- 3D-printed cartridge system for in-flow photo-oxygenation of 7-aminothienopyridinones
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A 3D-printed polypropylene (PP) continuous-photoflow cell based on a modular cartridge system was developed for the photo-oxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones, using ambient air as the sole co-reactant. This strategy takes advantage of the versatility of 3D-printing to construct cost-effective meso-scale reactors. In addition to scalability, a short residence time (tR 2 min) in 100-W blue LED light that minimizes the formation of dark, insoluble decomposition products is a tangible benefit of this technology.
- Rastelli, Ettore J.,Yue, Doris,Millard, Caroline,Wipf, Peter
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supporting information
(2020/12/29)
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- Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors
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Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.
- Yang, Bin,Vasbinder, Melissa M.,Hird, Alexander W.,Su, Qibin,Wang, Haixia,Yu, Yan,Toader, Dorin,Lyne, Paul D.,Read, Jon A.,Breed, Jason,Ioannidis, Stephanos,Deng, Chun,Grondine, Michael,Degrace, Nancy,Whitston, David,Brassil, Patrick,Janetka, James W.
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supporting information
p. 1061 - 1073
(2018/02/17)
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- A METHOD FOR THE SITE-SPECIFIC ENZYMATIC LABELLING OF NUCLEIC ACIDS IN VITRO BY INCORPORATION OF UNNATURAL NUCLEOTIDES
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Provided herein are analogs of unnatural nucleotides bearing predominantly hydrophobic nucleobase analogs that form unnatural base pairs during DNA polymerase- mediated replication of DNA or RNA polymerase-mediated transcription of RNA. In this manner, the unnatural nucleobases can be introduced in a site-specific way into oligonucleotides (single or double stranded DNA or RNA), where they can provide for site-specific cleavage, or can provide a reactive linker than can undergo functionalization with a cargo -bearing reagent by means of reaction with a primary amino group or by means of click chemistry with an alkyne group of the unnatural nucleobase linker.
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- Natural-like replication of an unnatural base pair for the expansion of the genetic alphabet and biotechnology applications
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We synthesized a panel of unnatural base pairs whose pairing depends on hydrophobic and packing forces and identify dTPT3-dNaM, which is PCR amplified with a natural base pair-like efficiency and fidelity. In addition, the dTPT3 scaffold is uniquely tolerant of attaching a propargyl amine linker, resulting in the dTPT3PA-dNaM pair, which is amplified only slightly less well. The identification of dTPT3 represents significant progress toward developing an unnatural base pair for the in vivo expansion of an organism's genetic alphabet and for a variety of in vitro biotechnology applications where it is used to site-specifically label amplified DNA, and it also demonstrates for the first time that hydrophobic and packing forces are sufficient to mediate natural-like replication.
- Li, Lingjun,Degardin, Melissa,Lavergne, Thomas,Malyshev, Denis A.,Dhami, Kirandeep,Ordoukhanian, Phillip,Romesberg, Floyd E.
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supporting information
p. 826 - 829
(2014/02/14)
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- Design and synthesis of piperazinylpyridine derivatives as novel 5-HT 1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS)
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We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT 1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piper-azine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.
- Asagarasu, Akira,Matsui, Teruaki,Hayashi, Hiroyuki,Tamaoki, Satoru,Yamauchi, Yukinao,Sato, Michitaka
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experimental part
p. 34 - 42
(2009/07/18)
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- SUBSTITUTED HETEROCYCLES AND THEIR USE AS CHK1, PDK1 AND PAK INHIBITORS
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This invention relates to novel compounds of Formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds possess CHK1 kinase inhibitory activity, PDK1 inhibitory activity and Pak kinase inhibitory activity and are accordingly useful in the treatment and/or prophylaxis of cancer.
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Page/Page column 114
(2008/06/13)
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- Sulfonic acid sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds
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The compounds of formula I herein exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, for treating a patient suffering from, or subject to, a physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- 1-SUBSTITUTED AMINO-3-THIENO-[3,2-c]PYRIDINYLOXY-2-PROPANOLS
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This invention provides new compounds of formula I, STR1 wherein X is sulphur or oxygen,R is alkyl of 3 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubstituted by alkyl of 1 to 4 carbon atoms, α-dialkylpropinyl of 5 to 9 carbon atoms or α-dialkyl-allyl of 5 to 9 carbon atoms, hydroxyalkyl of 2 to 7 carbon atoms or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the last two radicals being separated by at least two carbon atoms from the nitrogen atom to which R is bound, R 1 isI. hydrogen or alkyl of 1 to 4 carbon atoms in the 2,3,6 or 7 position, orIi. chlorine or bromine, in the 2, 3 or 7 position,Iii. nitro or--NHA wherein A is alkanoyl of 1 to 4 carbon atoms, in the 2, 3 or 7 position, orIv. fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, andR 2 isI. hydrogen or alkyl of 1 to 4 carbon atoms in the 2, 3, 6 or 7 position,Ii. chlorine or bromine, in the 2, 3 or 7 position, orIii. fluorine in the 2 or 3 position,Useful in the treatment of heart diseases.
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