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Microwave-Assisted Synthesis of C2-Symmetric HIV-1 Protease Inhibitors: Development and Applications of In Situ Carbonylations and other Palladium(0)-Catalyzed Reactions
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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. , p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 12
Keywords [en]
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
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-5804ISBN: 91-554-6254-5 (print)OAI: oai:DiVA.org:uu-5804DiVA, id: diva2:166444
Public defence
2005-05-20, B42, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Increasing Rates and Scope of Reactions: Sluggish Amines in Microwave-Heated Aminocarbonylation Reactions under Air
Open this publication in new window or tab >>Increasing Rates and Scope of Reactions: Sluggish Amines in Microwave-Heated Aminocarbonylation Reactions under Air
2003 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 68, no 14, p. 5750-5753Article in journal (Refereed) Published
Abstract [en]

Commercially available molybdenum hexacarbonyl serves as a convenient and solid carbon monoxide source in palladium-catalyzed aminocarbonylations of aryl bromides and iodides. This improved microwave protocol, relying on DBU as base and THF as solvent, enables rapid couplings using otherwise sluggish anilines, tert-butylamine, and free amino acids. In addition, Cr(CO)6 and W(CO)6 were found to be useful alternative CO-releasing reagents. Altogether, 16 different aromatic amides were synthesized under air in 35−95% yield after only 15 min of controlled microwave irradiation.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-93072 (URN)10.1021/jo034382d (DOI)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
2. Direct Microwave Synthesis of N,N'-diacylhydrazines and Boc-protected Hydrazides by in situ Carbonylations under Air
Open this publication in new window or tab >>Direct Microwave Synthesis of N,N'-diacylhydrazines and Boc-protected Hydrazides by in situ Carbonylations under Air
2004 (English)In: Synlett, p. 2335-2338Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93073 (URN)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2013-07-04Bibliographically approved
3. Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template
Open this publication in new window or tab >>Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template
2005 (English)In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 7, no 4, p. 574-583Article in journal (Refereed) Published
Abstract [en]

Progress in organometallic catalysis and recent advancements in the development of carbonylative reaction protocols without direct use of carbon monoxide have been utilized for efficient functionalizations of 4-aryl-dihydropyrimidone structures. The use of modern microwave technology enabled both high reaction rates and convenient handling. Examples of palladium-catalyzed cross-couplings, Heck reactions, amino- and alkoxycarbonylations, and direct N-amidations of 4-(bromophenyl)-dihydropyrimidones were performed. Further, the first N3-arylations of the dihydropyrimidone ring system were successfully completed using the copper-catalyzed Goldberg reaction. Altogether, these protocols provide new tools for rapid generation of novel and diverse dihydropyrimidone derivatives.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-93074 (URN)16004501 (PubMedID)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2018-01-13Bibliographically approved
4. High-Speed Synthesis of Potent C2-Symmetric HIV-1 Protease Inhibitors by in Situ Aminocarbonylations
Open this publication in new window or tab >>High-Speed Synthesis of Potent C2-Symmetric HIV-1 Protease Inhibitors by in Situ Aminocarbonylations
Show others...
2005 (English)In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 7, no 4, p. 611-617Article in journal (Refereed) Published
Abstract [en]

Two novel series of C2-symmetric HIV-1 protease inhibitors were synthesized by microwave-promoted, palladium-catalyzed aminocarbonylations of the o-iodo- and m-bromobenzyloxy P1/P1' substituted core structures. Molybdenum hexacarbonyl was used as a convenient solid source of carbon monoxide in these transformations. After the initial high-speed library generation, biological testing identified highly active HIV-1 protease inhibitors. Selected ortho- and meta-decorated inhibitors were subsequently resynthesized on a larger scale and retested for their affinity toward HIV-1 protease, showing micromolar to low nanomolar inhibition. The discovery of highly active inhibitors containing large phenyl amide ortho substituents in the P1/P1' positions indicates that larger groups than previously believed are tolerated in this part of the S1/S1' pocket.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93075 (URN)16004505 (PubMedID)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
5. A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
Open this publication in new window or tab >>A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
Show others...
2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5303-5315Article 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.

Keywords
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:nbn:se:uu:diva-93076 (URN)16621572 (PubMedID)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved

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