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Palladium-catalyzed carbonylative transformations of bromhexine into bioactive compounds as glucocerebrosidase inhibitors
Global Congress on Biochemistry, Glycomics & Amino Acids
December 08-09, 2016 San Antonio, USA

M Sharif

King Fahd University of Petroleum and Minerals, KSA

Posters & Accepted Abstracts: Biochem Anal Biochem


Moreover, recent medicinal work exhibited bromhexine and its metabolite ambroxol as inhibitors of the human glucocerebrosidase (β-glucosidase, GCase, EC enzyme. A defective glucocerebrosidase enzyme leads to the rare hereditary condition Gaucher�??s disease, which involves a glycosphingolipid storage disorder (OMIM #230800) and belongs to a class of lysosomal storage disorders (LSD). Numerous small molecule inhibitors were shown to enhance the activity of the respective enzyme in vivo, that is, intracellular. These pharmacological chaperones are regarded as a potential alternative therapeutic strategy. Ambroxol was able to enhance the activity of mutant forms of the enzyme, namely, N370S and L444P, which account for the most common misfolding mutations of Gaucher disease and thus, it stabilized its folding state and allowed the intracellular transport to the target organelle. This function of ambroxol can potentially attenuate the course of Gaucher disease, and, therefore, can ameliorate a patient�??s distress. It was hypothesized that the ability to function as a pharmacological chaperone is associated with the power of the inhibitory effect. Figure 1: Inhibition of recombinant GCase (Imiglucerase, Genzyme Corporation, Cambridge, MA, USA) by bromhexine and chosen compounds. The inhibitory curve for bromhexine at pH=6.7 displayed a significant diminishment of activity starting at 166 μm. The reduction at the maximal applied concentration of 333 μm was 36.3%. The reference compound ambroxol (red curve) showed a slightly stronger inhibition than bromhexine. A significant inhibition was obtained by starting at a concentration of 33.3 μm. The highest obtained inhibition was 46.2%. Compound 2b was more effective at the examined concentrations than the lead substance bromhexine and proved to be a stronger inhibitor than the pharmacological chaperone ambroxol. Compound 5c showed a sustained inhibition at the same level as bromhexine. Asterisks mark the significant difference between the effectiveness of ambroxol and compound 2b on glucocerebrosidase inhibition, that is, *p _ 0.05 and **p _ 0.01.

Biography :

Email: msharif@kfupm.edu.sa