| 1. |
- Collins, Patrick M., et al.
(författare)
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Taloside Inhibitors of Galectin-1 and Galectin-3
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 79:3, s. 339-346
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 and galectin-3 have roles in cancer and inflammation. Galectin-1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognize galactose is an important approach in the fight against cancer. Based on the analysis of crystal structures, we pursued the concept that if the galactose was replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific towards particular galectins. Our elucidation of X-ray crystal structures of two of our synthesized talosides in complex with galectin-1 and galectin-3 provides the first atomic information on the interactions of galectins, and indeed any protein, with talosides. These results have enabled a structure-based rationale for the specificity differences shown by galectin-1 and galectin-3 towards these talosides and demonstrate new opportunities for further exploitation as specific inhibitors of galectins.
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| 2. |
- Dahlgren, Markus K, et al.
(författare)
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Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides
- 2010
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 15:6, s. 4207-12
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Tidskriftsartikel (refereegranskat)abstract
- Salicylidene acylhydrazides are inhibitors of type III secretion in several Gramnegative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-aminopyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to thesalicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-aminopyrimidine)-2,2-difluoro-ethanols is described in this paper.
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| 3. |
- Hillgren, J. Mikael, et al.
(författare)
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Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges
- 2012
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 10:6, s. 1246-1254
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report the total syntheses of pseudoceramine A-D (2-5) and spermatinamine (1) isolated from the marine sponge Pseudoceratina sp. Direct acyl substitution of α-hydroxyiminoesters with amine nucleophiles was developed as a key transformation. The synthetic compounds confirm the reported structures and importantly gives access to non-symmetrical spermine based natural products carrying two different bromotyrosine building blocks. Our new synthesis of spermatinamine is two steps shorter and more efficient than the previously reported sequence.
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| 4. |
- Masuyer, Geoffrey, et al.
(författare)
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Inhibition mechanism of human galectin-7 by a novel galactose- benzylphosphate inhibitor
- 2012
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 279:2, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- Galectins are involved in many cellular processes due to their ability to bind carbohydrates. Understanding their functions has shown the necessity for potent and specific galectin inhibitors. Human galectin-7 (hGal-7), in particular, has been highlighted as an important marker in many types of cancer by either inhibiting or promoting tumour growth. Producing ligands able to selectively target hGal-7 will offer promising tools for deciphering cancer processes in which hGal-7 is involved as well as present potential solutions for future therapeutics. Here we report the high resolution crystal structure of hGal-7 in complex with a synthetic 2-O-benzylphosphate-galactoside inhibitor (which is > 60-fold more potent than its parent galactoside). The high resolution crystallographic analysis highlights the validity of using saccharide derivatives, conserving properties of the galactose binding, while enhanced affinity and specificity is provided by the added phosphate group. This structural information will allow the design of further inhibitors with improved potency and specificity.
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| 5. |
- Strand, Mårten, et al.
(författare)
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2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society Microbiology. - 0066-4804 .- 1098-6596. ; 56:11, s. 5735-5743
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.
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| 6. |
- Öberg, Christopher T., et al.
(författare)
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Arene-anion based arginine-binding motif on a galactose scaffold : Structure-activity relationships of interactions with arginine-rich galectins
- 2011
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Ingår i: Chemistry: A European Journal. - : Wiley. - 1521-3765 .- 0947-6539. ; 17:29, s. 8139-8144
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Tidskriftsartikel (refereegranskat)abstract
- Two series of C3-benzamido and O2-anion-substituted galactopyranosides were synthesized and studied as binders to arginine-rich proteins galectin-1, -3, -7, -8N (N-terminal domain), and -9N (N-terminal domain). The first series had a 4-methylbenzamide at C3 and the anionic O2-substituent was varied. The second series varied the 4-substituent of the C3-benzamide, whereas the anionic O2 substituent was kept as a sulfate. The influence of the O2-anion substituent correlated negatively with the oxygen charge density in case of galectin-1, -3, and -9N. In the second series, the electron-donating capacity of the 4-substituent of the C3-benzamides correlated positively with the magnitude of the affinity enhancement by the 2O-sulfate.
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| 7. |
- Öberg, Christopher T., et al.
(författare)
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Copper-free huisgen 1,3-dipolar cycloaddition to 3-benzotriazolo-3-deoxy-β-D-galactopyranoside : Cyclization of a galactopyranoside azide and benzyne
- 2010
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Ingår i: Trends in Carbohydrate Research. - 0975-0304. ; 2:2, s. 1-4
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Tidskriftsartikel (refereegranskat)abstract
- Methyl 2-O-acetyl-3-benzotriazolo-4,6-O-benzylidene-3-deoxy- β -D-galactopyranoside was assembled by reacting benzyne, from 2-trimethylsilyl-trifluoromethansulfonylbenzene, and a secondary galactopyranoside azide in a copper-free Huisgen 1,3-dipolar cycloaddition. Following deprotection, the resulting benzotriazoles were evaluated as galectin inhibitors resulting in a 2-4 fold increase in affinity against galectin-1, -2 and -4 N-terminus compared to the parent methyl galactoside.
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| 8. |
- Öberg, Christopher T, et al.
(författare)
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Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:7, s. 3170-3181
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Tidskriftsartikel (refereegranskat)abstract
- 2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound ( Antimicrob. Agents Chemother. 2010 , 54 , 3871 ). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 μM and low cell toxicity.
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