A5110238493- Alkaloids: synthesis and pharmacology
- Chemical Synthesis and Analysis
- Chemical synthesis and alkaloids
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Asymmetric Synthesis and Catalysis
- Plant-based Medicinal Research
- FOXO transcription factor regulation
- Pharmacological Receptor Mechanisms and Effects
- Cardiac electrophysiology and arrhythmias
- Synthesis and Biological Evaluation
- Steroid Chemistry and Biochemistry
- Ion channel regulation and function
- Melanoma and MAPK Pathways
- Cancer Treatment and Pharmacology
- Crystallography and molecular interactions
- Neuropeptides and Animal Physiology
- Carbohydrate Chemistry and Synthesis
- Receptor Mechanisms and Signaling
- Cancer therapeutics and mechanisms
- Organic Chemistry Cycloaddition Reactions
- Traditional and Medicinal Uses of Annonaceae
- Fluorine in Organic Chemistry
- Cyclopropane Reaction Mechanisms
- Protein Kinase Regulation and GTPase Signaling
Janssen (Belgium)
2006-2023
Johnson & Johnson (United States)
2008-2012
KU Leuven
2009
National Institutes of Health
1991-2004
National Institute of Diabetes and Digestive and Kidney Diseases
1991-2003
Delft University of Technology
1984-1999
SNV Netherlands Development Organisation
1994-1998
NTL Institute for Applied Behavioral Science
1993-1994
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The function of MELK attributed to its capacity disable critical cell-cycle checkpoints reduce replication stress. Most functional studies have relied on the use siRNA/shRNA-mediated gene silencing. In present study, we explored biological using MELK-T1, novel selective small-molecule inhibitor. Strikingly, MELK-T1 triggered rapid...
Abstract There is a growing number of biologically active peptides which have potential for the development new therapeutics. However, native are only rarely directly usable as drugs, due to inherent limitations include rapid proteolysis and metabolism, poor transport properties, excretion by liver kidneys, low oral activity. Furthermore, often aselective in their actions owing flexible structure. In efforts address these limitations, modified into mimetics with specific physical, chemical...
The word opium derives from ancient Greek ὄπιον (ópion) for the juice of any plant, but today means air-dried seed capsule latex Papaver somniferum. Alkaloid chemistry began with isolation morphine crude by Friedrich Wilhelm Adam Sertürner in 1804. More than a century later, Hungarian pharmacist János Kabay opened new perspectives direct dry poppy heads and straw without labor-intensive harvesting opium. In 2015,...
BACKGROUND AND PURPOSE The aim of this study was to characterize the functional impact KCNQ1‐encoded voltage‐dependent potassium channels (K v 7.1) in vasculature. EXPERIMENTAL APPROACH Mesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. K 7.1 channel expression established by fluorescence immunocytochemistry. Wire myography determined functionality these response selective blockers activators. Xenopus oocytes expressing used assess effectiveness...
Abstract The synthesis of a series epoxy 5‐phenylmorphans is being explored in order to determine the conformational requirements phenolic ring phenylmorphan molecule that may be needed both for binding specific opioid receptor and exhibiting agonist or antagonist activity. Of twelve possible ortho ‐ para ‐bridged isomers (a–f) ( Fig. 1 ), we now report ‐d isomer, rac ‐(3 R ,6a S ,11a )‐2‐methyl‐1,3,4,5,6,11a‐hexahydro‐2 H ‐3,6a‐methanobenzofuro[2,3‐ c ]azocin‐8‐ol 3 ). Compound was...
The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation tumorigenesis. While ATP-competitive inhibitors block pathway mutant cells, they induce conformational changes wild-type domain leading heterodimerization with C-Raf causing a paradoxical hyperactivation pathway. A new class (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting cells. In this study,...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at .sigma. receptors. 2. Piperazines, bicyclic amines, bridged miscellaneous compoundsBrian R. de Costa, Xiaoshu He, Joannes T. M. Linders, Celia Dominguez, Zi Qiang Gu, Wanda Williams, Wayne BowenCite this: J. Med. Chem. 1993, 36, 16, 2311–2320Publication Date (Print):August 1, 1993Publication History Published online1 May...
Abstract Diels‐Alder reaction of 6‐demethoxy‐β‐dihydrothebaine 6 with methyl vinyl ketone (3‐buten‐2‐one) yielded, in a 3:2 ratio, (+)‐7β‐acetyl‐3‐methoxy‐17‐methyl‐6β,14β‐ethenomorphinan‐4‐ol (7) and the novel (+)‐8β‐acetyl‐3‐methoxy‐17‐methyl‐6β,14β‐ethenomorphinan‐4‐ol (8). Performing microwave oven resulted faster cleaner reaction. 1 H NMR mass spectra 8 were studied structure was finally established by single‐crystal X‐ray analysis its 4‐ O ‐phenyl ether 13. In contrast to thebaine...
Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit identified, which bound the hinge region with an atypical binding mode, and this optimized using structure-based into a low-nanomolar cell-penetrant inhibitor, good selectivity profile, suitable for use as chemical probe elucidation of MELK biology.
A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein–ligand X-ray crystallography and incorporation a slender linkage capable bypassing large gate-keeper residue, thus enabling design molecules accessing both hinge regions. Optimization initial hit led to the identification low-nanomolar, cell-penetrant suitable...
Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach scanning mutagenesis, electrophysiology, chemical ligand modification, cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for binding site adamantane derivatives their putative access pathway Kv7.1/KCNE1 channels. The compounds, exemplified by JNJ303, are potent...
Abstract PRMT5 is a type II methyltransferase that specifically adds methyl groups to arginine as long-lasting post-translational modification. The PRMT5/MEP50 complex regulates plethora of cellular processes, such epigenetics and splicing, which are notable events involved in tumorigenesis. Although not frequently mutated or amplified tumors, elevated protein levels lung hematologic cancers correlated with poorer survival. inhibitor JNJ-64619178 has been selected clinical candidate based on...
The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation many key cellular processes in normal cancer tissues. While signaling through EGFR has been extensively studied on molecular level, signal transduction ERBB3/ERBB4 is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length functional membrane-integrated ERBB3 ERBB4 or alone, to serve as a defined model for...
Acyl-CoA:diacylglycerol acyltransferase (DGAT) catalyzes the terminal step in triglyceride (TG) synthesis using diacylglycerol (DAG) and fatty acyl-CoA as substrates. In liver, production of VLDL permits delivery hydrophobic TG from liver to peripheral tissues for energy metabolism. We describe here a novel high-content, high-throughput LC/MS/MS-based cellular assay determining DGAT activity. treated endogenous DGAT-expressing cells with stable isotope-labeled...
Abstract Two different types of Diels‐Alder additions to morphinan‐6, 8‐dienes have been found. 6‐Demethoxythebaine ( 2 ) yielded ethyl 4, 5α‐epoxy‐3‐methoxy‐ N ‐methyl‐6, 14‐ethenoisomorphinan–7α‐carboxylate 3 with acrylate, in analogy the reaction thebaine. The ester was converted into alcohol 4 , which 3‐methoxy ether hydrolyzed yield 5 . Similarly, gave 7α‐acetyl‐6, 14‐ethenoisomorphinan 7 methyl vinyl ketone. latter compound using methylmagnesium iodide. With propylmagnesium bromide,...
The synthesis of the ortho- and para-e isomers in oxide-bridged 5-phenylmorphan series rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9β-ol ((±)-10), an intermediate containing aromatic nitro-activated fluorine atom. atom used as leaving group for formation strained trans-fused 5,6-ring system rac-(1α,4aα,9aα)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((±)-11), although preference cis ring...
Likely due to conformational rearrangements, small molecule inhibitors may stabilize the active conformation of protein kinases and paradoxically promote tumorigenesis. We combined limited proteolysis with stable isotope labeling MS monitor changes upon binding molecules. Applying this method human serine/threonine kinase B-Raf, frequently mutated in cancer, we found that ATP or its nonhydrolyzable analogue AMP-PNP, but not ADP, stabilized structure both B-RafWT B-RafV600E. The...
Abstract The 1 H NMR and 13 C spectra of N ‐formylated morphinans were compared with those the ‐methyl ‐demethyl analogues. magnitude changes in chemical shift C‐9, C‐16 C‐10 depended crucially on nature substituent at nitrogen. For 6α, 14α‐ethenoisomorphinans 6β,14β‐ethenomorphinans, proton shifts 6,14‐etheno bridge across ring are differently affected by nitrogen atom. In 6α,14α‐ethenoisomorphinans, vinylic found between δ5.3 5.9, whereas 6β,14β‐ethenomorphinans these signals downfield...
In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent second rearrangement give us desired isomer. The structures and final product were unequivocally established by X-ray...
Abstract The synthesis of 6‐demethoxy‐ N ‐formyl‐ ‐northebaine ( 5 ) and its Diels‐Alder reactions with methyl vinyl ketone nitroethene are described. ‐Demethylation 6‐demethoxythebaine 3 diethyl azodicarboxylate, followed by hydrolysis, gave 4 which was ‐formylated ethyl formate in DMF to give , using “Ketjencat LA‐LPV Steamed” as a catalyst. Reaction microwave heating the expected 7α‐acetyl‐6α,14α‐ethenoisomorphinan 9 direct crystallization from reaction mixture. On other hand, afforded...