Palladium-catalysed Suzuki–Miyaura coupling reactions of Bromhexine and Ambroxol

Sharif, Muhammad; Pews‐Davtyan, Anahit; Lukáš, Jan; Pohlers, Susann; Rolfs, Arndt; Langer, Peter; Beller, Matthias

doi:10.1016/j.tet.2014.05.116

Cited by 10 publications

(1 citation statement)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The half-maximal inhibitory concentration represents the concentration of an inhibitor that is required to reduce enzyme activity by 50%. For ABX, we defined it as the concentration at which the half-maximal inhibitory effect was achieved, since the inhibition by ABX was incomplete (as known from previous studies) [ 12 , 30 ]. In the current experiment, the residual enzyme activity was about 70%.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol

Pantoom

Hules

Schöll

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid β-glucosidase (β-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on β-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits β-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant β-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated β-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant β-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional β-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize β-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.

show abstract

Section: Resultsmentioning

confidence: 99%