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Publications (10 of 32) Show all publications
Szałaj, N., Lu, L., Benediktsdottir, A., Zamaratski, E., Cao, S., Olanders, G., . . . Brandt, P. (2018). Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.. European Journal of Medicinal Chemistry, 157, 1346-1360, Article ID S0223-5234(18)30758-X.
Open this publication in new window or tab >>Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, p. 1346-1360, article id S0223-5234(18)30758-XArticle in journal (Refereed) Published
Abstract [en]

Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

Keywords
Antibacterial lipopeptides, Bacterial type I signal peptidase, Escherichia coli type I signal peptidase (EcLepB), P2–P1′ boronic ester-linked macrocycles
National Category
Medicinal Chemistry
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-362335 (URN)10.1016/j.ejmech.2018.08.086 (DOI)30196059 (PubMedID)
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-11-08Bibliographically approved
Belfrage, A. K., Abdurakhmanov, E., Åkerblom, E., Brandt, P., Alogheli, H., Neyts, J., . . . Johansson, A. (2018). Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold. European Journal of Medicinal Chemistry, 148, 453-464
Open this publication in new window or tab >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, p. 453-464Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
Funder
Swedish Research Council, D0571301
Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-05-31Bibliographically approved
De Rosa, M., Lu, L., Zamaratski, E., Szałaj, N., Cao, S., Wadensten, H., . . . Karlen, A. (2017). Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB). Bioorganic & Medicinal Chemistry, 25(3), 897-911
Open this publication in new window or tab >>Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
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2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 3, p. 897-911Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.

Keywords
Antibacterials, Escherichia coli, Oligopeptides, Solid-phase peptide synthesis, Type I signal peptidase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-314110 (URN)10.1016/j.bmc.2016.12.003 (DOI)000394201900009 ()28038943 (PubMedID)
Funder
Swedish Research Council, 521-2014-6711 521-2013-2904 521-2013-3105 621-2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Maria De Rosa and Lu Lu contributed equally to this work.

Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2018-01-13Bibliographically approved
Alogheli, H., Olanders, G., Schaal, W., Brandt, P. & Anders, K. (2017). Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide. Journal of Chemical Information and Modeling, 57(2), 190-202
Open this publication in new window or tab >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
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2017 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed) Published
Abstract [en]

In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
Funder
Swedish Research Council, 521-2014-6711
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-03-05Bibliographically approved
Wetzel, A., Bergman, J., Brandt, P., Larhed, M. & Brånalt, J. (2017). Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki-Heck Reactions.. Organic Letters, 19(7), 1602-1605
Open this publication in new window or tab >>Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki-Heck Reactions.
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2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 7, p. 1602-1605Article in journal (Refereed) Published
Abstract [en]

Pd(0)-catalyzed Mizoroki-Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-318049 (URN)10.1021/acs.orglett.7b00325 (DOI)000398985800028 ()28290201 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-01-13Bibliographically approved
Rydfjord, J., Skillinghaug, B., Brandt, P., Odell, L. R. & Larhed, M. (2017). Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation. Organic Letters, 19(15), 4066-4069
Open this publication in new window or tab >>Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation
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2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 15, p. 4066-4069Article in journal (Refereed) Published
Abstract [en]

We report a facile synthesis of 3-amidino indoles from indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via C-H bond activation of the indole in its 3-position followed by a 1,2-addition of the resulting indole-palladium σ-complex to a cyanamide, which provides the corresponding amidine. The preference for 4,5-diazafluoren-9-one (DAF) as the ligand is investigated using DFT calculations, and a plausible reaction pathway is presented.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-326815 (URN)10.1021/acs.orglett.7b01836 (DOI)000407307900031 ()28741950 (PubMedID)
Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2018-01-13Bibliographically approved
Roy, T., Brandt, P., Wetzel, A., Bergman, J., Branalt, J., Sävmarker, J. & Larhed, M. (2017). Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction. Organic Letters, 19(10), 2738-2741
Open this publication in new window or tab >>Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction
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2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 10, p. 2738-2741Article in journal (Refereed) Published
Abstract [en]

We report a highly diastereoselective synthesis of cydopentene-spirooxindole derivatives via an intramolecular Heck-Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF-water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-326242 (URN)10.1021/acs.orglett.7b01094 (DOI)000402023500071 ()28471686 (PubMedID)
Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-10Bibliographically approved
Bergman, S., Brandt, P., Nordeman, P., Larhed, M., Odell, L. R. & Eriksson, J. (2017). Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation. Molecules, 22(10), Article ID 1688.
Open this publication in new window or tab >>Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
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2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, article id 1688Article in journal (Refereed) Published
Abstract [en]

Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [C-11] carbon monoxide. Starting with amines and [C-11] carbon monoxide, both symmetrical and unsymmetrical C-11-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [C-11] carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/mu mol-319 GBq/mu mol). DFT calculations were found to support a reaction mechanism proceeding through an C-11-labelled isocyanate intermediate.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-332289 (URN)10.3390/molecules22101688 (DOI)000414670600115 ()
Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2018-03-12Bibliographically approved
Belfrage, A. K., Abdurakhmanov, E., Åkerblom, E., Brandt, P., Oshalim, A., Gising, J., . . . Sandström, A. (2016). Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease. Bioorganic & Medicinal Chemistry, 24(12), 2603-2620
Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
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2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

Keywords
Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
Funder
Swedish Research Council, D0571301
Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
Borhade, S. R., Svensson, R., Brandt, P., Artursson, P., Arvidsson, P. I. & Sandström, A. (2015). Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties. ChemMedChem, 10(3), 455-460
Open this publication in new window or tab >>Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
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2015 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 10, no 3, p. 455-460Article in journal (Refereed) Published
Abstract [en]

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

Keywords
acidity, acyl sulfonimidamides, bioisosteres, lipophilicity, permeability
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-248814 (URN)10.1002/cmdc.201402497 (DOI)000350456200003 ()25630705 (PubMedID)
Available from: 2015-04-09 Created: 2015-04-08 Last updated: 2018-01-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2885-2016

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