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1.
Apirat Laobuthee Hatsuo Ishida Suwabun Chirachanchai 《Journal of inclusion phenomena and macrocyclic chemistry》2003,46(3-4):179-185
This study was carried out with the aim to optimize the dissolution propertiesof diclofenac (DIC) – a non-steroidal anti-inflammatory drug sparingly solublein water – through association -with -cyclodextrin (CD). Theeffect of CD on the aqueous solubility of DIC was evaluated by thephase solubility method. The amount of DIC dissolved increased linearly withthe addition of CD according to an AL type plot and without precipitationof the complex. The apparent stability constant of the complex, calculated supposinga 1:1 stoichiometry, was 295 M-1; this value was confirmed by circulardichroism analysis. DIC/CD interactions were also studied in water by1H and 13C NMR spectroscopy. Equimolar DIC/CD solid systems were prepared by physical-mixing, kneading, co-evaporation andfreeze-drying, and their properties in the solid state studied by DifferentialScanning Calorimetry, X-ray powder diffractometry and Fourier-TransformInfrared analysis. For sake of comparison, the mixture of DIC and CDseparately lyophilized was investigated too. The results demonstrated that thefreeze-dried product had the highest degree of amorphization and they were inagreement with the existence of an inclusion complex in the solid state. Thedissolution profiles of the drug from each solid system were affected by its physico-chemical properties, the freeze-dried being the most rapidly dissolvingforms. 相似文献
2.
Christina Heroven Victoria Georgi Gaurav K. Ganotra Prof. Paul Brennan Finn Wolfreys Prof. Dr. Rebecca C. Wade Amaury E. Fernández‐Montalván Apirat Chaikuad Prof. Dr. Stefan Knapp 《Angewandte Chemie (International ed. in English)》2018,57(24):7220-7224
Prolonged drug residence times may result in longer‐lasting drug efficacy, improved pharmacodynamic properties, and “kinetic selectivity” over off‐targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5‐iodotubercidin (5‐iTU) derivatives as a model for an archetypal active‐state (type I) kinase–inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen–aromatic π interactions in the haspin–inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding‐energy calculations. 相似文献
3.
Thitiporn Rungsimanon Apirat Laobuthee Mikiji Miyata Suwabun Chirachanchai 《Journal of inclusion phenomena and macrocyclic chemistry》2008,62(3-4):333-338
N,N-bis(2-hydroxyalkylbenzyl)alkylamine (HBA) is a derivative obtained from a single time ring opening of benzoxazines. For HBA with methyl group at ortho and para positions, and at N atom, the reaction between this derivative and ditosylated compound gives [1+1] dibenzo-monoaza-crowns. For HBA without methyl group at ortho position, the compound gives [2+2] macrocyclic ethers. The studies on inclusion phenomena using Pedersen’s and molar ratio techniques clarify the alkali metal ion guest inclusion to be 2:1 for [2+2] and 5:2 for [1+1] macrocycles. 相似文献
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Mehmet Karatas Apirat Chaikuad Bianca Berger Michael H. G. Kubbutat Frank Totzke Stefan Knapp Conrad Kunick 《Molecules (Basel, Switzerland)》2021,26(6)
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines. 相似文献
6.
Moses Moustakim Dr. Peter G. K. Clark Laura Trulli Dr. Angel L. Fuentes de Arriba Dr. Matthias T. Ehebauer Dr. Apirat Chaikuad Dr. Emma J. Murphy Jacqui Mendez-Johnson Dr. Danette Daniels Dr. Chun-Feng D. Hou Yu-Hui Lin Dr. John R. Walker Dr. Raymond Hui Dr. Hongbing Yang Prof. Dr. Lucy Dorrell Dr. Catherine M. Rogers Octovia P. Monteiro Dr. Oleg Fedorov Dr. Kilian V. M. Huber Prof. Dr. Stefan Knapp Dr. Jag Heer Prof. Dr. Darren J. Dixon Prof. Dr. Paul E. Brennan 《Angewandte Chemie (International ed. in English)》2017,56(3):908-908
7.
Kaewvilai A Rujitanapanich S Wattanathana W Veranitisagul C Suramitr S Koonsaeng N Laobuthee A 《Molecules (Basel, Switzerland)》2012,17(1):511-526
A series of benzoxazine monomer supramolecules with different substituted groups on their benzene ring was prepared with a Mannich reaction and characterized by FTIR, 1H-NMR and MS. The obtained products were 3,4-dihydro-3-(2'-hydroxyethylene)-6-methyl-2H-benzoxazine (BM1), 3,4-dihydro-3-(2'-hydroxyethylene)-6-ethyl-2H-benz-oxazine (BM2), and 3,4-dihydro-3-(2'-hydroxyethylene)-6-methoxy-2H-benzoxazine (BM3). The efficiency of alkali metal ion extraction from the products was determined with Pedersen's technique, while the complexation of the Ce(III) ion was confirmed by the Job's and the mole ratio methods. The evidence of complex formation between benzoxazine monomers and Ce(III) ions was obtained with FTIR and a computational simulation. Single phase ceria (CeO?) as observed with XRD was successfully prepared by calcinating the Ce(III)-benzoxazine monomer complexes at 600 °C for 2 h. In addition, the geometry of the ceria nanoparticles confirmed by TEM is spherical, with an average diameter of 10-20 nm. 相似文献
8.
Vclav Nmec Michaela Hylsov Luk Maier Jana Flegel Sonja Sievers Slava Ziegler Martin Schrder Benedict‐Tilman Berger Apirat Chaikuad Barbora Val
íkov Stjepan Uldrijan Stanislav Drpela Karel Sou
ek Herbert Waldmann Stefan Knapp Kamil Paruch 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(4):1074-1078
Reported is the identification of the furo[3,2‐b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc‐like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal‐mediated couplings, including assembly of the furo[3,2‐b]pyridine scaffold by copper‐mediated oxidative cyclization. Optimization of the subseries containing 3,5‐disubstituted furo[3,2‐b]pyridines afforded potent, cell‐active, and highly selective inhibitors of CLKs. Profiling of the kinase‐inactive subset of 3,5,7‐trisubstituted furo[3,2‐b]pyridines revealed sub‐micromolar modulators of the Hedgehog pathway. 相似文献
9.
Amornrat Lertworasirikul Nu‐orn Choothong Hiroaki Yoshida Michiya Matsusaki Toshiyuki Kida Apirat Laobuthee Mitsuru Akashi 《Journal of polymer science. Part A, Polymer chemistry》2012,50(23):4823-4828
The thermosensitivity of biodegradable and non‐toxic amphiphilic polymer derived from a naturally occurring polypeptide and a derivative of amino acid was first reported. The amphiphilic polymer consisted of poly(γ‐glutamic acid) (γ‐PGA) as a hydrophilic backbone, and L ‐phenylalanine ethyl ester (L ‐PAE) as a hydrophobic branch. Poly(γ‐glutamic acid)‐graft‐L ‐phenylalanine (γ‐PGA‐graft‐L ‐PAE) with grafting degrees of 7–49% were prepared by varying the content of a water‐soluble carbodiimide (WSC). γ‐PGA‐graft‐L ‐PAE with a grafting degree of 49% exhibited thermoresponsive phase transition behavior in an aqueous solution at around 80°C. The copolymers with grafting degrees in the range of 30–49% showed thermoresponsive properties in NaCl solution. A clouding temperature (Tcloud) could be adjusted by changing the polymer concentration and/or NaCl concentration. The thermoresponsive behavior was reversible. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012 相似文献
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Olivier E. Nonga Darja Lavogina Erki Enkvist Katrin Kestav Apirat Chaikuad Sarah E. Dixon-Clarke Alex N. Bullock Sergei Kopanchuk Taavi Ivan Ramesh Ekambaram Kaido Viht Stefan Knapp Asko Uri 《Molecules (Basel, Switzerland)》2021,26(14)
We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg)6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology. 相似文献