β-Aminoketones as prodrugs with pH-controlled activation

Simplı́cio, Ana Luı́sa; Clancy, John M.; Gilmer, John F.

doi:10.1016/j.ijpharm.2006.11.055

Cited by 30 publications

(21 citation statements)

References 12 publications

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“…In principle, the long-lasting effect observed on EGFR autophosphorylation could be ascribed to different phenomena: (i) accumulation of the inhibitor in cells, as previously demonstrated for some reversible quinazolines; 66 (ii) conversion of the competitive inhibitor into an irreversible one at the active site of the enzyme (mechanism-based inhibition), as described for other β-aminocarbonyl compounds; 38 (iii) generation of the corresponding reactive acrylamide, as described for aryl β-aminoethyl ketones that have potential application as prodrugs of unsaturated ketones. 67 As previously described, 54,66 some reversible quinazoline EGFR inhibitors are sequestered in cells generating falsepositive results in the autophosphorylation assay based on the 8 h washout protocol. As an example, the fully reversible compound 1, which is strongly sequestered in cells, produced 46.4% ± 6.7% inhibition of EGFR autophosphorylation (A459 cells) at 1 μM concentration 8 h after removal from the medium.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with offtargets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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“…Second, the MSNBs are more stable than the ␤-aminoketones at physiological pH. Mannich bases are usually stable under acidic conditions but are cleaved into a reactive ␣,␤-unsaturated ketone at basic pH (73,74). The released ␣,␤-unsaturated ketone can contribute to nonspecific protein binding and general toxicity (75)(76)(77).…”

Section: Discussionmentioning

confidence: 99%

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TR␤ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T 3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPAR␥ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TR␤ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TR␤ to disrupt SRC2 association.

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“…This is particularly important for chemotherapeutic drugs, where the active drug ideally only acts on tumor cells in order to reduce toxic side effects [18]. Prodrugs can be activated by photo irradiation [19], change in pH [20] or enzymatically [21], for instance by CYPs [22]. Polymorphisms in CYPs can result in ineffective or aberrant activation of prodrugs [22], which can lead to toxicity [4].…”

Section: Introductionmentioning

confidence: 99%

Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy

et al. 2013

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The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.

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β-Aminoketones as prodrugs with pH-controlled activation

Cited by 30 publications

References 12 publications

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy

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