Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation

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Fältnamn	Indikatorer	Metadata
000		04062nam a2200385 4500
001		oai:DiVA.org:uu-100377
003		SwePub
008		090331s2009 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
020		a 9789155474928q print
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1003772 URI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a dok2 swepub-publicationtype
100	1	a Lagerlund, Olofu Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 aut
245	1 0	a Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
264	1	a Uppsala :b Acta Universitatis Upsaliensis,c 2009
300		a 55 s.
338		a electronic2 rdacarrier
490	0	a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,x 1651-6192 ;v 95
520		a Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed. A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS. A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized. The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Läkemedelskemi0 (SwePub)301032 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medicinal Chemistry0 (SwePub)301032 hsv//eng
653		a Pharmaceutical chemistry
653		a Farmaceutisk kemi
653		a Medicinal Chemistry
653		a läkemedelskemi
700	1	a Larhed, Mats,c Professoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Karlén, Anders,c Professoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Hallberg, Anders,c Professoru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 ths
700	1	a Begtrup, Michael,c Professoru Danish University Pharmaceutical Sciences, Dept Med Chem, Copenhagen, Denmark4 opn
710	2	a Uppsala universitetb Avdelningen för organisk farmaceutisk kemi4 org
856	4	u https://uu.diva-portal.org/smash/get/diva2:210273/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100377

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