The SiOH-Containing α-Amino Acid HOMe2SiCH2CH(NH2)COOH and Its Immobilization on Silica via an Si−O−Si Linkage

Tacke, Reinhold; Schmid, Thomas; Merget, Markus

doi:10.1021/om040127n

Cited by 21 publications

(13 citation statements)

References 7 publications

(11 reference statements)

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“…The following hydrolysis, to afford silanediol 19, was carried out using NaOD in [D 3 ]MeCN/D 2 O, to enable monitoring of the reaction and characterization of the product by 1 H NMR. Unencumbered silanediols are at risk of polymerization; [39,42] to decrease the risk of polymerization the reaction mixture was used directly in the enzymatic assay (Scheme 3).…”

Section: Chemistrymentioning

confidence: 99%

The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11

et al. 2013

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Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochemical profiling of a series of compounds, including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compound collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn(2+) -dependent HDACs. Potent inhibition was observed with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate class I and class IIb HDAC inhibitors.

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Section: Chemistrymentioning

confidence: 99%

The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11

et al. 2013

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“…We sought bioorthogonal, single-bond linkers with the flexibility to conform to the demands of linking pharmacophoric sites while maintaining good drug-like properties and evading metabolism and conjugation. In earlier studies, Tacke et al installed silanol moieties in place of carbinols of known drugs, and demonstrated the retention of biological activity in vitro and in vivo, good stability, toleration, and pharmacokinetics, with resistance to dehydration and metabolism, and no detectable glucuronide conjugates [57]. In several instances, disiloxane dimers of these silanol drug analogs were noted in the solid state and concentrated solutions, but dimers were not exploited and did not appear to contribute to the pharmacology [58].…”

Section: Discussionmentioning

confidence: 99%

A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

et al. 2018

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β-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC₅₀ at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.

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“…Under these strongly acidic CO conditions the phenylsilane was also hydrolyzed. This phenylalanine derivative was found to be monomeric when dissolved in water, but exclusively dimeric 43 when isolated [25]. An unexpected preparation of silanol 42 occurred when diazido amino acid 44 was reduced catalytically [26].…”

Section: Synthesis Of B-silylalanine and Derivativesmentioning

confidence: 98%

Chemistry of Silicon‐Containing Amino Acids

Sieburth

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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The SiOH-Containing α-Amino Acid HOMe₂SiCH₂CH(NH₂)COOH and Its Immobilization on Silica via an Si−O−Si Linkage

Cited by 21 publications

References 7 publications

The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11

The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11

A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

Chemistry of Silicon‐Containing Amino Acids

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