| 1. |
- Andersson, Hanna, 1979, et al.
(författare)
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Photochemically Induced Aryl Azide Rearrangement: Solution NMR Spectroscopic Identification of the Rearrangement Product
- 2017
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 82:3, s. 1812-1816
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Tidskriftsartikel (refereegranskat)abstract
- Photolysis of ethyl 3-azido-4,6-difluorobenzoate at room temperature in the presence of oxygen results in the regioselective formation of ethyl 5,7-difluoro-4-azaspiro[2.4]hepta-1,4,6-triene-1-carboxylate, presumably via the corresponding ketenimine intermediate which undergoes a photochemical four-electron electrocyclization followed by a rearrangement. The photorearrangement product was identified by multinuclear solution NMR spectroscopic techniques supported by DFT calculations.
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| 2. |
- Nyandoro, Stephen S., 1975, et al.
(författare)
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N-Cinnamoyltetraketide Derivatives from the Leaves of Toussaintia orientalis
- 2015
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Ingår i: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 78:8, s. 2045-2050
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Tidskriftsartikel (refereegranskat)abstract
- Seven N-cinnamoyltetraketides (1–7), including the new Z-toussaintine E (2), toussaintine F (6), and toussaintine G (7), were isolated from the methanol extract of the leaves of Toussaintia orientalis using column chromatography and HPLC. The configurations of E-toussaintine E (1) and toussaintines A (3) and D (5) are revised based on single-crystal X-ray diffraction data from racemic crystals. Both the crude methanol extract and the isolated constituents exhibit antimycobacterial activities (MIC 83.3–107.7 μM) against the H37Rv strain of Mycobacterium tuberculosis. Compounds 1, 3, 4, and 5 are cytotoxic (ED50 15.3–105.7 μM) against the MDA-MB-231 triple negative aggressive breast cancer cell line.
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| 3. |
- Lindblad, Sofia, et al.
(författare)
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The Influence of Secondary Interactions on the [N−I−N]+ Halogen Bond
- 2021
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Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 27:55, s. 13748-13756
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Tidskriftsartikel (refereegranskat)abstract
- [Bis(pyridine)iodine(I)]+ complexes offer controlled access to halonium ions under mild conditions. The reactivity of such stabilized halonium ions is primarily determined by their three-center, four-electron [N−I−N]+ halogen bond. We studied the importance of chelation, strain, steric hindrance and electrostatic interaction for the structure and reactivity of halogen bonded halonium ions by acquiring their 15N NMR coordination shifts and measuring their iodenium release rates, and interpreted the data with the support of DFT computations. A bidentate ligand stabilizes the [N−I−N]+ halogen bond, decreasing the halenium transfer rate. Strain weakens the bond and accordingly increases the release rate. Remote modifications in the backbone do not influence the stability as long as the effect is entirely steric. Incorporating an electron-rich moiety close by the [N−I−N]+ motif increases the iodenium release rate. The analysis of the iodine(I) transfer mechanism highlights the impact of secondary interactions, and may provide a handle on the induction of stereoselectivity in electrophilic halogenations.
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| 4. |
- Danelius, Emma, et al.
(författare)
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Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins
- 2016
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Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 14, s. 10386-10393
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Tidskriftsartikel (refereegranskat)abstract
- © 2016 The Royal Society of Chemistry.Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity. To gain further insight into the binding of inhibitors to MDM2, the flexibility of four cyclic β-hairpins that act as α-helical mimetics and potential MDM2/p53 interaction inhibitors was investigated in relation to their inhibitory activity. MDM2-binding of the mimetics was determined using fluorescence polarization and surface plasmon resonance assays, whereas their conformation and dynamics in solution was described by the combined experimental and computational NAMFIS analysis. Molecular flexibility was shown to be important for the activity of the cyclic β-hairpin based MDM2 inhibitors.
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| 5. |
- Erdelyi, Mate, 1975, et al.
(författare)
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The Binding Mode of Side Chain- and C3-Modified Epothilones to Tubulin
- 2010
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:6, s. 911-920
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Tidskriftsartikel (refereegranskat)abstract
- The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of -His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.
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| 6. |
- Erdelyi, Mate, 1975, et al.
(författare)
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The Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution
- 2008
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Ingår i: J. Med. Chem.. - : American Chemical Society (ACS). ; 51:5, s. 1469-73
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Tidskriftsartikel (refereegranskat)abstract
- The conformational properties of the microtubule-stabilizing agent epothilone A (1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulinbound conformation of epothilone A (1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.
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| 7. |
- Varedian, M, et al.
(författare)
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Interplaying Factors for the Formation of Photoswitchable beta-Hairpins: the Advantage of a Flexible Switch.
- 2009
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Ingår i: J. Pept. Sci.. ; 15, s. 107-113
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Tidskriftsartikel (refereegranskat)abstract
- A series of peptidomimetics intended to promote the β-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form β-hairpinswas evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.
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| 8. |
- Wilcox, Scott, 1993-, et al.
(författare)
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Probing Halogen Bonding via Paramagnetic NMR
- 2018
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Ingår i: EMBO Course: Multidimensional NMR in Structural Biology, Joachimsthal, 12-17 Aug, 2018.
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Konferensbidrag (refereegranskat)abstract
- Halogen Bonding is a spectacle that has recently received widespread attention, despite the fact that it was discovered over 200 years ago. This fundamental interaction is vastly abundant in today’s world, and a better understanding of it would enable us to both design and improve upon existing drugs, materials and catalysts, to name a few. Halogen bonds (XB) are roughly 180°, non-covalent interactions that exploit the anisotropic electron density of a halogen atom. Analogous to hydrogen bonding, a halogen bond acceptor (being an electron donor in the form of a Lewis base (LB)) and a halogen bond donor (being an electron acceptor consisting of a halogen with a σ-hole) must exist. σ-Holes are electrophilic regions that arise on the opposite tip of an R-X bond in the anti-bonding orbital and to maximise these holes, one can make ‘R’ more electron withdrawing and/or ‘X’ larger with a more diffuse outer electron shell (I > Br > Cl > F).Halogen bonding, like many other weak bonding interactions, is incredibly difficult to measure accurately in solution. Thus, we hypothesize that paramagnetic NMR techniques are potentially useful for their detection and characterization. This involves the use of a compound containing free electrons, and when these are subjected to the large magnetic field of an NMR spectrometer, they exhibit unique qualities that one can fruitfully exploit. In these studies, we mainly focus on measuring Pseudocontact Shifts (PCS) that arise from vast spectral broadening due to the free electrons. With this technique, we are able to assess very weak bonding interactions by the detection of small chemical shift differences due to a much larger spectral window than commonly detected.In this work, building upon previous studies carried out within the group,1 we synthesise cyclen-based organic ligands which complex a paramagnetic lanthanide (Ln3+) species. Attached to one amine in the cyclen core is a Lewis Base (or halogen bond acceptor) which is utilised in probing halogen bonding between itself and a free halogen bond donor in solution. Expected PCS measurements will give an accurate value of the weak bonding interaction between donor and acceptor in solution- the resolution of which is something that is simply not possible via classical NMR studies.
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| 9. |
- Abdissa, Negera, et al.
(författare)
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Naphthalene Derivatives from the Roots of Pentas parvifolia and Pentas bussei
- 2016
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Ingår i: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 79:9, s. 2181-2187
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Tidskriftsartikel (refereegranskat)abstract
- The phytochemical investigation of the CH2Cl2/MeOH (1:1) extract of the roots of Pentas parvifolia led to the isolation of three new naphthalenes, parvinaphthols A (1), B (2), and C (3), two known anthraquinones, and five known naphthalene derivatives. Similar investigation of the roots of Pentas bussei afforded a new polycyclic naphthalene, busseihydroquinone E (4), a new 2,2′-binaphthralenyl-1,1′-dione, busseihydroquinone F (5), and five known naphthalenes. All purified metabolites were characterized by NMR and MS data analyses, whereas the absolute configurations of 3 and 4 were determined by single-crystal X-ray diffraction studies. The E-geometry of compound 5 was supported by DFT-based chemical shift calculations. Compounds 2-4 showed marginal cytotoxicity against the MDA-MB-231 human triple-negative breast cancer cell line with IC50 values ranging from 62.3 to 129.6 μM. © 2016 The American Chemical Society and American Society of Pharmacognosy.
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| 10. |
- Andersson, Hanna, et al.
(författare)
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Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
- 2010
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Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 53, s. 8059-8071
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and is believed to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastereomeric Ang IV analogues was performed using a combination of solution NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The compounds encompassing l-amino acids only (4, 8, and 12) showed significantly higher bioactivity compared to their lld-epimers (5, 9, and 13). The best inhibitors in the series, compounds 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 and 5.2 nM, respectively.
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