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Ryuichi Ohta, Yuko Ueno, Katsuhiro Ajito
The Raman spectroscopy of pharmaceutical cocrystals based on caffeine and oxalic acid in nanosized pores of mesoporous silica has been demonstrated at various molar amounts. The Raman peak shifts of caffeine molecules express the existence of pharmaceutical cocrystals in mesoporous silica. The molar amount dependence of the peak shifts describes that caffeine and oxalic acid cocrystallized on the surface of the nanosized pores and piled up layer by layer. This is the first report that shows the Raman spectroscopy is a powerful tool to observe the synthesis of pharmaceutical cocrystals incorporated in the nanosized pores of mesoporous silica...
2017: Analytical Sciences: the International Journal of the Japan Society for Analytical Chemistry
Renu Chadha, Dimpy Rani, Parnika Goyal
PURPOSE: To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties. METHODS: Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters...
December 29, 2016: Pharmaceutical Research
Sergey G Arkhipov, Evgeniy A Losev, Elena V Boldyreva
Molecular salts and cocrystals of amino acids have potential applications as molecular materials with nonlinear optical, ferroelectric, piezoelectric, and other various target physical properties. The wide choice of amino acids and coformers makes it possible to design various crystal structures. The amino acid-maleic acid system provides a perfect example of a rich variety of crystal structures with different stoichiometries, symmetries and packing motifs built from the molecular building blocks, which are either exactly the same, or differ merely by protonation or as optical isomers...
January 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
Ksenia V Drozd, Alex N Manin, Andrei V Churakov, German L Perlovich
Experimental multistage cocrystal screening of the antituberculous drug 4-aminosalicylic acid (PASA) has been conducted with a number of coformers (pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF) and theophylline (TPH)). The crystal structures of 4-aminosalicylic acid cocrystals with isonicotinamide ([PASA+iNAM] (2:1)) and methanol solvate with caffeine ([PASA+CAF+MeOH] (1:1:1)) have been determined by single X-ray diffraction experiments. For the first time for PASA cocrystals it has been found that the structural unit of the [PASA+iNAM] cocrystal (2:1) is formed by 2 types of heterosynthons: acid-pyridine and acid-amide...
December 20, 2016: European Journal of Pharmaceutical Sciences
Mark D Chappell, Renhua Li, Stephon C Smith, Bruce A Dressman, Eric G Tromiczak, Allie E Tripp, Maria-Jesus Blanco, Tatiana Vetman, Steven J Quimby, James Matt, Thomas C Britton, Adam M Fivush, Jeffrey M Schkeryantz, Daniel Mayhugh, Jon A Erickson, Mark G Bures, Carlos Jaramillo, Mercedes Carpintero, José Eugenio de Diego, Mario Barberis, Susana Garcia-Cerrada, José F Soriano, Stephen Antonysamy, Shane Atwell, Iain MacEwan, Bradley Condon, Christine Sougias, Jing Wang, Aiping Zhang, Kris Conners, Chris Groshong, Stephen R Wasserman, John W Koss, Jeffrey M Witkin, Xia Li, Carl Overshiner, Keith A Wafford, Wesley Seidel, Xu-Shan Wang, Beverly A Heinz, Steven Swanson, John T Catlow, David W Bedwell, James A Monn, Charles H Mitch, Paul L Ornstein
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist...
December 22, 2016: Journal of Medicinal Chemistry
Howard Bregman, Jeffrey R Simard, Kristin L Andrews, Shawn Ayube, Hao Chen, Hakan Gunaydin, Angel Guzman-Perez, Jiali Hu, Liyue Huang, Xin Huang, Paul H Krolikowski, Sonya G Lehto, Richard T Lewis, Klaus Michelsen, Pamela Pegman, Matthew H Plant, Paul L Shaffer, Yohannes Teffera, Shuyan Yi, Maosheng Zhang, Jacinthe Gingras, Erin F DiMauro
Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices...
December 21, 2016: Journal of Medicinal Chemistry
Jonathan R Chekan, Joseph D Koos, Chuhan Zong, Mikhail O Maksimov, A James Link, Satish K Nair
Lasso peptides are a class of bioactive ribosomally synthesized and post-translationally modified peptides (RiPPs), with a threaded knot structure that is formed by an isopeptide bond attaching the N-terminus of the peptide to a side chain carboxylate. Some lasso peptide biosynthetic clusters harbor an enzyme that specifically hydrolyzes the isopeptide bond to yield the linear peptide. We describe here the 2.4 Å resolution structure of a lasso peptide isopeptidase revealing a topologically novel didomain architecture consisting of an open β-propeller appended to an α/β hydrolase domain...
December 21, 2016: Journal of the American Chemical Society
Masataka Ito, Kaori Nambu, Aya Sakon, Hidehiro Uekusa, Etsuo Yonemochi, Shuji Noguchi, Katsuhide Terada
Valproic acid is widely used as an antiepileptic agent. Valproic acid is in liquid phase while sodium valproate is in solid phase at room temperature. Sodium valproate is hard to manufacture because of its hygroscopic and deliquescent properties. To improve these, cocrystal and salt screening for valproic acid was employed in this study. Two solid salt forms, l-arginine valproate and l-lysine valproate, were obtained and characterized. By using dynamic vapor sorption method, the critical relative humidity of sodium valproate, l-arginine valproate, and l-lysine valproate were measured...
December 13, 2016: Journal of Pharmaceutical Sciences
Christoph Nitsche, Linlin Zhang, Lena F Weigel, Jonas Schilz, Dominik Graf, Ralf Bartenschlager, Rolf Hilgenfeld, Christian D Klein
A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile, and dengue virus proteases. The resulting compounds have Ki values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure-activity relationships and a high resolution X-ray cocrystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens...
December 14, 2016: Journal of Medicinal Chemistry
Sanket J Mishra, Suman Ghosh, Andrew R Stothert, Chad A Dickey, Brian S J Blagg
Glucose regulated protein 94 kDa, Grp94, is the endoplasmic reticulum (ER) localized isoform of heat shock protein 90 (Hsp90) that is responsible for the trafficking and maturation of toll-like receptors, immunoglobulins, and integrins. As a result, Grp94 has emerged as a therapeutic target to disrupt cellular communication, adhesion, and tumor proliferation, potentially with fewer side effects compared to pan-inhibitors of all Hsp90 isoforms. Although, the N-terminal ATP binding site is highly conserved among all four Hsp90 isoforms, recent cocrystal structures of Grp94 have revealed subtle differences between Grp94 and other Hsp90 isoforms that has been exploited for the development of Grp94-selective inhibitors...
December 13, 2016: ACS Chemical Biology
Guangfeng Liu, Jie Liu, Xin Ye, Lina Nie, Peiyang Gu, Xutang Tao, Qichun Zhang
The molecular-level motions of a coronene-based supramolecular rotator are amplified into macroscopic changes of crystals by co-assembly of coronene and TCNB (1,2,4,5-tetracyanobenzene) into a charge-transfer complex. The as-prepared cocrystals show remarkable self-healing behavior and thermo-mechanical responses during thermally-induced reversible single-crystal-to-single-crystal (SCSC) phase transitions. Comprehensive analysis of the microscopic observations as well as differential scanning calorimetry (DSC) measurements and crystal habits reveal that a thermally-reduced-rate-dependent dynamic character exists in the phase transition...
January 2, 2017: Angewandte Chemie
Nathaniel E Clark, Adam Katolik, Kenneth M Roberts, Alexander B Taylor, Stephen P Holloway, Jonathan P Schuermann, Eric J Montemayor, Scott W Stevens, Paul F Fitzpatrick, Masad J Damha, P John Hart
Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2',5'- and 3',5'-phosphodiester linkages. The 2',5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Tze Shyang Chia, Ching Kheng Quah
As a function of temperature, the hexamethylenetetramine-2-methylbenzoic acid (1/2) cocrystal, C6H12N4·2C8H8O2, undergoes a reversible structural phase transition. The orthorhombic high-temperature phase in the space group Pccn has been studied in the temperature range between 165 and 300 K. At 164 K, a t2 phase transition to the monoclinic subgroup P21/c space group occurs; the resulting twinned low-temperature phase was investigated in the temperature range between 164 and 100 K. The domains in the pseudomerohedral twin are related by a twofold rotation corresponding to the matrix (100/0-10/00-1...
December 1, 2016: Acta Crystallographica. Section C, Structural Chemistry
Yi Ren, Semin Lee, Jeffery Bertke, Danielle L Gray, Jeffrey S Moore
Radical salts and charge-transfer complexes (CTCs) containing tetracyanoquinodimethane (TCNQ) display electrical conductivity, which has led to the development of many TCNQ derivatives with enhanced electron-accepting properties that are applicable toward organic electronics. To expand the family of TCNQ derivatives, we report the synthesis and structures of 11,11,12,12-tetracyano-2,6-diiodo-9,10-anthraquinodimethane (abbreviated as DITCAQ), C20H6I2N4, and its charge-transfer complexes with various electron donors, namely DITCAQ-anthracene (2/1), C20H6I2N4·0...
December 1, 2016: Acta Crystallographica. Section C, Structural Chemistry
Dnyaneshwar P Kale, Sandeep S Zode, Arvind K Bansal
The last 2 decades have witnessed increased research in the area of cocrystals resulting in deeper scientific understanding, increase in intellectual property landscape, and evolution in the regulatory environment. Pharmaceutical cocrystals have received significant attention as a new solid form on account of their ability to modulate poor physicochemical properties of drug molecules. However, pharmaceutical development of cocrystals could be challenging, thus limiting their translation into viable drug products...
February 2017: Journal of Pharmaceutical Sciences
Renu Chadha, Yashika Bhalla, Avdesh Nandan, Kunal Chadha, Maninder Karan
Solvent free mechanochemical approach is utilized to synthesise new cocrystals of chrysin using supramolecular chemistry based upon reliable synthons. Chrysin, a flavone nutraceutical with wide range of beneficial effects has critically low bioavailability on account of its poor aqueous solubility and consequently poor absorption from the gastrointestinal tract. The present study focuses on this critical aspect and has exploited non covalent interactions to prepare its cocrystals with cytosine and thiamine hydrochloride...
February 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
Yu Wang, Weigang Zhu, Huanli Dong, Xiaotao Zhang, Rongjin Li, Wenping Hu
Organic cocrystals that are composed of two or more components usually exhibit novel, unpredictable, and even unique properties rather than a simple combination of the properties of their components, such as white-light emission, ambipolar charge transport, nonlinear optics, and ferroelectricity. Since cocrystal engineering represents a novel strategy for synthesizing multifunctional materials, which opens the door for molecular collaborative innovation, it has aroused much attention in recent years. However, as it is also a relatively new research field, it is only in its early stages of development...
December 2016: Topics in Current Chemistry (Journal)
Eleonora Freire, Griselda Polla, Ricardo Baggio
Lamotrigine is a drug used in the treatment of epilepsy and related convulsive diseases. The drug in its free form is rather inadequate for pharmacological use due to poor absorption by the patient, which limits its bioavailability. On the other hand, the lamotrigine molecule is an excellent hydrogen-bonding agent and this has been exploited intensively in the search for better formulations. The formulation presently commercialized (under the brand name Lamictal) is rather complex and includes a number of anions in addition to the active pharmaceutical ingredient (API)...
November 1, 2016: Acta Crystallographica. Section C, Structural Chemistry
Yuan Jun Gao, Chen Li, Rui Liu, Wei Jun Jin
X-ray single crystal diffraction reveals that a series of cocrystals are assembled by three ring angular diazaphenanthrenes including 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline with 1,4-/1,2-diiodotetrafluorobenzenes via C-I···N halogen bonding (XB) as main driving force. Raman shift of the symmetric CI stretching vibration coupling with ring elongation and lateral ring expansion to a lower frequency by 2 to 7cm(-1) for 1,4-DITFB in cocrystals shows the existence of C-I···N halogen bonding...
February 15, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Kyle V Butler, Anqi Ma, Wenyu Yu, Fengling Li, Wolfram Tempel, Nicolas Babault, Fabio Pittella-Silva, Jason Shao, Junyi Wang, Minkui Luo, Masoud Vedadi, Peter J Brown, Cheryl H Arrowsmith, Jian Jin
Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases...
November 10, 2016: Journal of Medicinal Chemistry
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