Publications by authors named "Trond Vidar Hansen"

51 Publications

A new synthetic protectin D1 analog 3-oxa-PD1 reduces neuropathic pain and chronic itch in mice.

Org Biomol Chem 2021 03 9;19(12):2744-2752. Epub 2021 Mar 9.

Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These enzymatically oxygenated polyunsaturated fatty acids belong to distinct families of specialized pro-resolving autacoids. The protectin family of mediators has attracted an interest because of their potent pro-resolving and anti-inflammatory actions verified in several in vivo disease models. Herein, we present the stereoselective synthesis and biological evaluations of 3-oxa-PD1, a protectin D1 analog. Results from mouse models indicate that the mediators protectin D1, PD1 and the new analog 3-oxa-PD1 all relieved streptozotocin-induced diabetic neuropathic pain at doses of 90 and 300 pmol, equivalent to 30 and 100 ng, respectively, following intrathecal (I.T.) injection. Of interest, at a low dose of only 30 pmol (10 ng; I.T.) only 3-oxa PD1 was able to alleviate neuropathic pain, directly compared to vehicle controls. Moreover, using a chronic itch model of cutaneous T-cell lymphoma (CTCL), all three compounds at 300 pmol (100 ng) showed a significant reduction in itching for several hours. The biomolecular information on the structure-functions of the protectins and the new synthetic analog 3-oxa-PD1 is of interest towards developing new immunoresolvents.
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http://dx.doi.org/10.1039/d0ob02136aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016805PMC
March 2021

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4.

J Org Chem 2021 Feb 3;86(4):3535-3545. Epub 2021 Feb 3.

Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway.

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV-Vis and LC-MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.
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http://dx.doi.org/10.1021/acs.joc.0c02913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901022PMC
February 2021

Stereoselective syntheses and biological activities of E-series resolvins.

Org Biomol Chem 2021 01 7;19(4):705-721. Epub 2021 Jan 7.

Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

Recent research efforts focusing on the many mechanisms participating in the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators. These endogenous molecules include the lipoxins, resolvins, protectins and maresins, collectively coined specialized pro-resolving mediators (SPMs). SPMs are oxygenated polyunsaturated fatty acids biosynthesized by lipoxygenases and cyclooxygenases enzymes. These chemically sensitive molecules are produced in nano- to pico-gram amounts in vivo and exhibit potent anti-inflammatory and pro-resolving bioactions. In addition, SPMs clear bacterial infections, reduce pain and display bioactivities towards host defense, organ protection and tissue remodeling. Altogether, these bioactions and the need for synthetic SPMs for determination of absolute configuration and in vivo experiments have spurred a great interest in the synthetic and biomolecular communities. This review covers reported stereoselective total syntheses and outlines the most significant bioactions of the E-series resolvins.
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http://dx.doi.org/10.1039/d0ob02218gDOI Listing
January 2021

Stereoselective synthesis of MaR2.

Tetrahedron Lett 2020 Feb 9;61(7). Epub 2019 Dec 9.

Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway.

The first total synthesis of the n-3 docosapentaenoic derived oxygenated product MaR2 has been achieved. The 13 and 14 stereogenic centers were introduced using 2-deoxy--ribose in a chiral pool strategy. The geometry of the ,,-triene moiety was prepared using highly -selective Wittig- and Takai-olefination reactions as well as the -stereoselective Lindlar reduction. LC/MS-MS data of synthetic MaR2 matched data for the biosynthetic formed product that enabled the configurational assignment of this oxygenated natural product to be (7,9,11,13,14,16,19)-13,14-dihydroxydocosa-7,9,11,16,19-pentaenoic acid.
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http://dx.doi.org/10.1016/j.tetlet.2019.151510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709930PMC
February 2020

The PPAR Pocket: Renewed Opportunities for Drug Development.

PPAR Res 2020 1;2020:9657380. Epub 2020 Jul 1.

Section for Pharmaceutical Chemistry, Department of Pharmacy, University of Oslo, 0316 Oslo, Norway.

The past decade of PPAR research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPAR ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPAR ligands, capable of isolating central therapeutic effects of PPAR modulation, while displaying markedly lower toxicities than previous generations of PPAR ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPAR and PPAR. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the pockets of PPAR and PPAR. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPAR and PPAR. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.
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http://dx.doi.org/10.1155/2020/9657380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351019PMC
July 2020

Synthesis and Biological Evaluation of Analogs of Didehydroepiandrosterone as Potential New Anticancer Agents.

Molecules 2020 Jul 3;25(13). Epub 2020 Jul 3.

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC values < 10µM. The most interesting analog exhibited an IC value of 0.59 µM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent compound reduced the activity of CDK8 to 35%.
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http://dx.doi.org/10.3390/molecules25133052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412091PMC
July 2020

The First Total Synthesis of the Lipid Mediator PD2.

J Nat Prod 2020 07 16;83(7):2255-2260. Epub 2020 Jun 16.

Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway.

The resolution of inflammation is governed by the active biosynthesis of specialized pro-resolving mediators using ω-6 and ω-3 polyunsaturated fatty acids as substrates. These mediators act as resolution agonists and display several interesting bioactivities. PD2 is an oxygenated polyunsaturated fatty acid biosynthesized from n-3 docosapentaenoic acid belonging to the specialized pro-resolving lipid mediator family named protectins. The protectins exhibit anti-inflammatory properties and pro-resolving bioactivities. These endogenously produced compounds are of interest as leads in resolution pharmacology and drug development. Herein, together with its NMR, MS, and UV data, a stereoselective total synthesis of PD2 is presented.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467816PMC
July 2020

Triacylglycerol-Rich Oils of Marine Origin are Optimal Nutrients for Induction of Polyunsaturated Docosahexaenoic Acid Ester of Hydroxy Linoleic Acid (13-DHAHLA) with Anti-Inflammatory Properties in Mice.

Mol Nutr Food Res 2020 06 22;64(11):e1901238. Epub 2020 Apr 22.

Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, Prague, 14220, Czech Republic.

Scope: The docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) is a bioactive lipid with anti-inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA).

Methods And Results: To explore the biosynthesis of 13-DHAHLA from dietary oils, C57BL/6N mice are gavaged for 8 days with various corn oil/marine oil mixtures containing the same amount of DHA. Plasma levels of omega-3 FAHFAs are influenced by the lipid composition of the mixtures but do not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol-bound DHA and linoleic acid serve as more effective precursors for 13-DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)- and 13(R)-DHAHLA inhibit antigen and PGE -induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)-DHAHLA is identified as the predominant isomer in mouse adipose tissue.

Conclusion: Here, the optimal nutritional source of DHA is identified, which supports production of anti-inflammatory FAHFAs, as triacylglycerol-based marine oil and also reveals a possible role of triacylglycerols in the synthesis of FAHFA lipokines.
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http://dx.doi.org/10.1002/mnfr.201901238DOI Listing
June 2020

New CDK8 inhibitors as potential anti-leukemic agents - Design, synthesis and biological evaluation.

Bioorg Med Chem 2020 05 27;28(10):115461. Epub 2020 Mar 27.

Centre for Pharmacy, Department of Clinical Science, University of Bergen, PO Box 7800, N-5007 Bergen, Norway.

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating cell transcription either through its association with the mediator complex or by the phosphorylation of transcription factors. CDK8-mediated activation of oncogenes has proved to be important in a variety of cancer types including hematological malignancies. We have designed and synthesized a series of new synthetic steroids. The compounds were evaluated as CDK8 inhibitors in vitro. The three most potent compounds exhibit K-values towards CDK8 in the low nanomolar range (3.5-18 nM). Furthermore, the compounds displayed selectivity for CDK8 in a panel of 465 different kinases. The cell studies indicated a selectivity to kill AML-cancer cell lines compared to normal cell lines.
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http://dx.doi.org/10.1016/j.bmc.2020.115461DOI Listing
May 2020

Enzymatic studies with 3-oxa n-3 DPA.

Bioorg Chem 2020 03 8;96:103653. Epub 2020 Feb 8.

Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway; Department of Pharmacy, Section of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address:

Cyclooxygenase-2 and several lipoxygenases convert polyunsaturated fatty acids into a large variety of products. During inflammatory processes, these enzymes form several distinct families of specialized pro-resolving lipid mediators possessing potent anti-inflammatory and pro-resolving effects. These mediators have attracted a great interest as leads in drug discovery and have recently been the subject of biosynthetic pathway studies using docosahexaenoic and n-3 docosapentaenoic acid as substrates. Herein we present enzymatic studies with cyclooxygenase-2 and 5-, 12- and 15-lipoxygenase enzymes using 3-oxa n-3 DPA as a synthetic mimic of n-3 docosapentaenoic acid. Structural elucidation based on data from RP-HPLC UV and LC/MS-MS experiments enabled the identification of novel enzymatically formed products. These findings constitute the basis for further biosynthetic studies towards understanding the mechanisms regulating substrate utilization in the biosynthesis of specialized pro-resolving lipid mediators.
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http://dx.doi.org/10.1016/j.bioorg.2020.103653DOI Listing
March 2020

Synthesis, Structural Confirmation, and Biosynthesis of 22-OH-PD1.

Molecules 2019 Sep 5;24(18). Epub 2019 Sep 5.

Department of Pharmacy, Section of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068 Blindern, N-0316 Oslo, Norway.

PD1 belongs to the protectin family of specialized pro-resolving lipid mediators. The protectins are endogenously formed mediators that display potent anti-inflammatory properties and pro-resolving bioactivities and have attracted interest in drug discovery. However, few studies have been reported of the secondary metabolism of the protectins. To investigate the metabolic formation of the putative C22 mono-hydroxylated product, coined 22-OH-PD1, a stereoselective synthesis was performed. LC/MS-MS data of synthetic 22-OH-PD1 matched the data for the biosynthetic formed product. Cellular studies revealed that 22-OH-PD1 is formed from n-3 docosapentaenoic acid in human serum, and we confirmed that 22-OH-PD1 is a secondary metabolite produced by ω-oxidation of PD1 in human neutrophils and in human monocytes. The results reported are of interest for enabling future structure-activity relationship studies and provide useful molecular insight of the metabolism of the protectin class of specialized pro-resolving mediators.
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http://dx.doi.org/10.3390/molecules24183228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767081PMC
September 2019

Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist.

Bioorg Med Chem 2019 09 19;27(18):4059-4068. Epub 2019 Jul 19.

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway. Electronic address:

The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the currently available PPARα targeting agents show low subtype-specificity and consequently a search for more potent agonists have emerged. In this study, previously isolated oxohexadecenoic acids from the marine algae Chaetoceros karianus were used to design a PPARα-specific analogue. Herein we report the design, synthesis, molecular modelling studies and biological evaluations of the novel 3,5-disubstituted isoxazole analogue 6-(5-heptyl-1,2-oxazol-3-yl)hexanoic acid (1), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as CPT1A, in the Huh7 cell line and primary mouse hepatocytes. In addition, ADAM exhibits a moderate ability to regulate PPARγ target genes and drive adipogenesis. Molecular modelling studies indicated that ADAM docks its carboxyl group into opposite ends of the PPARα and -γ LBD. ADAM interacts with the receptor-activating polar network of amino acids (Tyr501, His447 and Ser317) in PPARα, but not in PPARγ LBD. This may explain the lack of PPARγ agonism, and argues for a PPARα-dependent adipogenic function. Such compounds are of interest towards developing new lipid-lowering remedies.
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http://dx.doi.org/10.1016/j.bmc.2019.07.032DOI Listing
September 2019

Catalytic enantioselective iodolactonization reactions.

Org Biomol Chem 2019 03;17(12):3079-3092

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

The halolactonization reaction is a useful chemical transformation for the construction of lactones from γ- or δ-substituted alkenoic carboxylic acids or carboxylic esters. Traditionally, the stereoselectivity of these reactions has been controlled by the substrates or the reagents. The substrate-controlled method has been extensively studied and applied in the synthesis of many natural products. However, catalytic, enantioselective iodolactonizations of γ- or δ-substituted alkenoic carboxylic acids have only recently been developed. This review article highlights the advances that have emerged over the last decade.
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http://dx.doi.org/10.1039/c8ob03160fDOI Listing
March 2019

The Protectin Family of Specialized Pro-resolving Mediators: Potent Immunoresolvents Enabling Innovative Approaches to Target Obesity and Diabetes.

Front Pharmacol 2018 17;9:1582. Epub 2019 Jan 17.

Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, United States.

A western type diet and lifestyle play an important role in the development of chronic diseases, yet little insight into the precise cellular and biomolecular mechanisms has emerged. It is known that an unbalanced diet may result in obesity and diabetes. Sufficient amounts and proper balance of omega-6 and omega-3 polyunsaturated fatty acids is key for maintenance of health. The resolution of inflammation is now held to be a biosynthetically actively driven process precisely regulated and controlled by a superfamily of specialized pro-resolving mediators. Specialized pro-resolving mediators are biosynthesized from both omega-6 and omega-3 polyunsaturated fatty acids and are resolution agonists acting on distinct G-coupled protein receptors. These mediators display potent anti-inflammatory and pro-resolving bioactions with EC-values in the low nanomolar to picomolar range. The protectin (PD) family of specialized pro-resolving mediators is biosynthesized from the two omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and n-3 docosapentaenoic acid (n-3 DPA). All of the PDs display interesting bioactions as anti-inflammatory and pro-resolving agents. This review covers the bioactions, G-coupled protein receptors pharmacology, biosynthesis, and medicinal chemistry of the PD family of specialized pro-resolving mediators with an emphasis on obesity and anti-diabetic effects. In order to enable drug development and medicinal chemistry efforts against these diseases, stereoselective total organic synthesis of each of these mediators is required for confirmation of structure, stereochemical biosynthesis, and their functions. We provide an overview of our ongoing efforts and the current knowledge.
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http://dx.doi.org/10.3389/fphar.2018.01582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344435PMC
January 2019

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1.

Chemistry 2019 Jan 20;25(6):1476-1480. Epub 2018 Dec 20.

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, 0316, Oslo, Norway.

New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1 has been achieved using the underutilized sp -sp Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.
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http://dx.doi.org/10.1002/chem.201806029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368681PMC
January 2019

Synthetic manipulations of polyunsaturated fatty acids as a convenient strategy for the synthesis of bioactive compounds.

Org Biomol Chem 2018 12;16(48):9319-9333

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

Stereoselective synthesis of Z-configured double bonds is central in organic synthesis due to the presence of such motifs in polyunsaturated fatty acids and many natural products. Traditionally, reductions of internal alkynes or Wittig, Ando or Still-Gennari reactions, are often used for preparing such compounds. The substrate scope is limited for both the Ando and the Still-Gennari reactions, while the Wittig reaction often gives low Z-selectivity for the synthesis of polyunsaturated Z-configured methylene interrupted (skipped) double bonds. Reductions of internal alkynes are challenging due to diminished Z-selectivity, poor catalyst reproducibility and over-reductions. An alternative and highly attractive approach is to employ naturally occurring and commercially available polyunsaturated fatty acids as starting materials. The main advantage of this strategy is the conservation of the multiple Z-configured double bonds present in the starting material, allowing a precise incorporation of the desired double bonds into the final product. In particular, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid have been used for the stereoselective synthesis of polyunsaturated fatty acids, their derivatives and other polyunsaturated natural products. Herein, such efforts are reviewed.
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http://dx.doi.org/10.1039/c8ob02586jDOI Listing
December 2018

Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects.

Eur J Med Chem 2018 Jul 18;155:736-753. Epub 2018 Jun 18.

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.

Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.034DOI Listing
July 2018

Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists.

Bioorg Med Chem 2018 07 23;26(12):3580-3587. Epub 2018 May 23.

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern N-0316, Oslo, Norway; Faculty of Chemistry, Biology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, N-1432 Ås, Norway. Electronic address:

The oxoeicosanoid receptor 1 (OXER1) is a member of the G-protein coupled receptors (GPCR) family, and is involved in inflammatory processes and oncogenesis. As such it is an attractive target for pharmacological intervention. The present study aimed to shed light on the molecular fundaments of OXER1 modulation using chemical probes structurally related to the natural agonist 5-oxo-ETE. In a first step, 5-oxo-ETE and its closely related derivatives (5-oxo-EPE and 4-oxo-DHA) were obtained by conducting concise and high-yielding syntheses. The biological activity of obtained compounds was assessed in terms of potency (EC) and efficacy (E) for arrestin recruitment. Finally, molecular modelling and simulation were used to explore binding characteristics of 5-oxo-ETE and derivatives with the aim to rationalize biological activity. Our data suggest that the tested 5-oxo-ETE derivatives (i) insert quickly into the membrane, (ii) access the receptor via transmembrane helices (TMs) 5 and 6 from the membrane side and (iii) drive potency and efficacy by differential interaction with TM5 and 7. Most importantly, we found that the methyl ester of 5-oxo-ETE (1a) showed even a higher maximum response than the natural agonist (1). In contrast, shifting the 5-oxo group into position 4 results in inactive compounds (4-oxo DHA compounds (3) and (3a)). All in all, our study provides relevant structural data that help understanding better OXER1 functionality and its modulation. The structural information presented herein will be useful for designing new lead compounds with desired signalling profiles.
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http://dx.doi.org/10.1016/j.bmc.2018.05.036DOI Listing
July 2018

Synthesis, molecular modeling and biological evaluation of potent analogs of 2-methoxyestradiol.

Steroids 2018 08 18;136:47-55. Epub 2018 May 18.

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address:

The endogenous steroid 2-methoxyestradiol (1) has attracted a great interest as a lead compound towards the development of new anti-cancer drugs. Herein, the synthesis, molecular modeling, anti-proliferative and anti-angiogenic effects of ten 2-ethyl and four 2-methoxy analogs of estradiol are reported. The ethyl group was introduced to the steroid A-ring using a novel Friedel-Crafts alkylation protocol. Several analogs displayed potent anti-proliferative activity with IC-values in the submicromolar range towards the CEM human leukemia cancer cell line. As such, all of these compounds proved to be more active than the lead compound 2-methoxyestradiol (1) in these cells. The six most cytostatic analogs were also tested as anti-angiogenic agents using an in vitro tube formation assay. The IC-values were determined to be in the range of 0.1 μM ± 0.03 and 1.1 μM ± 0.2. These six compounds were also modest inhibitors against tubulin polymerization with the most potent inhibitor was 14b (IC = 2.1 ± 0.1 μM). Binding studies using N,N'-ethylene-bis(iodoacetamide) revealed that neither14a or 14b binds to the colchicine binding site in the tubulin protein, in contrast to 2-methoxyestradiol (1). These observations were supported by molecular modeling studies. Results from a MDA-MB-231 cell cycle assay showed that both 10e and 14b gave accumulation in the G2/M phase resulting in induction of apoptosis. The results presented herein shows that the novel analogs reported exhibit their anticancer effects via several modes of action.
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http://dx.doi.org/10.1016/j.steroids.2018.05.002DOI Listing
August 2018

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation.

Free Radic Res 2018 Feb 6;52(2):273-287. Epub 2018 Feb 6.

a Department of Pharmaceutical Biosciences , School of Pharmacy, University of Oslo , Oslo , Norway.

Oestrogens with no or reduced oestrogen receptor (ER) binding properties are reported to have neuroprotective functions. However, we have previously shown that the hormonally inactive isomer of 17β-estradiol (17β-E), 17α-estradiol (17α-E), down-regulates glutathione (GSH) synthesis, and fails to rescue serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in micromolar concentration. The present study examined cellular protective effects of new 17β-E analogs and 2-methoxyestradiol (2-ME) analogs with no or little oestrogen activity. 17β-E, 17α-E, 2-ME, and an antagonist of the G protein-coupled oestrogen receptor (GPER), G36, were also included. Both 17α-E and 2-ME protected against deprivation-induced cell death in PC12 cells at 1 nM, but they enhanced the deprivation-induced cell death accompanied by caspase 3 activity and decreased intracellular GSH levels during deprivation at 10 µM. In addition, 10 μM 17α-E activated the p38 mitogen activated protein kinase pathway, which was linked to the enhanced death and reduced GSH levels. Analogs of 2-ME modified with a 6-isoquinoline moiety (6iq) protected against deprivation-induced cell death at 1 nM and did not interfere with the GSH levels nor increase p38 protein levels at 10 µM. The promoter activity of the catalytic subunit of the rate-limiting enzyme, glutamate cysteine ligase (GCLC) in GSH synthesis as well as protein levels of GCLC and Nrf2, increased with the 2-ME analogs at 10 µM. In conclusion, the steroids have differential protective effects, and modifying 2-ME may give the steroid more favourable properties than 17α-E, 2-ME, and G36 in regard to GSH regulation.
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http://dx.doi.org/10.1080/10715762.2018.1430363DOI Listing
February 2018

Interleukin 27 is increased in carotid atherosclerosis and promotes NLRP3 inflammasome activation.

PLoS One 2017 27;12(11):e0188387. Epub 2017 Nov 27.

Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet,Oslo, Norway.

Aim: Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro.

Methods: Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro.

Results: Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 β.

Conclusions: We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188387PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703457PMC
December 2017

Stereopermutation on the Putative Structure of the Marine Natural Product Mucosin.

Molecules 2017 Oct 13;22(10). Epub 2017 Oct 13.

Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, 1433 Ås, Norway.

A stereodivergent total synthesis has been executed based on the plausibly misassigned structure of the unusual marine hydrindane mucosin (). The topological connectivity of the four contiguous -carbon stereocenters has been examined by selective permutation on the highlighted core. Thus, capitalizing on an unprecedented stereofacial preference of the -fused bicycle[4.3.0]non-3-ene system when a Michael acceptor motif is incorporated, copper-mediated conjugate addition furnished a single diastereomer. Cued by the relative relationship reported for the appendices in the natural product, the resulting -adduct was elaborated into a probative target structure .
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http://dx.doi.org/10.3390/molecules22101720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151738PMC
October 2017

Stereocontrolled synthesis and investigation of the biosynthetic transformations of 16(S),17(S)-epoxy-PD.

Org Biomol Chem 2017 Oct;15(40):8606-8613

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

PD1 is a specialized pro-resolving lipid mediator that displays potent anti-inflammatory properties and pro-resolving bioactivities. Such naturally occurring compounds are of current interest in biomolecular chemistry and drug discovery. To investigate the involvement of an epoxide intermediate in the biosynthesis of PD1 from n-3 docosapentaenoic acid, the epoxy acid 16(S),17(S)-epoxy-PD, herein named ePD, was prepared by stereoselective total synthesis. The synthetic material of ePD allowed investigations of its role in the biosynthesis of PD1. The obtained results establish that the biosynthesis of PD1 in neutrophils occurs with ePD as the intermediate, and that 15-LOX produces ePD from n-3 docosapentaenoic acid. Furthermore, support for the involvement of a hydrolytic enzyme in the biosynthetic conversion of ePD to PD1 was found. In addition, ePD was found to regulate the formation of the potent neutrophil chemoattractant LTB with equal potencies to that obtained with PD1.
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http://dx.doi.org/10.1039/c7ob02113eDOI Listing
October 2017

Regioselective monoalkylation of 17β-estradiol for the synthesis of cytotoxic estrogens.

Steroids 2017 08 15;124:54-59. Epub 2017 Jun 15.

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address:

The regioselective synthesis of estrogens and their derivatives continues to be of interest. Most reported syntheses require multistep protocols associated with poor overall yield and lack of regioselectivity. New preparative protocols are still desired. Herein, 11 2-alkylated 17β-estradiol analogs were synthesized in a highly regioselective manner. The products were obtained using a convenient, one pot and high-yielding protocol. The anti-proliferative activity of the compounds was tested in human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human dermal microvascular endothelial (HMEC-1) cells.
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http://dx.doi.org/10.1016/j.steroids.2017.06.001DOI Listing
August 2017

The novel lipid mediator PD1: An overview of the structural elucidation, synthesis, biosynthesis and bioactions.

Prostaglandins Other Lipid Mediat 2017 Nov 7;133:103-110. Epub 2017 Jun 7.

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, United States.

Resolvins, protectins and maresins are individual families of specialized pro-resolving mediators biosynthesized from the dietary n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid. These enzymatically oxygenated polyunsaturated lipid mediators were first elucidated during the resolution phase of acute inflammation in animal models of self-limited inflammation. Specialized pro-resolving mediators display potent bioactions when administrated in vivo. Biosynthetic pathway studies have revealed that individual lipoxygenases and cyclooxygenase-2 converts eicosapentaenoic acid and docosahexaenoic acid into distinct families of the resolvins, protectins and maresins. Recently n-3 docosapentaenoic acid was found to be a substrate for the biosynthesis of several novel families of specialized pro-resolving mediators. One example is PD1. During the 6th European Workshop on Lipid Mediators, Frankfurt, Germany, the structural elucidation, total organic synthesis, studies on the biosynthetic pathway, as well as the potent anti-inflammatory and pro-resolving properties of PD1 were presented. Herein, we provide an overview of these topics for the new member PD1 of the super-family of pro-resolving mediators.
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http://dx.doi.org/10.1016/j.prostaglandins.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720935PMC
November 2017

Structural review of PPARγ in complex with ligands: Cartesian- and dihedral angle principal component analyses of X-ray crystallographic data.

Proteins 2017 Sep 23;85(9):1684-1698. Epub 2017 Jun 23.

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, Oslo, 0316, Norway.

Two decades of research into the ligand-dependent modulation of the activity of the peroxisome proliferator-activated receptor γ (PPARγ) have demonstrated the heterogeneous modes of action of PPARγ ligands, in terms of their interaction surfaces in the ligand-binding pocket, binding stoichiometry and ability to interact with functionally important parts of the receptor, through both direct and allosteric mechanisms. These findings signal the complex mechanistic bases of the distinct biological effects of different classes of PPARγ ligands. Today, the development of PPARγ ligands focuses on partial- and non-agonists as opposed to classical agonists, due to the severe side effects observed with PPARγ classical agonists as therapeutic agents. To aid this development, we performed principal component analyses of the atomic (Cartesian) coordinates (cPCA) and dihedral angles (dPCA) of the structures of human PPARγ from X-ray crystallography, available in the public domain, seeking to reveal ligand-induced trends. In the cPCA, projections of the structures along the principal components (PCs) demonstrated a moderate correlation between cPC1 and structural parameters related to the stabilization of helix 12, which is central to the transcriptional activation by PPARγ classical agonists. Consequently, the presented cPCA mapping of the PPARγ-ligand complexes may guide in silico drug discovery programs seeking to avoid stabilization of helix 12 in their development of partial- and non-agonistic PPARγ ligands. Notably, while the dPCA could identify key regions of dihedral fluctuation in the structural ensemble, the distributions along dPC1 - 2 could not be classified according to the same parameters as the distribution along cPC1. Proteins 2017; 85:1684-1698. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/prot.25325DOI Listing
September 2017

Recent advances in the chemistry and biology of anti-inflammatory and specialized pro-resolving mediators biosynthesized from n-3 docosapentaenoic acid.

Bioorg Med Chem Lett 2017 06 31;27(11):2259-2266. Epub 2017 Mar 31.

School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.

Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary cells. These compounds belong to a distinct family of specialized pro-resolving mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endogenously formed specialized pro-resolving mediators have attracted a great interest as lead compounds in drug discovery programs towards the development of new classes of drugs that dampen inflammation without interfering with the immune response. Detailed information on the chemical structures, cellular functions and distinct biosynthetic pathways of specialized pro-resolving lipid mediators is a central aspect of these biological actions. Herein, the isolation, structural elucidation, biosynthetic pathways, total synthesis and bioactions of the n-3 docosapentaenoic acid derived mediators PD1 and MaR1 are discussed. In addition, a brief discussion of a novel family of mediators derived from n-3 docosapentaenoic acid, termed 13-series resolvins is included.
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http://dx.doi.org/10.1016/j.bmcl.2017.03.079DOI Listing
June 2017

Atomic determinants of BK channel activation by polyunsaturated fatty acids.

Proc Natl Acad Sci U S A 2016 11 14;113(48):13905-13910. Epub 2016 Nov 14.

Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104;

Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.
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http://dx.doi.org/10.1073/pnas.1615562113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137720PMC
November 2016

Synthesis of 5-(S)-HETE, 5-(S)-HEPE and (+)-zooxanthellactone: Three hydroxylated polyunsaturated fatty acid metabolites.

Chem Phys Lipids 2016 Mar 29;196:1-4. Epub 2016 Jan 29.

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway. Electronic address:

Short and stereoselective syntheses of the two hydroxylated polyunsaturated fatty acid metabolites, namely 5-(S)-HETE and 5-(S)-HEPE, are reported in 23% and 30% overall yields, respectively. In addition, synthesis of the polyunsaturated fatty acid natural product (+)-zooxanthellactone has been achieved in 19% overall yield. The three aforementioned compounds have been conveniently prepared in six steps, starting from the corresponding commercially available polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, respectively. All three hydroxylated polyunsaturated natural products were prepared using a biomimetic synthesis.
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http://dx.doi.org/10.1016/j.chemphyslip.2015.12.005DOI Listing
March 2016