- Synthetic Indolactam V Analogues as Inhibitors of PAR2-Induced Calcium Mobilization in Triple-Negative Breast Cancer Cells
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Human proteinase-activated receptor 2 (PAR2), a transmembrane G-protein-coupled receptor (GPCR), is an attractive target for a novel anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure–activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target, protein kinase C (PKC). For this purpose, an efficient gram-scale total synthesis of indolactam V (i.e., the parent structure of all teleocidins) was developed, and a library of derivatives was prepared. Some compounds were indeed found to exhibit high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (relative to teleocidin A2). The pseudopeptidic fragment bridging the C3 and C4 positions of the indole core proved to be essential for target binding, whereas activity and target selectivity depends on the substituents at N1 or C7. This study revealed novel derivatives that show high efficacy in PAR2 antagonism combined with increased selectivity.
- Stein, Jan,Stahn, Sonja,Neud?rfl, J?rg-M.,Sperlich, Julia,Schmalz, Hans-Günther,Teusch, Nicole
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p. 147 - 154
(2018/02/06)
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- CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF
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The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.
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- Expeditious synthesis of enantiopure, orthogonally protected bis-α-amino acids (OPBAAs) and their use in a study of Nod1 stimulation
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A convenient approach towards the synthesis of orthogonally protected chiral bis-a-amino acids (OPBAAs) is described. The key transformations include: (1) a highly stereoselective conjugation (alkylation) of the Sch?llkopf bislactim ethers and oxazolidinyl alkyl halides to build a backbone skeleton; and (2) our orthogonal protection strategy. A series of enantiopure OPBAAs bearing a variety of alkyl chain as a spacer; two stereogenic centers; and three protecting groups were prepared as examples. These versatile molecules were applied to the synthesis of biologically interesting di- or tri-peptide analogues, including chiral iE-meso-DAP and A-iE-meso-DAP, for the study of Nod1 activation in the innate immune response.
- Chen, Po-Ting,Lin, Cheng-Kun,Tsai, Chih-Ju,Huang, Duen-Yi,Nien, Fu-Yao,Lin, Wan-Wan,Cheng, Wei-Chieh
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p. 474 - 482
(2015/01/30)
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- PROCESSES OF PREPARING A JAK1 INHIBITOR AND NEW FORMS THERETO
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This invention relates to processes for preparing a JAKl inhibitor having Formula la: as well as new forms of the inhibitor.
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- GLYCINE TRANSPORTER-INHIBITING SUBSTANCES
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The present invention relates to novel compounds of formula [I] or pharmaceutically acceptable salts thereof: The compounds of the present invention are useful in the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobias, acute stress disorder), depression, drug dependence, spasm, tremor, pain, Parkinson's disease, attention deficit hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorders, which is based on the glycine uptake-inhibiting action.
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Paragraph 0404-0406
(2014/01/08)
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- Synthesis of optically active homotryptophan and its oxygen and sulfur analogues
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d-Homotryptophan and its sulfur analogue have been synthesized by Sonogashira coupling between 3-iodoheteroarenes and ethynyloxazolidine followed by reduction of triple bond and oxidation of alcohol to acid. l-Homotryptophan and its oxygen analogue have b
- Goswami, Koushik,Paul, Sibasish,Bugde, Sandesh T.,Sinha, Surajit
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p. 280 - 286
(2012/01/05)
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- Total synthesis of (-)-indolactam v
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The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from l-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.
- Xu, Zhengren,Zhang, Fengying,Zhang, Lihe,Jia, Yanxing
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p. 2512 - 2517
(2011/05/06)
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- Synthetic aromatic amino acids from a negishi cross-coupling reaction
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An N,O-protected, iodinated bishomoalanine derivative, safely available from glutamic acid, reacts with aryl halides in a Negishi reaction in high yields. From the coupling product, Fmoc-protected amino acids with aromatic and heteroaromatic side chains were generated in high yields by racemization-free procedures. These monomers could be used for solid-phase peptide synthesis. Georg Thieme Verlag Stuttgart.
- Suhartono, Marcel,Schneider, Angelika E.,Duerner, Gerd,Goebel, Michael W.
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experimental part
p. 293 - 303
(2010/03/30)
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS
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The present invention relates to novel compounds of the formula (I), wherein R'-R7, X, Y, D and n are as defined in the specification. These compounds are cysteine protease inhibitors which include but are not limited to inhibitors of cathepsms K, L, S an
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Page/Page column 34-35; 71-72
(2008/12/04)
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- A new diastereoselective synthetic approach to the enantiopure peptidomimetic scaffold 2-oxo-1-azabicyclo[4.4.0]decane
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A general method for the synthesis of unsubstituted and C-7-substituted azabicyclo[4.4.0]decane dipeptides (23, 30a, and 30b) that can serve as dipeptide mimetics has been developed. The key step of this new method involves the coupling reaction of the ox
- Truchot, Cyrille,Wang, Qian,Sasaki, N. Andre
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p. 1765 - 1776
(2007/10/03)
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- Synthesis of orthogonally protected enantiopure 2,9-diaminodecanedioic acid: A model for a new general method for the synthesis of orthogonally protected α,α′-diaminodicarboxylic acids
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A new method for the synthesis of orthogonally protected enantiopure α,α′-diaminodicarboxylic acids is described. A key step involves the Julia olefination of an aldehyde and a sulfone, both of which are derived from an optically pure dicarboxylic amino a
- Truchot, Cyrille,Sasaki, N. Andre
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p. 393 - 406
(2007/10/03)
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- Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors
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The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11- , 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.
- Ksander, Gary M.,De Jesus, Reynalda,Yuan, Andrew,Ghai,Trapani,McMartin, Colin,Bohacek, Regine
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p. 495 - 505
(2007/10/03)
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- Synthesis of solenopsin B via stereoselective reduction of Bicyclic N,O-ketals
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A new enantioselective total synthesis of (-)-solenopsin B was described starting from L-glutamic acid as an optically active natural source, in which stereoselective reduction of bicyclic N,O-ketals with DIBALH was used as the key reaction step.
- Kotsuki, Hiyoshizo,Kusumi, Toshio,Inoue, Mase,Ushio, Yasuyuki,Ochi, Masamitsu
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p. 4159 - 4162
(2007/10/02)
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- SYNTHESES OF 3'-SUBSTITUTED-2-(CARBOXYCYCLOPROPYL)GLYCINES VIA INTRAMOLECULAR CYCLOPROPANATION. THE FOLDED FORM OF L-GLUTAMATE ACTIVATES THE NON-NMDA RECEPTOR SUBTYPE
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Four stereoisomers of 3'-methoxymethyl-L-2-(carboxycyclopropyl)glycines, conformationally constrained analogues of L-glutamate, were synthesized in a stereoselective manner from D-serinal derivative.Selective activation of either the NMDA or Non-NMDA receptor by these isomers was observed.
- Shimamoto, Keiko,Ohfune, Yasufumi
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p. 4049 - 4052
(2007/10/02)
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