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Advances in Experimental Medicine and... 1997Phenylacetate and analogs represent a new class of pleiotropic growth regulators that alter tumor cell biology by affecting gene expression at both the transcriptional... (Review)
Review
Phenylacetate and analogs represent a new class of pleiotropic growth regulators that alter tumor cell biology by affecting gene expression at both the transcriptional and post transcriptional levels. Based on these findings, NaPA and NaPB entered clinical trials at the National Cancer Institute. Ongoing phase I studies with NaPA, involving adults with prostate and brain cancer, have confirmed that therapeutic levels can be achieved with no significant toxicities, and provide preliminary evidence for benefit to patients with advanced disease (Thibault et al., submitted).
Topics: Adult; Antimetabolites, Antineoplastic; Brain Neoplasms; Cell Differentiation; Clinical Trials, Phase I as Topic; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasms; Phenylacetates; Phenylbutyrates; Prostatic Neoplasms; Transcription, Genetic; Tumor Cells, Cultured
PubMed: 9547596
DOI: 10.1007/978-1-4615-5325-0_67 -
Journal of Cellular Biochemistry.... 1995Differentiating agents, including butyrate, phenylacetate and several other agents, have long been known to alter abnormal or transformed cell lines in vitro to a more... (Review)
Review
Differentiating agents, including butyrate, phenylacetate and several other agents, have long been known to alter abnormal or transformed cell lines in vitro to a more normal state including phenotype and function. The effect depends on prolonged exposure to a minimum concentration of the agent. In vivo studies of butyrate and analogues have been limited, largely due to rapid in vivo metabolism. A butyrate prodrug, the triglyceride tributyrin, shows great promise in achieving effective and prolonged serum levels when given orally to mice and rats, and has been recommended for human trial. In vitro, butyrate and its mono- and triglyceride have shown potent synergy with retinoic acid, suggesting a ten-fold reduction in serum level requirements. Other butyrate prodrugs have been prepared and studied; several sugar esters of butyrate show promise. Phenylacetate, a normal mammalian metabolite, is also a potent differentiating agent, but its clinical use is limited by its objectionable odor per se and in treated subjects. Phenylbutyrate, a prodrug of phenylacetate, is more acceptable and may have greater promise. The availability of effective prodrugs of effective differentiating agents, such as tributyrin and phenylbutyrate, creates many opportunities for possible therapeutic and chemopreventive applications, especially if synergy in vivo can be demonstrated with retinoids (e.g., retinoic acid) or deltanoids (e.g., active vitamin D analogues), confirming in vitro studies. Particular disease targets would include certain leukemias, thalassemia, and sickle cell anemia.
Topics: Animals; Antimetabolites, Antineoplastic; Butyrates; Butyric Acid; Cell Differentiation; Drug Synergism; Humans; Mice; Phenylacetates; Rats; Triglycerides
PubMed: 8538206
DOI: 10.1002/jcb.240590831 -
Food and Chemical Toxicology : An... Jan 2022The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose...
The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that phenethyl phenylacetate is not genotoxic. Data provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog benzyl benzoate (CAS # 120-51-4) provide an MOE >100 for the developmental toxicity endpoint. The fertility and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to phenethyl phenylacetate is below the TTC (0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from analog benzyl phenylacetate (CAS # 102-16-9) show that there are no safety concerns for phenethyl phenylacetate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; phenethyl phenylacetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenethyl phenylacetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.
Topics: Academies and Institutes; Acetates; Animals; Dermatitis, Photoallergic; Dermatitis, Phototoxic; Endpoint Determination; Environmental Exposure; Europe; Fertility; Humans; Mutagenicity Tests; North America; Odorants; Perfume; Phenols; Phenylacetates; Registries; Reproduction; Respiratory System; Risk Assessment; Safety; Skin; Toxicity Tests
PubMed: 34843869
DOI: 10.1016/j.fct.2021.112711 -
Chembiochem : a European Journal of... Sep 2020The green and sustainable synthesis of chemicals from renewable feedstocks by a biotransformation approach has gained increasing attention in recent years. In this work,...
The green and sustainable synthesis of chemicals from renewable feedstocks by a biotransformation approach has gained increasing attention in recent years. In this work, we developed enzymatic cascades to efficiently convert l-phenylalanine into 2-phenylethanol (2-PE) and phenylacetic acid (PAA), l-tyrosine into tyrosol (p-hydroxyphenylethanol, p-HPE) and p-hydroxyphenylacetic acid (p-HPAA). The enzymatic cascade was cast into an aromatic aldehyde formation module, followed by an aldehyde reduction module, or aldehyde oxidation module, to achieve one-pot biotransformation by using recombinant Escherichia coli. Biotransformation of 50 mM l-Phe produced 6.76 g/L PAA with more than 99 % conversion and 5.95 g/L of 2-PE with 97 % conversion. The bioconversion efficiencies of p-HPAA and p-HPE from l-Tyr reached to 88 and 94 %, respectively. In addition, m-fluoro-phenylalanine was further employed as an unnatural aromatic amino acid substrate to obtain m-fluoro-phenylacetic acid; >96 % conversion was achieved. Our results thus demonstrated high-yielding and potential industrial synthesis of above aromatic compounds by one-pot cascade biocatalysis.
Topics: Aldehydes; Biocatalysis; Biotransformation; Carboxy-Lyases; Molecular Structure; Nucleoside Deaminases; Oxidoreductases; Phenylacetates; Phenylethyl Alcohol
PubMed: 32291886
DOI: 10.1002/cbic.202000182 -
ChemSusChem May 2022Natural phenethyl acetate (PEA), phenylacetic acid (PAA), ethyl phenylacetate (Et-PA), and phenethyl phenylacetate (PE-PA) are highly desirable aroma chemicals, but with...
Natural phenethyl acetate (PEA), phenylacetic acid (PAA), ethyl phenylacetate (Et-PA), and phenethyl phenylacetate (PE-PA) are highly desirable aroma chemicals, but with limited availability and high price. Here, green, sustainable, and efficient bioproduction of these chemicals as natural products from renewable feedstocks was developed. PEA and PAA were synthesized from l-phenylalanine (l-Phe) via novel six- and five-enzyme cascades, respectively. Whole-cell-based cascade biotransformation of 100 mm l-Phe in a two-phase system (aqueous/organic: 1 : 0.5 v/v) containing ethyl oleate or biodiesel as green solvent gave 13.6 g L PEA (83.1 % conv.) and 11.6 g L PAA (87.1 % conv.), respectively. Coupled fermentation and biotransformation approach produced 10.4 g L PEA and 9.2 g L PAA from glucose or glycerol, respectively. The biosynthesized PAA was converted to natural Et-PA and PE-PA by esterification using lipases with ethanol or 2-phenylethanol derived from sugar, affording 2.7 g L Et-PA (83.1 % conv.) and 4.6 g L PE-PA (96.3 % conv.), respectively.
Topics: Acetates; Fermentation; Phenylacetates; Phenylalanine
PubMed: 35068056
DOI: 10.1002/cssc.202102645 -
Journal of Pharmaceutical Sciences Jul 2023Zinc phenylacetate (Zn-PA), a substitute for sodium phenylacetate as an ammonia-scavenging drug is hydrophobic, which poses problems for drug dissolution and solubility....
Zinc phenylacetate (Zn-PA), a substitute for sodium phenylacetate as an ammonia-scavenging drug is hydrophobic, which poses problems for drug dissolution and solubility. We were able to co-crystallize the zinc phenylacetate with isonicotinamide (INAM) and produce a novel crystalline compound (Zn-PA-INAM). The single crystal of this new crystal was obtained, and its structure is reported here for the first time. Zn-PA-INAM was characterized computationally by ab initio, Hirshfeld calculations, CLP-PIXEL lattice energy calculation, and BFDH morphology analysis, and experimentally by PXRD, Sc-XRD, FTIR, DSC, and TGA analyses. Structural and vibrational analyses showed a major modification in intermolecular interaction of Zn-PA-INAM compared to Zn-PA. The dispersion-based pi-stacking in Zn-PA is replaced by coulomb-polarization effect of hydrogen bonds. As a result, Zn-PA-INAM is hydrophilic, improving the wettability and powder dissolution of the target compound in an aqueous solution. Morphology analysis revealed, unlike Zn-PA, Zn-PA-INAM has polar groups exposed on its prominent crystalline faces, reducing the hydrophobicity of the crystal. The shift in average water droplet contact angle from 128.1° (Zn-PA) to 27.1° (Zn-PA-INAM) is strong evidence of a marked decrease in hydrophobicity of the target compound. Finally, HPLC was used to obtain the dissolution profile and solubility of Zn-PA-INAM compared to Zn-PA.
Topics: Crystallization; Zinc; Phenylacetates; Hydrophobic and Hydrophilic Interactions; Water
PubMed: 36893962
DOI: 10.1016/j.xphs.2023.02.026 -
Food and Chemical Toxicology : An... Mar 2023
Topics: Odorants; Perfume; Phenylacetates; Registries
PubMed: 36657702
DOI: 10.1016/j.fct.2023.113622 -
The Journal of Clinical Endocrinology... Aug 1999There is increasing evidence that phenylacetate inhibits growth and modulates differentiation in a variety of tumors with effects on gene expression, and protein...
There is increasing evidence that phenylacetate inhibits growth and modulates differentiation in a variety of tumors with effects on gene expression, and protein prenylation and glycosylation at concentrations that have been safely used in humans. We evaluated the antineoplastic effects of phenylacetate in five thyroid cancer cell lines of follicular cell origin in vitro. We found early growth inhibition occurred with phenylacetate treatment at a dose of 2.5-10 mmol/L. The growth inhibition was cytostatic with the thyroid carcinoma cells arrested in the G0-1 cell phase. When evaluating the effect of phenylacetate on the differentiated functions of thyroid carcinoma cells, phenylacetate exposure: 1) decreased the TSH (10 mU/mL) growth response; 2) increased radioactive iodine (125I) uptake in two out of five cell lines; and 3) inhibited thyroglobulin secretion. Phenylacetate also inhibited the secretion of vascular endothelial growth factor (a glycoprotein dependent on glycosylation for efficient cellular excretion) from the thyroid cancer cell lines. Our results support that phenylacetate has an antiproliferative effect in many cell types, but the differentiating effects were not uniform. Importantly, we have identified that phenylacetate inhibits the secretion of vascular endothelial growth factor, which possibly mediates the antiangiogenic effects observed in vivo. Because of the minimal toxicity associated with phenylacetate treatment in humans, at concentrations we show to have a significant antineoplastic effect in thyroid carcinoma cells, phenylacetate could be useful in patients with differentiated thyroid cancer who fail conventional therapy or as an adjuvant to radioactive iodine therapy in patients with aggressive tumors.
Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Endothelial Growth Factors; Humans; Lymphokines; Phenylacetates; Thyroid Neoplasms; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 10443689
DOI: 10.1210/jcem.84.8.5913 -
Surgery Sep 1998Phenylacetate is growth inhibitor for a variety of tumors at concentration that have been safely achieved in human beings. This antitumor effect is related to inhibition...
BACKGROUND
Phenylacetate is growth inhibitor for a variety of tumors at concentration that have been safely achieved in human beings. This antitumor effect is related to inhibition of the isoprenoid synthetic pathway by blocking the enzyme, mevalonate pyrophosphate (MVAPP) decarboxylase. The purpose of this study was to evaluate the effects of phenylacetate on human pancreatic carcinoma.
METHODS
For in vitro studies, six human pancreatic carcinoma cell lines (BxPc, AsPc, MIAPaCa-2 Panc-1, CFPAc, and HS 766T) were studied. For in vivo studies, nude mice were inoculated with pancreatic cells (BxPc and MIA PaCa-2) and randomized to receive phenylacetate or saline control.
RESULTS
Phenylacetate produces reversible in vitro growth arrest at doses of 2.5 to 10 mmol. The antiproliferative effect is cytostatic, producing accumulation of cells in G1, and is not associated with cell toxicity. Systemic treatment of nude mice bearing heterotopic human pancreatic carcinoma results in growth inhibition of tumors without host toxicity. Phenylacetate blocks the processing of mevalonate to isopentenyl-pyrophosphate by inhibiting MVAPP and exhibits suppression of biosynthetic pathways requiring isoprenoids, including cholesterol and dolichol biosynthesis, protein glycosylation, and isoprenylation of proteins.
CONCLUSIONS
These results indicate that phenylacetate has cytostatic activity in pancreatic carcinoma and support the conclusion that suppression of multiple biosynthetic pathways requiring isoprenoids is contributing to the drug's antiproliferative action. The safety profile and efficacy of phenylacetate make it an attractive agent for the treatment of pancreatic cancer.
Topics: Animals; Antimetabolites, Antineoplastic; Carboxy-Lyases; Cell Division; Flow Cytometry; Glycosylation; Lipid Metabolism; Mevalonic Acid; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Phenylacetates; Tumor Cells, Cultured
PubMed: 9736908
DOI: No ID Found -
Current Microbiology Jul 2008Phenylacetate-CoA ligase (E.C. 6.2.1.30), the initial enzyme in the metabolism of phenylacetate, was studied in Thermus thermophilus strain HB27. Enzymatic activity was...
Phenylacetate-CoA ligase (E.C. 6.2.1.30), the initial enzyme in the metabolism of phenylacetate, was studied in Thermus thermophilus strain HB27. Enzymatic activity was upregulated during growth on phenylacetate or phenylalanine. The phenylacetate-CoA ligase gene (paaK) was cloned and heterologously expressed in Escherichia coli and the recombinant protein was purified. The enzyme catalyzed phenylacetate + CoA + MgATP --> phenylacetyl-CoA + AMP + MgPP(i) with a V(max) of 24 micromol/min/mg protein at a temperature optimum of 75 degrees C. The apparent K(m) values for ATP, CoA, and phenylacetate were 6, 30, and 50 microM: , respectively. The protein was highly specific toward phenylacetate and showed only low activity with 4-hydroxyphenylacetate. Despite an amino acid sequence identity of >50% with its mesophilic homologues, phenylacetate-CoA ligase was heat stable. The genome contained further homologues of genes, which are postulated to be involved in the CoA ester-dependent metabolic pathway of phenylacetate (hybrid pathway). Enzymes of this thermophile are expected to be robust and might be useful for further studies of this yet unresolved pathway.
Topics: Coenzyme A Ligases; Escherichia coli; Gene Expression; Molecular Sequence Data; Molecular Weight; Phenylacetates; Recombinant Fusion Proteins; Substrate Specificity; Temperature; Thermus thermophilus
PubMed: 18414813
DOI: 10.1007/s00284-008-9147-3