Chemistry

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The extent of alloying and the alloy composition, which are crucial in determining the activity and selectivity of bimetallic catalysts, were studied in porous silica encapsulated AgPd catalysts using XRD, HRTEM and HAADF-STEM. Water-dispersible ligand protected Pd ultra-small clusters and Ag nanoparticles of three different sizes were used as the precursors. The high reactivity of Pd ultra-small clusters enhanced the alloying of larger Ag nanoparticles to some extent. Encapsulation appeared to have minimised the sintering of the resultant nanoparticles. The earlier suggestions of the role of d-band positions with respect to adsorption energies holds good for the AgPd system and alloying enhances the activity. Alloy with the composition of Ag50Pd50 was found to be the most active with the reaction rate enhanced two fold compared to that in other compositions. Other factors like particle size and sinter-resistance also played important roles in enhancing the activity of these catalysts. © 2017 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

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(SoNS) School of Natural Sciences

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New Journal of Chemistry

Understanding alloy structure and composition in sinter-resistant AgPd@SiO2 encapsulated catalysts and their effect on catalytic properties

A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC50 values &lt;10 µg/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides. © 2017 Elsevier Ltd

Bioorganic and Medicinal Chemistry Letters

Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents

Natural products are the source of innumerable pharmaceutical drug candidates and also form an important aspect of herbal remedies. They are also a source of various bioactive compounds. Herein we have leveraged the structural attributes of several natural products in building a library of architecturally diverse chiral molecules by harnessing R-tryptophan as the chiral auxiliary. It is converted to its corresponding methyl ester 1 which in turn provided a bevy of 1-aryl-tetrahydro-β-carbolines 2a-d, which were then converted to chiral compounds via a diversity oriented synthetic strategy (DOS). In general, intermolecular and intramolecular ring rearrangements facilitated the formation of the final compounds. Four different classes of molecules with distinct architectures were generated, adding up to nearly twenty-two individual molecules. Phenotypic screening of a representative section of the library revealed two molecules that selectively inhibit MCF7 breast cancer cells with IC50 of ∼5 μg mL-1 potency. © 2017 The Royal Society of Chemistry.

Organic and Biomolecular Chemistry

A diversity oriented synthesis of natural product inspired molecular libraries

Molecular couplings between DNA and water together with the accompanying processes of energy exchange are mapped via the ultrafast response of DNA backbone vibrations after OH stretch excitation of the water shell. Native salmon testes DNA is studied in femtosecond pump-probe experiments under conditions of full hydration and at a reduced hydration level with two water layers around the double helix. Independent of their local hydration patterns, all backbone vibrations in the frequency range from 940 to 1120 cm-1 display a quasi-instantaneous reshaping of the spectral envelopes of their fundamental absorption bands upon excitation of the water shell. The subsequent reshaping kinetics encompass a one-picosecond component, reflecting the formation of a hot ground state of the water shell, and a slower contribution on a time scale of tens of picoseconds. Such results are benchmarked by measurements with resonant excitation of the backbone modes, resulting in distinctly different absorption changes. We assign the fast changes of DNA absorption after OH stretch excitation to structural changes in the water shell which couple to DNA through the local electric fields. The second slower process is attributed to a flow of excess energy from the water shell into DNA, establishing a common heated ground state in the molecular ensemble. This interpretation is supported by theoretical calculations of the electric fields exerted by the water shell at different temperatures. © 2017 Author(s).

Structural Dynamics

Molecular couplings and energy exchange between DNA and water mapped by femtosecond infrared spectroscopy of backbone vibrations

Drug toxicity is a long-standing concern of modern medicine. A typical anti-pain/fever drug paracetamol often causes hepatotoxicity due to peroxynitrite ONOO−. Conventional blood tests fail to offer real-time unambiguous visualization of such hepatotoxicity in vivo. Here we report a luminescent approach to evaluate acute hepatotoxicity in vivo by chromophore-conjugated upconversion nanoparticles. Upon injection, these nanoprobes mainly accumulate in the liver and the luminescence of nanoparticles remains suppressed owing to energy transfer to the chromophore. ONOO− can readily bleach the chromophore and thus recover the luminescence, the presence of ONOO− in the liver leads to fast restoring of the near-infrared emission. Taking advantages of the high tissue-penetration capability of near-infrared excitation/emission, these nanoprobes achieve real-time monitoring of hepatotoxicity in living animals, thereby providing a convenient screening strategy for assessing hepatotoxicity of synthetic drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angewandte Chemie - International Edition

Real-Time In Vivo Hepatotoxicity Monitoring through Chromophore-Conjugated Photon-Upconverting Nanoprobes

Bioisosteric modification of known fucosidase inhibitors A and B, resulted in three new types of molecules, 4b, 5c and 6a (belonging to furopyridinedione, thiohydantoin and hydantoin chemotypes) that could potentially bind to α-l-fucosidase (bovine kidney origin). Molecular docking revealed and compared the putative binding interaction between 4b, 5c and 6a with A and B against the active site of a homology model of α-l-fucosidase. Based on this initial investigation, design and synthesis of a library of small molecules based on furopyridinedione, thiohydantoin and hydantoin, followed by their in vitro screening against α-l-fucosidase (bovine kidney origin) generated a potent inhibitor (compound 4e) with IC50 of ∼0.7 μM. Compound 4e possessed no cytotoxic properties when tested against healthy mammalian COS-1 cells. Reaction kinetics study suggested it to be a mixed inhibitor. Finally compounds 4a, b, e and f, bearing the furopyridinedione motif also exhibited substantial inhibition of the proliferation of MCF 7 breast cancer cells. © The Royal Society of Chemistry.

RSC Advances

Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of α-l-fucosidase

An efficient solvent free Pd(pCH2S)2dba catalyzed green-chemical strategy for the synthesis of diaryl disulfides from aryl thiols in moderate to excellent yield is reported. Variety of diaryl disulfides were synthesized. The catalyst is recyclable up to four cycles. © 2016 Elsevier Ltd

Tetrahedron Letters

Solvent free, palladium catalyzed highly facile synthesis of diaryl disulfides from aryl thiols

C(sp)–C(sp2) bond formation via Sonogashira cross-coupling reactions on 6-halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-ones with appropriate alkynes was explored. Optimization of reaction conditions with various catalysts, ligands, bases, and solvents was conducted. The combination of PdCl2(MeCN)2 with X-Phos proved to be the best metal–ligand system for this conversion in the presence of triethylamine (Et3N) in tetrahydrofuran at room temperature for iodosubstrates, at 80°C for the bromosubstrates in 8 h, and also for the chlorosubstrates in 16 h. We also demonstrated synthesis of a successful diversity-oriented synthesis library of highly functionalized quinazolinones via Cu-free Sonogashira coupling of diverse aryl halides and azido-alkyne (“click”) ligation reactions with substituted azides. The library exhibited significant antimicrobial activity when screened against several microorganisms. © 2017 Wiley Periodicals, Inc.

Journal of Heterocyclic Chemistry

Cu-free Sonogashira Type Cross-Coupling of 6-Halo-2-cyclopropyl-3-(pyridyl-3-ylmethyl) Quinazolin-4(3H)-ones as Potential Antimicrobial Agents

Furosemide (FS), a loop diuretic drug, exhibits polymorphism not only in pure entity, but also in cocrystal/salt forms. In continuation of our previous report of color cocrystals polymorphism of FS and 4,4′-bipyridine (4BPY), FS was further screened for color cocrystals by cocrystallization with other pyridines using a slow evaporative solution crystallization method. Interestingly, 2:1 molecular salt of FS and 1,2-bis(4-pyridyl)ethylene (4BPE) displayed color polymorphism in isopropanol yielding an orange (form 1I, plates) and the yellow (form 1II, blocks) crystals concomitantly. The yield of orange crystals, which appeared within 10-15 h, has always been more compared to the later formed yellow crystals, thus signifying the preference for orange crystals. The cocrystallization experiment once also yielded a yellow-colored 2:3 molecular salt (form 1III); however these crystals could not be reproduced later. Further, cocrystallization of FS and 4BPE from THF, dioxane, and their mixture produced comparatively unstable solvates, form 1IV, form 1V, and form 1VI crystals, respectively. Cocrystallization of FS with other pyridines like 1,2 bis(4-pyridyl)ethane (4BPA), 1,2 bis(4-pyridyl)propane (4BPP), 1,2 bis(2-pyridyl)ethylene (2BPE), and 1,10-phenanthroline (Phen) also gave colorless molecular salts 2, 4 and cocrystals 3 and 5 respectively. The single crystal structure analysis revealed the formation of a common sandwich motif between FS and pyridines through varying geometry π-stacking interactions in all the crystals. The significant color difference between the polymorphs could be attributed to the different levels of conjugation generated by dissimilar π-stacking patterns between the two components. Investigation on the origin of the color difference using density functional theory calculations revealed the decrease in the highest occupied molecular orbital-lowest unoccupied molecular orbital gap for orange crystals compared to yellow crystals. © 2017 American Chemical Society.

Crystal Growth and Design

Salts and Cocrystals of Furosemide with Pyridines: Differences in π-Stacking and Color Polymorphism

Nonheme iron complexes bearing tetradentate N-atom-donor ligands with cis labile sites show great promise for chemoselective aliphatic C-H hydroxylation. However, several challenges still limit their widespread application. We report a mechanism-guided development of a peroxidase mimicking iron complex based on the bTAML macrocyclic ligand framework (Fe-bTAML: biuret-modified tetraamido macrocyclic ligand) as a catalyst to perform selective oxidation of unactivated 3° bonds with unprecedented regioselectivity (3°:2° of 110:1 for adamantane oxidation), high stereoretention (99\%), and turnover numbers (TONs) up to 300 using mCPBA as the oxidant. Ligand decomposition pathways involving acid-induced demetalation were identified, and this led to the development of more robust and efficient Fe-bTAML complexes that catalyzed chemoselective C-H oxidation. Mechanistic studies, which include correlation of the product formed with the FeV(O) reactive intermediates generated during the reaction, indicate that the major pathway involves the cleavage of C-H bonds by FeV(O). When these oxidations were performed in the presence of air, the yield of the oxidized product doubled, but the stereoretention remained unchanged. On the basis of 18O labeling and other mechanistic studies, we propose a mechanism that involves the dual activation of mCPBA and O2 by Fe-bTAML, leading to formation of the FeV(O) intermediate. This high-valent iron oxo remains the active intermediate for most of the reaction, resulting in high regio- and stereoselectivity during product formation. © 2017 American Chemical Society.