Multi gram-scale synthesis of galactothionolactam and its transformation into a galactonoamidine

Bioorganic & Medicinal Chemistry

Striegler

et al. 2016

Self Cite

Several galactonoamidines were previously identified as very potent competitive inhibitors that exhibit stabilizing hydrophobic interactions of the aglycon in the active site of β-galactosidase (A. oryzae). To elucidate the contributions of the glycon to the overall inhibition ability of the compounds, three glyconoamidine derivatives with alteration in the glycon at C-2 and C-4 were synthesized and evaluated herein. All amidines are competitive inhibitors of β-galactosidase (E. coli) and show significantly reduced inhibition ability when compared to the parent. The results highlight strong hydrogen-bonding interactions between the hydroxyl group at C-2 of the amidine glycon and the active site of the enzyme. Slightly weaker H-bonds are promoted through the hydroxyl group at C-4. The inhibition constants were determined to be picomolar for the parent galactonoamidine, and nanomolar for the designed derivatives rendering all glyconooamidines very potent inhibitors of glycosidases albeit the derivatized amidines show up to 700-fold lower inhibition activity than the parent.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…25–27 Activation of 16a–c with Meerwein’s salt and subsequent coupling with p -methylbenzylamine yielded perbenzylated glyconoamidines 17a–c . 25,10,7 …”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Illuminating the binding interactions of galactonoamidines during the inhibition of β-galactosidase (E. coli)

Fan

Bioorganic & Medicinal Chemistry

Striegler

et al. 2016

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Evaluating hydrophobic galactonoamidines as transition state analogs for enzymatic β-galactoside hydrolysis

Mills

Wang

et al. 2018

Bioorganic Chemistry

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A spectroscopic examination of six galactonoamidines with inhibition constants and efficacy in the low nanomolar concentration range (K = 6-11 nM, IC = 12-36 nM) suggested only two of them as putative transition state analogs for the hydrolysis of β-galactosides by β-galactosidase (A. oryzae). A rationale for the experimental results was elaborated using docking and molecular dynamics studies. An analysis of the combined observations reveals several common factors of the compounds suggested as transition state analogs (TSAs): the putative TSAs have a similar orientation in the active site; show conserved positioning of the glycon; display a large number of H-bond interactions toward the catalytically active amino acid residues via their glycon; and exhibit hydrophobic interactions at the outer rim of the active site with small changes of the position and orientation of their respective aglycons.

Arabinoamidine synthesis and its inhibition toward β-glucosidase (sweet almonds) in comparison to a library of galactonoamidines

Bioorganic & Medicinal Chemistry

Striegler

Fan

2016

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Aiming at the development of potent inhibitors of -glucosidases, a small library of galactonoamidines and one arabinoamidine derived in analogy were studied as inhibitors of sweet almond -glucosidase. The five-membered glycon in arabinoamidine was shown to interact with the proton donor in the active site of the retaining enzyme, but not with the nucleophile. By contrast, the corresponding galactonoamidine with a six-membered glycon and identical aglycon interacts with both hydrolysis-promoting amino acids in the active site and inhibits the enzymatic hydrolysis of -glucosides in the low nanomolar concentration range. While both inhibitors are competitive, their inhibition ability is more than 37,000-fold different.