| 1. |
- Bremberg, Ulf
(författare)
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Asymmetric catalysis : ligand design and microwave acceleration
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals partly with the design and synthesis ofligands for use in asymmetric catalysis, and partly with theapplication of microwave heating on metal-based asymmetriccatalytic reactions.Enantiomerically pure pyridyl alcohols and bipyridylalcohols were synthesized from the chiral pool for future usein asymmetric catalysis. Lithiated pyridines were reacted withseveral chiral electrophiles, yielding diastereomeric mixturesthat could be separated without the use of resolutiontechniques.New pyridino- and quinolinooxazolines were synthesized andtested in palladium-catalyzed asymmetric allylation using1,3-diphenyl-2-propenyl acetate and dimethyl malonate. Theconformational preferences of the ligands in palladiumcomplexes were studied with crystallography, 2D-NMR techniquesand DFT calculations. Conclusions about how the chirality wastransferred from the ligand to the substrate could be drawnfrom the conformational analysis.The effect of heating Pd- and Mo-catalyzed asymmetricallylic substitution reactions was investigated with oil bathheating and microwave irradiation. With a few exceptions,ligands with high room temperature selectivity were shown toretain their selectivity on heating. Reaction rates, catalyststability and product selectivities of microwave-heatedreactions were compared with those of reactions performed inoil bath.Palladium-catalyzed asymmetric allylation was studied withseveral ligand types, allylic substrates and nucleophiles. Someof the experimental procedures had to be adapted to microwaveheating conditions.The procedure for asymmetric allylation catalyzed bybispyridylamide molybdenum complexes was developed into aone-pot microwave-mediated reaction. With microwaves, Mo(CO)6could be used as an easily-handled metal sourceand inert conditions could be omitted. Derivatives of thebispyridylamide ligandswere synthesized and tested withmolybdenum as catalysts to investigate the effects ofsubstituents on the pyridine ring.Keywords: ligand, asymmetric catalysis, pyridylalcohols, oxazolines, conformational study, Pd-allyl, fastchemistry, microwave chemistry, Mo-allyl, bispyridylamides.
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| 2. |
- Fryknäs, Mårten, et al.
(författare)
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Iron chelators target both proliferating and quiescent cancer cells
- 2016
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
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| 3. |
- Karlsson, Henning, et al.
(författare)
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Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:18, s. 30217-30234
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Tidskriftsartikel (refereegranskat)abstract
- Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties. Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50. Results: VLX60 showed ?3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells. Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.
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| 4. |
- Wakchaure, Prasad B., et al.
(författare)
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Synthesis of enantiopure angiotensin II type 2 receptor [AT(2)R] antagonist EMA401
- 2015
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 71:38, s. 6881-6887
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Tidskriftsartikel (refereegranskat)abstract
- We report a facile synthesis of the angiotensin II type 2 receptor antagonist EMA401, which recently passed phase II clinical trials, in high overall yield. The synthesis of the key phenylalanine intermediate involved the formation of an a-nitro cinnamic ester and its reduction followed by a Pictet-Spengler cyclization, which furnished the tetrahydroisoquinoline core structure. Next, EMA401 was separated from its enantiomer EMA402 by four recrystalizations of a diastereomeric salt in 98% ee. All steps were performed on gram scale with emphasis on avoiding column purification and using readily available low cost starting materials and reagents.
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| 5. |
- Wannberg, Johan, et al.
(författare)
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A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
- 2018
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 28:3, s. 519-522
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Tidskriftsartikel (refereegranskat)abstract
- A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.
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| 6. |
- Yang, Jie, et al.
(författare)
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Macrocyclic peptides as inhibitors of human LSD1
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lysine demethylase 1 (LSD1) regulates the degree of methylation of Lys4 of histone 3 in the nucleosome core particle. As LSD1 is overexpressed in certain cancers, inhibitors have potential for use as drugs. Guided by the structures of two peptidic ligands bound to LSD1 we prepared truncated, mono-substituted and macrocyclic peptides to find leads for development of specific and revserible inhibitors. Surface plasmon resonance biosensor analysis revealed that some stapled, macrocyclic peptides had up to 10-fold higher affinity for LSD1 than the corresponding linear native peptide. Furthermore, peptides cyclized by lactamization were low mM inhibitors of LSD1, with the most effective one being >25-fold more potent than the linear native reference.
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