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Easy-to-Execute Carbonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2005 (English)In: The Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, no 8, 3094-3098 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 70, no 8, 3094-3098 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95747OAI: oai:DiVA.org:uu-95747DiVA: diva2:170075
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease: Focus on C-Terminal Acyl Sulfonamides
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Protease: Focus on C-Terminal Acyl Sulfonamides
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis C is a global health problem that affects approximately 120–180 million people. This viral infection causes serious liver diseases and the therapy available suffers from low efficiency and severe side effects. Consequently, there is a huge unmet medical need for new therapeutic agents to combat the hepatitis C virus (HCV). Inhibition of the viral NS3 protease has recently emerged as a promising approach to defeat this infection, and the first HCV NS3 protease inhibitors have now entered clinical trials.

In this project, several novel HCV NS3 protease inhibitors have been designed, synthesized and biochemically evaluated. Inhibitors with various P1 C-terminal functional groups intended as potential bioisosteres to the carboxylic acid found in product-based inhibitors have been revealed. Special focus has been placed on establishing structure–activity relationships of inhibitors containing the promising P1 C-terminal acyl sulfonamide group. The properties of the acyl sulfonamide functionality that are important for producing potent inhibitors have been identified. In addition, the advantages of the acyl sulfonamide group compared to the carboxylic acid have been demonstrated in both enzymatic and cell-based assays.

Besides the acyl sulfonamide functionality, the acyl cyanamide and the acyl sulfinamide groups have been identified as new carboxylic acid bioisosteres in HCV NS3 protease inhibitors.

The synthetic work included the development of a fast and convenient methodology for the preparation of aryl acyl sulfonamides. The use of microwave heating and Mo(CO)6 as a solid carbon monoxide source provided aryl acyl sulfonamides from aryl halides in excellent yields. This method was subsequently used in the decoration of novel HCV NS3 protease inhibitors comprising a non-natural P1 moiety. This new class of compounds can be used as lead structures in a future optimization process aimed at producing more drug-like HCV NS3 protease inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 53
Keyword
Pharmaceutical chemistry, hepatitis C virus, HCV, NS3 protease inhibitor, acyl sulfonamide, bioisostere, palladium, carbonylation, microwave, molybdenum hexacarbonyl, Farmaceutisk kemi
Identifiers
urn:nbn:se:uu:diva-7814 (URN)978-91-554-6862-0 (ISBN)
Public defence
2007-05-04, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2009-11-30Bibliographically approved

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