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Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico.
Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico.
Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico.
Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico.
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2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 16, 5125-9 p.Article in journal (Refereed) Published
Abstract [en]

A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

Place, publisher, year, edition, pages
2008. Vol. 51, no 16, 5125-9 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-99766DOI: 10.1021/jm8003784ISI: 000258637400032PubMedID: 18665580OAI: oai:DiVA.org:uu-99766DiVA: diva2:208723
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications
Open this publication in new window or tab >>Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors.

The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus.

As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water.

Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated.

Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 93
Keyword
Suzuki coupling, Heck reaction, palladium, microwave heating, water, vinyl ethregioselective, HIV-1 integrase inhibitor
National Category
Medicinal Chemistry
Research subject
Pharmaceutical Biochemistry
Identifiers
urn:nbn:se:uu:diva-99776 (URN)978-91-554-7475-1 (ISBN)
Public defence
2009-05-08, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-16 Created: 2009-03-19 Last updated: 2009-04-16Bibliographically approved
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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