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Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
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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2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 4, 1053-1057 p.Article in journal (Refereed) Published
Abstract [en]

A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.

Place, publisher, year, edition, pages
2008. Vol. 51, no 4, 1053-1057 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-102908DOI: 10.1021/jm070680hISI: 000253353800037PubMedID: 18215014OAI: oai:DiVA.org:uu-102908DiVA: diva2:216968
Available from: 2009-05-12 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors: Microwave Applications in Batch and Continuous Flow Organic Synthesis
Open this publication in new window or tab >>Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors: Microwave Applications in Batch and Continuous Flow Organic Synthesis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day.

HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures.

Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM.

The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 97 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 151
Keyword
HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, continuous-flow, microwave, non-resonant, MAOS
National Category
Medicinal Chemistry Pharmaceutical Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-160190 (URN)978-91-554-8224-4 (ISBN)
Public defence
2011-12-16, lecture hall B41, BMC, Hussargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-11-24 Created: 2011-10-17 Last updated: 2012-01-09

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