytotoxicity on the cancer cells by disrupting the tubulin polymerization. They were found to be non-toxic for healthy cells. Immuno Fluorescence study for the most active molecules (between ~6 μM concentration) against A549 and HeLa cells demonstrated complete disruption and shrinkage of the microtubule structures. These compounds also inhibited indoleamine-2, 3-dioxygenase with low micromolar IC50. © 2018 Elsevier B.V.

European Journal of Pharmaceutical Sciences

Design, synthesis and biological evaluation of a novel library of antimitotic C2-aroyl/arylimino tryptamine derivatives that are also potent inhibitors of indoleamine-2, 3-dioxygenase (IDO)

Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na+ levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490 nM from 17.54 µM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action. © 2018 Elsevier Ltd

Life Sciences

Bioorganic and Medicinal Chemistry Letters

Benzoxazine derivatives of phytophenols show anti-plasmodial activity via sodium homeostasis disruption

Isomerization of double bonds from an allylic to propenyl position is generally mediated by expensive metal catalysts, demanding an additional synthetic step, thereby reducing sustainability of the reaction. However, such functionalities are inherent in naturally occurring compounds, enabling a versatile protocol for their industrial utility. Herein, we report the synthesis of benzoxazine monomers based on biosourced isomeric phenols, eugenol (E) and isoeugenol (IE), and biobased amine, furfurylamine (fa) to form E-fa and IE-fa monomer, respectively. The structural variation in the phenols revealed a differential chemical reactivity, during both the synthesis of the monomer and the polymerization reaction, confirming a significant influence of isomerism. The monomers only differ in the position of the double bond in the para-substituted propylene unit forming nonconjugated vs conjugated alkylene chain with the benzene ring containing benzoxazine in E-fa and IE-fa, respectively. The structure of the monomers was confirmed by 1H NMR, 13C NMR, FTIR, XRD, and mass spectrometry. The high purity of monomer was further affirmed by HPLC and DSC to demonstrate the effect of isomerization on the polymerization behavior. The extended conjugation of the double bond in IE-fa with the proximal benzoxazine ring showed a higher reactivity toward ring-opening polymerization, polymer conversion, and cross-linking reactions as supported by FTIR, NMR, and DSC-based kinetic studies. Thermal stability, mechanical properties, and adhesive analysis by TGA, DMTA, and lap shear strength measurements further supported the effect of structural isomerism of monomers with a higher potential of PIE-fa over the PE-fa network. Current work illustrates an economic, one-step, microwave-assisted, and VOC's- and catalyst-free synthesis with a simultaneous solventless processing of synthesized monomers using renewable materials as feedstocks for high-performance polymers. © 2018 American Chemical Society.