| 1. |
- Larsson, Andreas, et al.
(författare)
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Quantitative studies of the binding of the class II PapG adhesin from uropathogenic Escherichia coli to oligosaccharides.
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 11:10, s. 2255-2261
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Tidskriftsartikel (refereegranskat)abstract
- Binding of the class II PapG adhesin, found at the tip of filamentous pili on Escherichia coli, to the carbohydrate moiety of globoseries glycolipids in the human kidney is a key step in development of pyelonephritis, a severe form of urinary tract infection. An assay based on surface plasmon resonance for quantification of the binding of the class II PapG adhesin to oligosaccharides has been developed. Using this assay dissociation constants ranging from 80 to 540 M were determined for binding of the PapG adhesin to di-pentasaccharide fragments from the globoseries of glycolipids. A series of galabiose derivatives, modified at the anomeric position, O-2′ or O-3′, was also investigated. The anomeric position appeared to be the most promising for development of improved inhibitors of PapG-mediated adhesion of E. coli. p-Methoxyphenyl galabioside was found to be most potent (Kd=140 M), and binds to PapG almost as well as the Forssman pentasaccharide.
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| 2. |
- Tuite, Eimer, 1966, et al.
(författare)
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Intercalative interactions of ethidium dyes with triplex structures
- 1995
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Ingår i: Bioorganic and Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 3:6, s. 701-711
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Tidskriftsartikel (refereegranskat)abstract
- The binding of phenanthridine dyes to tripler poly(dT)*poly(dA). poly(dT) and its precursor duplex poly(dA). poly(dT) is characterized using linear dichroism and circular dichroism spectroscopy, and thermal denaturation. The two monomeric dyes ethidium bromide and propidium iodide are shown to behave similarly to each other in intercalating into and stabilizing both the duplex and the tripler structures. However, contrary to expectations, the extra cationic side-chain of propidium iodide provides no significant extra stabilization of tripler compared with ethidium bromide, although propidium does stabilize the duplex more than ethidium. The monomeric dyes appear to have somewhat different binding geometries with the duplex and tripler polymers. The dimeric dye ethidium homodimer is found to bis-intercalate in the tripler as well as the duplex but, in contrast to the monomers, no variation in geometry between duplex and tripler is observed. However, although dimer stabilizes the duplex, it has no effect on the thermal stability of the tripler. This lack of binding preferentiality of the dimer for tripler compared with the monomeric dyes indicates greater constraints on the accommodation of a bis-intercalator in the tripler structure than in the duplex.
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| 3. |
- Dahlgren, Anders, et al.
(författare)
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New inhibitors of the malaria aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:16, s. 3423-3437
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Tidskriftsartikel (refereegranskat)abstract
- New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.
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| 4. |
- Dahlgren, Anders, et al.
(författare)
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Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors : design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:6, s. 1829-1839
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Tidskriftsartikel (refereegranskat)abstract
- A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.
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| 5. |
- Dahlgren, Anders, et al.
(författare)
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Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:6, s. 827-841
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.
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| 6. |
- Dahlgren, Anders, et al.
(författare)
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Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:5, s. 1567-1580
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Tidskriftsartikel (refereegranskat)abstract
- With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC50~5.9 µM. © 2002 Elsevier Science Ltd. All rights reserved.
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| 7. |
- Ersmark, Karolina, et al.
(författare)
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C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II : synthesis and theoretical predictions
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:17, s. 3723-3733
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Tidskriftsartikel (refereegranskat)abstract
- A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results.
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| 8. |
- Gazit, Aviv, et al.
(författare)
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Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:9, s. 2007-2018
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Tidskriftsartikel (refereegranskat)abstract
- Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
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| 10. |
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