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Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition |
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| Institution: | 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria, Australia;2. Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, Australia;3. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;4. Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, 246 Clayton Road, Clayton, Victoria, Australia;5. Monash Haematology, Monash Health, 246 Clayton Road, Clayton, Victoria, Australia;1. Department of Occupational Health and Safety Engineering, School of Health, Alborz University of Medical Sciences, Karaj, Iran;2. Research Center for Health, Safety and Environment, Alborz University of Medical Sciences, Karaj, Iran;3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran;1. The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate 020-8550, Japan;2. Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003, Japan;3. Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Aomori 036-8561, Japan;1. Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education; College of Chemistry, Central China Normal University, Wuhan 430079, China;2. School of Chemistry and Chemical Engineering, Jiangxi Science and Technology Normal University, Nanchang 330013, China |
| Abstract: | N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site. |
| Keywords: | BRD4 Bromodomain Acetyl-lysine NMP Olinone Fragment-based drug design ATAD2"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"ATPase Family AAA Domain-containing Protein 2 BCP"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"Bromodomain-containing Protein BET"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"Bromodomain and Extra-terminal BRD#"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"Bromodomain-containing Protein # BRD4 BD1"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"First Bromodomain of BRD4 CBP"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"Cyclic AMP Response Element Binding Protein Binding Protein FBDD"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "_":"Fragment-based Drug Design FRET"} {"#name":"keyword" "$":{"id":"k0115"} "$$":[{"#name":"text" "_":"Fluorescence Resonance Energy Transfer GST"} {"#name":"keyword" "$":{"id":"k0125"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"Glutathione "} {"#name":"italic" "_":"S"} {"#name":"__text__" "_":"-transferase K-ac"} {"#name":"keyword" "$":{"id":"k0135"} "$$":[{"#name":"text" "_":"Acetyl-lysine IRF-4"} {"#name":"keyword" "$":{"id":"k0145"} "$$":[{"#name":"text" "_":"Interferon Regulatory Factor 4 LE"} {"#name":"keyword" "$":{"id":"k0155"} "$$":[{"#name":"text" "_":"Ligand Efficiency LPS"} {"#name":"keyword" "$":{"id":"k0165"} "$$":[{"#name":"text" "_":"Lipopolysaccharide NHA"} {"#name":"keyword" "$":{"id":"k0175"} "$$":[{"#name":"text" "_":"Non-hydrogen Atom NMP"} {"#name":"keyword" "$":{"id":"k0185"} "$$":[{"#name":"text" "$$":[{"#name":"italic" "_":"N"} {"#name":"__text__" "_":"-Methylpyrrolidone NMR"} {"#name":"keyword" "$":{"id":"k0195"} "$$":[{"#name":"text" "_":"Nuclear Magnetic Resonance PB1"} {"#name":"keyword" "$":{"id":"k0205"} "$$":[{"#name":"text" "_":"Polybromo-1 PHIP"} {"#name":"keyword" "$":{"id":"k0215"} "$$":[{"#name":"text" "_":"Pleckstrin Homology Domain Interacting Protein RMS"} {"#name":"keyword" "$":{"id":"k0225"} "$$":[{"#name":"text" "_":"Root Mean Square SAR"} {"#name":"keyword" "$":{"id":"k0235"} "$$":[{"#name":"text" "_":"Structure-Activity Relationship SMARCA4"} {"#name":"keyword" "$":{"id":"k0245"} "$$":[{"#name":"text" "_":"SWI/SNF Related Matrix Associated Actin Dependent Regulator of Chromatin Subfamily A Member 4 vdW"} {"#name":"keyword" "$":{"id":"k0255"} "$$":[{"#name":"text" "_":"van der Waals |
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