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Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
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.
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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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, 2724-2736 p.Article in journal (Refereed) Published
Abstract [en]

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

Place, publisher, year, edition, pages
2012. Vol. 55, no 6, 2724-2736 p.
Keyword [en]
HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-160186DOI: 10.1021/jm201620tISI: 000301767000017OAI: oai:DiVA.org:uu-160186DiVA: diva2:448672
Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2017-12-08Bibliographically 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
2. Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
Open this publication in new window or tab >>Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction.

Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 90 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 162
Keyword
Mizoroki-Heck arylation, Suzuki coupling, domino reaction, stereoselective, palladium, chelation control, vinyl ether, HIV-protease inhibitors, HIV-integrase inhibitors
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-173068 (URN)978-91-554-8370-8 (ISBN)
Public defence
2012-06-08, B42, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.Available from: 2012-05-16 Created: 2012-04-18 Last updated: 2012-08-01Bibliographically approved

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Trejos, AlejandroPersson, MagnusLarhed, Mats

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