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A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, 5303-5315 p.Article in journal (Refereed) Published
Abstract [en]

In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.

Place, publisher, year, edition, pages
2006. Vol. 14, no 15, 5303-5315 p.
Keyword [en]
Amides/chemical synthesis/*chemistry/pharmacology, Catalysis, Computer Simulation, Crystallography; X-Ray, Drug Design, HIV Protease/*chemistry/drug effects, HIV Protease Inhibitors/*chemical synthesis/*chemistry/pharmacology, Microwaves, Models; Molecular, Molecular Structure, Palladium/chemistry, Quantitative Structure-Activity Relationship, Stereoisomerism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93076PubMedID: 16621572OAI: oai:DiVA.org:uu-93076DiVA: diva2:166443
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2013-12-10Bibliographically approved
In thesis
1. Microwave-Assisted Synthesis of C2-Symmetric HIV-1 Protease Inhibitors: Development and Applications of In Situ Carbonylations and other Palladium(0)-Catalyzed Reactions
Open this publication in new window or tab >>Microwave-Assisted Synthesis of C2-Symmetric HIV-1 Protease Inhibitors: Development and Applications of In Situ Carbonylations and other Palladium(0)-Catalyzed Reactions
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The HIV protease is an essential enzyme for HIV replication and constitutes an important target in the treatment of HIV/AIDS. Efficient combination therapies using inhibitors of the reverse transcriptase and protease enzymes have led many to reevaluate HIV infections from a terminal condition to a chronic-but-manageable disease in the developed world. Unfortunately, the emergence of drug resistant viral strains and severe treatment-related adverse effects limit the benefits of current anti-HIV/AIDS drugs for many patients. Furthermore, less than one in ten patients infected with HIV in low- and middle-income countries have access to proper treatment. These important shortcomings highlight the need for new, cost effective anti-HIV/AIDS drugs with unique properties.

Microwave heating has recently emerged as a productivity-enhancing tool for the medicinal chemist. Reaction times can often be reduced from hours to minutes or seconds and chemistry previously considered impractical or unattainable can now be accessed.

In this thesis, the search for unique HIV-1 protease inhibitors and the development and application of new microwave-promoted synthetic methods useful in small-scale medicinal chemistry applications are presented. Protocols for rapid amino- and hydrazidocarbonylations were developed. Mo(CO)6 was used as a solid source of carbon monoxide, enabling a safe, efficient and simple way to exploit carbonylation chemistry without the direct use of toxic carbon monoxide gas. The aminocarbonylation methodology was applied in the synthesis of two series of new HIV-1 protease inhibitors. A biological evaluation suggested that ortho-substitution of P1 and/or P1’ benzyl side chains might provide a new approach to HIV-1 protease inhibitors with novel properties. To assess the scope and limitations of the ortho-substitution concept, a new series of compounds exhibiting fair potency was prepared by various microwave-heated, palladium-catalyzed coupling reactions. Finally, computer modeling was applied to rationalize the binding-modes and structure-activity relationships of these HIV-1 protease inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 12
Keyword
Pharmaceutical chemistry, HIV, protease inhibitors, palladium, carbonylations, molybdenum hexacarbonyl, dihydropyrimidone, DHPM, microwave, cross-coupling, diazylhydrazines, carbon monoxide, synthesis, C2-symmetric, HIV-1 protease inhibitors, aminocarbonylation, fluorous, Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-5804 (URN)91-554-6254-5 (ISBN)
Public defence
2005-05-20, B42, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-04-29 Created: 2005-04-29Bibliographically approved

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Wannberg, JohanKarlén, AndersHallberg, AndersLarhed, Mats

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