| 1. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
-
Enhanement of amyloid fibril binding by ring expansion of thiazolino fused 2-pyridone peptidomimetics
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Thiazolino fused 2-pyridones undergo thiazoline ring opening by reaction with 2-nitrobenzyl bromide through thi- oether attack, and base promoted fragmentation of the resulting sulfonium ions. Subsequent deprotonation of the benzylic carbon and intramolecular 1,4-addition leads to ring closure, generating dihydrothiazine fused 2-pyridones by net ring expansion of the thiazoline ring. Application of the ring expansion procedure to the pyridine and pyrimidine fused thiazolino 2-pyridones provided compounds with enhanced fibril binding activity.
|
|
| 2. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
-
Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
|
|
| 3. |
- Begnini, Fabio, et al.
(författare)
-
Mining Natural Products for Macrocycles to Drug Difficult Targets
- 2021
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:2, s. 1054-1072
-
Tidskriftsartikel (refereegranskat)abstract
- Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein- protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keapl and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections.
|
|
| 4. |
|
|
| 5. |
- Bharate, Jaideep B., et al.
(författare)
-
K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
- 2021
-
Ingår i: Organic and biomolecular chemistry. - : The Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 19:44, s. 9758-9772
-
Tidskriftsartikel (refereegranskat)abstract
- We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.
|
|
| 6. |
- Lindgren, Cecilia, et al.
(författare)
-
Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
- 2018
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:11, s. 4774-4790
-
Tidskriftsartikel (refereegranskat)abstract
- Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Sethio, Daniel, et al.
(författare)
-
Simulation Reveals the Chameleonic Behavior of Macrocycles
- 2023
-
Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:1, s. 138-146
-
Tidskriftsartikel (refereegranskat)abstract
- Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations-standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.
|
|
| 10. |
- Sharma, Janpriy, et al.
(författare)
-
Avenues of decarbonisation in the dynamics of processed food supply chains : Towards responsible production consumption
- 2024
-
Ingår i: Heliyon. - : Cell Press. - 2405-8440. ; 10:5
-
Tidskriftsartikel (refereegranskat)abstract
- Nowadays, the demand for processed food items is surging. To fulfil the enhanced demand, a significant impact is laid on the environment, which enhances the carbon footprint being generated. Hence, to overcome this, the avenues of decarbonisation need to be explored. The presented work is aimed at promoting the decarbonisation of the existing practices within the processed food supply chains. It finds strong compliance with the sustainable development goal (SDG-12), focusing on responsible production-consumption mechanisms. For the same, key enactors of decarbonisation are identified and mapped with the practices at various stages of food supply chains, i.e. upstream, downstream, and other allied practices. Based upon these enactors, a relational, hierarchical framework is developed to provide a comprehensive perspective on complex intricacies. This framework is analysed with an innovative approach which comprises the fundamentals of Interval-Valued Intuitionistic Hesitant Fuzzy Set with the Entropy measures. It results in the outranking of the enactors relative to its importance in the decarbonisation of processed food supply chains. Furthermore, the empirical findings are validated by the sensitivity analysis to felicitate robust decision-making. The outcomes of the presented work provide a roadmap and stepped approach to achieve the decarbonisation goals and make productionconsumption mechanisms sustainable. It finds implications in the development of the framework, policy formulation, and decisional attributes for the decarbonisation of food supply chains. It focuses on the adoption of strategies that align with global efforts to mitigate climate change and promote a sustainable future.
|
|
