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Ru(ii)–arene azole complexes as anti-amyloid-β agents
Ryan M. Hacker ; Daniela M. Grimard ; Katie A. Morgan , et al. Dalton Trans.,2024,53,18845-18855. DOI: 10.1039/D4DT01740D PubMed ID: 39093049
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Abstract: With the recent clinical success of anti-amyloid-β (Aβ) monoclonal antibodies, there is a renewed interest in agents which target the Aβ peptide of Alzheimer's disease (AD). Metal complexes are particularly well-suited for this development, given their structural versatility and ability to form stabile interactions with soluble Aβ. In this report, a small series of ruthenium–arene complexes were evaluated for their respective ability to modulate both the aggregation and cytotoxicity of Aβ. First, the stability of the complexes was evaluated in a variety of aqueous media where the complexes demonstrated exceptional stability. Next, the ability to coordinate and modulate the Aβ peptide was evaluated using several spectroscopic methods, including thioflavin T (ThT) fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Overall, the complex RuBO consistently gave the greatest inhibitory action towards Aβ aggregation, which correlated with its ability to coordinate to Aβ in solution. Furthermore, RuBO also had the lowest affinity for serum albumin, which is a key consideration for a neurotherapeutic, as this protein does not cross the blood brain barrier. Lastly, RuBO also displayed promising neuroprotective properties, as it had the greatest inhibition of Aβ-inducted cytotoxicity.
CAS No. : | 934-32-7 | MDL No. : | MFCD00005596 |
Formula : | C7H7N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JWYUFVNJZUSCSM-UHFFFAOYSA-N |
M.W : | 133.15 | Pubchem ID : | 13624 |
Synonyms : |
2-Iminobenzimidazoline;1H-Benzimidazol-2-ylamine
|
Chemical Name : | 1H-Benzo[d]imidazol-2-amine |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H317-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | In ethanol; for 4h;Reflux; | 2-Aminobenzimidazole (0.80 g,6 mmol) and compound 1 (0.99 g, 6 mmol) were dissolved in25 mL ethanol. The resulting solution was heated at reflux for4 h. The solvent was removed by a rotary evaporator at reducedpressure. The crude product was purified by silica gel columnchromatography (ethyl acetate/n-hexane 1:3) and recrystallizedwith ethanol to yield yellow solid. Yield: 1.03 g (61.2%);1H NMR (400 MHz, DMSO-d6) delta 3.05 (s, 6H, CH3), 6.16-7.53(m, 7H, Ar-H), 9.34 (s, 1H, CH=N), 12.41 (s, 1H, NH), 12.85(s, 1H, OH); ESIMS: 280.1408 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With copper(l) iodide; 8-quinolinol; caesium carbonate; In tert-butyl alcohol; at 90℃; for 16h;Sealed tube; | General procedure: To a 2-5mL microwave vial was added 2-aminobenzimidazole (150mg, 1.13mmol), Cs2CO3 (918mg, 2.82mmol, 2.5 eq.), CuI (21mg, 0.11mmol, 0.1 eq.), 8-hydroxyquinoline (25mg, 0.17mmol, 0.15 eq.) and the appropriately substituted bromo or iodobenzene (1.24mmol, 1.1 eq.) were suspended in t-BuOH (2mL). The vial was sealed and heated at 110C (for bromobenzenes) or 90C (for iodobenzenes) for 16h. The cooled mixture was poured into EtOAc/MeOH (20:1) (30mL), filtered through Celite and evaporated under reduced pressure. The residue was purified by column chromatography using DCM/MeOH/NH4OH (89:10:1) to give typically colourless amorphous solids. This method produced compounds 2a-2l, 3a-3r, 4a, 4b, 5a, 5b, 6a-6d, 7, 8a-8c, 10. |
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