1-Methylhydantoin

Aromatic interaction of hydantoin compounds leads to virucidal activities.[Pubmed:34004504]

Biophys Chem. 2021 Aug;275:106621.

Virus inactivation or disinfection is the first line of protection against virus infection. Here, we report for the first time the virus inactivation (virucidal) activities of hydantoin and its derivative, 1-Methylhydantoin against enveloped herpes simplex virus type-1. These hydantoin compounds showed favorable interaction with aromatic amino acids, similarly to arginine hydrochloride also exhibiting aromatic interaction and virucidal activities on the same virus. Among them, 1-Methylhydantoin demonstrated a greater virucidal activity. Solubility measurements in organic solvents and salting-out salt solutions showed that 1-Methylhydantoin is more hydrophobic than others, suggesting that the hydrophobic nature and aromatic interaction play a role in interaction with viral proteins and thereby virucidal activity.

Serum Creatinine Electrochemical Biosensor on Printed Electrodes Using Monoenzymatic Pathway to 1-Methylhydantoin Detection.[Pubmed:32923804]

ACS Omega. 2020 Aug 27;5(35):22459-22464.

The rising prevalence of Chronic Kidney Disease (CKD) has necessitated efforts towards the development of cost-effective and accurate biosensors for serum creatinine, which is a potent biomarker reflecting kidney function. This work presents a novel and cost-effective technique to estimate serum creatinine without any sample preprocessing. The technique involves the conversion of creatinine by a monoenzymatic pathway to 1-Methylhydantoin. The concentration of 1-Methylhydantoin is then quantified by utilizing its innate ability to form a complex with transition metals such as cobalt. The complex formation has been validated using optical spectroscopy and the transmittance at 290 nm wavelength is used to identify the optimum concentration of cobalt chloride in sensing chemistry. This chemical assay is shown to be robust against interference from serum albumin, the abundant plasma protein that can potentially influence the sensor response. The electrochemical biosensor developed using screen-printed electrodes thus provides highly selective creatinine estimation over the range of 0.2-4 mg/dL in a sample volume of 300 muL with no preprocessing and hence can be easily translated into a viable point-of-care (POC) device.

Toxicology of paraquat and pharmacology of the protective effect of 5-hydroxy-1-methylhydantoin on lung injury caused by paraquat based on metabolomics.[Pubmed:32019966]

Sci Rep. 2020 Feb 4;10(1):1790.

Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-Methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5' monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.

Protective mechanism of 1-methylhydantoin against lung injury induced by paraquat poisoning.[Pubmed:31560695]

PLoS One. 2019 Sep 27;14(9):e0222521.

Paraquat (PQ), one of the most widely used herbicides worldwide, causes severe toxic effects in humans and animals. 1-Methylhydantoin (MH) is an active ingredient of Ranae Oviductus, which has broad pharmacological activities, e.g., eliminating reactive oxygen species and inhibiting inflammation. This study investigated the effects of MH on lung injury induced by PQ. A PQ poisoning model was established by intragastric infusion of PQ (25 mg/kg), and the control group was simultaneously gavaged with the same dose of saline. The MH group was intraperitoneally injected with 100 mg/kg once per day after intragastric infusion of PQ (25 mg/kg) for five consecutive days. All animals were sacrificed on the sixth day, and the lung tissues were dissected for metabolomics analysis. The lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, TNF-alpha and malondialdehyde (MDA) content were determined according to the instructions of the detection kit. Compared with that in the control group, the content of LDH, TNF-alpha and MDA in the lung tissue of the PQ group was significantly higher, and the activity of SOD in the lung tissue was significantly lower (all p<0.05). Compared with that in the control group, the content of LDH, TNF-alpha and MDA in the MH group was significantly higher, and the activity of SOD was significantly lower (all p<0.05). However, the differences in SOD activity, LDH activity between the PQ and MH groups were not statistically significant (all p > 0.05). There were significant differences in MDA and TNF-alpha content between the PQ group and MH group (all p<0.05). MH decreased the production of malondialdehyde and TNF-alpha to protect against the lung injury caused by PQ poisoning, but it had no significant effect on the activity of LDH and SOD. There were significant differences in metabolomics between the MH group and the PQ poisoning group, primarily in bile acid biosynthesis and metabolism of cholesterol, nicotinate, nicotinamide, alanine, aspartate, glutamate, glycine, threonine, serine, phenylalanine and histidine. Therefore, this study highlights that MH has non-invasive mechanisms and may be a promising tool to treat lung injury induced by PQ poisoning.

Antitussive and Anti-inflammatory Dual-active Agents Developed from Natural Product Lead Compound 1-Methylhydantoin.[Pubmed:31247960]

Molecules. 2019 Jun 26;24(13). pii: molecules24132355.

Natural products play an important role in drug discovery. This work employed a natural product 1-Methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae, which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-Methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.

[Exploration about the protection mechanism of 5-hydroxy-1-methylhydantoin on paraquat poisoning model].[Pubmed:30592955]

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2018 Dec;30(12):1184-1189.

OBJECTIVE: To investigate the effects of 5-hydroxy-1-Methylhydantoin (HMH) on kidney injury induced by paraquat (PQ). METHODS: Fifteen SPF healthy Kunming mice were randomly divided into normal saline (NS) control group, PQ poisoning model group and HMH intervention group, with 5 mice in each group. PQ poisoning model was challenged by one-time gavage of 30 mg/kg PQ solution. The NS group received the same amount of NS by gavage. The HMH group was given 100 mg/kg of HMH immediately after the model was made and continued to be gavaged. Mice in each group were sacrificed 1 day after HMH gavage and heart blood and renal tissue were harvested for examination. The morphological changes of renal tissue were observed under light microscope by hematoxylin-eosin (HE) staining. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in renal tissue were detected according to the instructions of the kit. The expression of heme oxygenase-1 (HO-1) and interleukin-1beta (IL-1beta) in renal tissues were detected by Western Blot. The serum metabolites were detected by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS), the overall distribution of each sample was observed by principal component analysis (PCA), the accuracy of the model was evaluated by multidimensional analysis orthogonal partial least squares-discriminant analysis (OPLS-DA), and the difference metabolites were screened by variable importance in the projection (VIP) value > 1. RESULTS: Light microscopic observation showed that: glomerular structure in NS group was clear, there was no hyperemia and inflammatory cell infiltration in renal interstitium and blood vessels. In PQ group, some glomeruli atrophy and necrosis, capillary congestion in glomeruli, infiltration of inflammatory cells around glomeruli, swelling of renal tubular epithelial cells, slight stenosis of lumen, and occasional necrosis and exfoliation of epithelial cells occurred. The degree of kidney injury in HMH group was significantly less than that in PQ group. Compared with the NS group, the content of MDA in the PQ group was significantly increased (nmol/g: 6.70+/-0.84 vs. 2.70+/-0.43, P < 0.01) and the activity of SOD was significantly decreased (kU/L: 33.30+/-4.66 vs. 50.20+/-3.23, P < 0.05), the protein expression of HO-1 and IL-1beta were significantly increased (HO-1/beta-actin: 1.11+/-0.12 vs. 0.61+/-0.13, IL-1beta/beta-actin: 0.93+/-0.13 vs. 0.32+/-0.06, both P < 0.05). Compared with the PQ group, the content of MDA in the HMH group was significantly decreased (nmol/g: 5.10+/-0.93 vs. 6.70+/-0.84, P < 0.05) and the activity of SOD was significantly increased (kU/L: 61.00+/-9.02 vs. 33.30+/-4.66, P < 0.05), the protein expression of HO-1 was significantly decreased (HO-1/beta-actin: 0.77+/-0.07 vs. 1.11+/-0.12, P < 0.05), however, there was no significant difference in the protein expression of IL-1beta (IL-1beta/beta-actin: 0.87+/-0.13 vs. 0.93+/-0.13, P > 0.05). Metabolite detection results showed that: compared with NS group, the levels of creatinine, glycine, succinic acid, fumaric acid and citric acid were significantly increased in the PQ group (VIP value was 1.50, 1.58, 1.64, 1.74 and 1.95 respectively, all P < 0.05), while the levels of palmitic acid,alpha-tocopherol and 6-phosphogluconic acid were significantly decreased (VIP value was 1.10, 1.55 and 1.56 respectively, all P < 0.05). Compared with the PQ group, the levels of creatinine and citric acid were significantly decreased in the HMH group (VIP value was 1.50 and 1.86, both P < 0.05), while trans-4-hydroxy-proline, D-glyceric acid, 2, 6-fructose phosphate, 6-phosphate gluconic acid and aminomalonic acid were significantly increased (VIP value was 1.36, 1.55, 1.63, 1.68 and 1.76 respectively, all P < 0.05). CONCLUSIONS: HMH protects kidney injury caused by PQ poisoning by correcting tricarboxylic acids cycle disturbance, lipid peroxidation and energy metabolism disturbance, and its mechanism is related to the regulation of HO-1 protein expression through Nrf2 pathway.

Phthalate exposure and childhood overweight and obesity: Urinary metabolomic evidence.[Pubmed:30208345]

Environ Int. 2018 Dec;121(Pt 1):159-168.

OBJECTIVE: Metabolomics may unravel global metabolic changes in response to environmental exposures and identify important biological pathways involved in the pathophysiology of childhood obesity. Phthalate has been considered an obesogen and contributing to overweight and obesity in children. The purpose of this study is to evaluate changes in urine metabolites in response to the environmental phthalate exposure among overweight or obese children, and to investigate the metabolic mechanisms involved in the obesogenic effect of phthalate on children at puberty. METHODS: Within the national Puberty Timing and Health Effects in Chinese Children (PTHEC) study, 69 overweight/obese children and 80 normal weight children were selected into the current study according to their puberty timing and WGOC (The Working Group for obesity in China) references. Urinary concentrations of six phthalate monoesters (MMP, MEP, MnBP, MEHP, MEOHP and MEHHP) were measured using API 2000 electrospray triple quadrupole mass spectrometer (ESIMS/MS). Metabolomic profiling of spot urine was performed using gas chromatography-mass spectrometry. Differentially expressed urinary metabolites associated with phthalate monoesters exposure were examined using orthogonal partial least square-discriminant analysis and multiple linear regression models. In addition, the candidate metabolites were regressed to obesity indices with multiple linear regression models and logistic regression models in all subjects. RESULTS: Compared with normal weight children, higher levels of MnBP were detected in urinary samples of children with overweight and obesity. After adjusting for confounders including chronological age, gender, puberty onset, daily energy intake and physical activity and socio-economic level, positive association remained between urinary MnBP concentration and childhood overweight/obesity [OR=1.586, 95% CI:1.043,2.412]. We observed elevated MnBP concentration was significantly correlated with increased levels of monostearin, 1-monopalmitin, stearic acid, itaconic acid, glycerol 3-phosphate, 5-methoxytryptamine, kyotorphin, 1-Methylhydantoin, d-alanyl-d-alanine, pyrrole-2-carboxylic acid, 3,4-Dihydroxyphenylglycol, and butyraldehyde. Meanwhile, increased MnBP concentration was also significantly correlated with decreased levels of lactate, glucose 6-phosphate, d-fructose 6-phosphate, palmitic acid, 4-acetamidobutyric acid, l-glutamic acid, n-acetyl-l-phenylalanine, iminodiacetic acid, hydroxyproline, pipecolinic acid, l-ornithine, n-acetyl-l-glutamic acid, guanosine, cytosin, and (s)-mandelic acid in the normal weight subjects. The observations indicated that MnBP exposure was related to global urine metabolic abnormalities characterized by disrupting arginine and proline metabolism and increasing oxidative stress and fatty acid reesterification. Among the metabolic markers related to MnBP exposure, 1-Methylhydantoin, pyrrole-2-carboxylic acid and monostearin were found to be positively correlated with obesity indices, while hydroxyproline, l-ornithine, and lactate were negatively associated with overweight/obesity in children. CONCLUSIONS: Our results suggested that the disrupted arginine and proline metabolism associated with phthalate exposure might contribute to the development of overweight and obesity in school-age children, providing insights into the pathophysiological changes and molecular mechanisms involved in childhood obesity.

[Determination of 1-methylhydantoin Concentration in Blood by GC-MS Method and Its Application in Forensic Medicine].[Pubmed:29441771]

Fa Yi Xue Za Zhi. 2017 Dec;33(6):619-621.

OBJECTIVES: To establish a gas chromatographic-mass spectrometric GC-MS analysis method for quantifying 1-Methylhydantoin concentration in whole blood. To provide technical support to forensic identification related cases of 1-Methylhydantoin. METHODS: As an internal standard, 500 ng SKF525A was added to 0.5 mL blood sample, and then 2 mL 0.01 mol/L dilute hydrochloric acid and 0.5 g ammonium carbonate were added in order to buffer the pH value to 9, and following 2 mL ethyl acetate. The organic solvent layer was obtained after centrifuge and then analysed by GC-MS after drying. RESULTS: Good linear relationship of 1-Methylhydantoin in blood was obtained in the range of 0.5-50 ng/mL. The equation of linear regression was y=0.015 51 x+0.007 26R(2)=0.999 7 with 0.1 ng/mL detection limit, and the recovery was 93.02%-108.12%. The intra-day and inter-day precision were less than 6.07% and 13.37%, respectively. CONCLUSIONS: The results gotten by this method is accurate and reproducible, which can be used for the determination of 1-Methylhydantoin concentration in blood samples.

5-Methylhydantoin: From Isolated Molecules in a Low-Temperature Argon Matrix to Solid State Polymorphs Characterization.[Pubmed:28640617]

J Phys Chem A. 2017 Jul 20;121(28):5267-5279.

The molecular structure, vibrational spectra and photochemistry of 5-methylhydantoin (C4H6N2O2; 5-MH) were studied by matrix isolation infrared spectroscopy and theoretical calculations at the DFT(B3LYP)/6-311++G(d,p) theory level. The natural bond orbital (NBO) analysis approach was used to study in detail the electronic structure of the minimum energy structure of 5-MH, namely the specific characteristics of the sigma and pi electronic systems of the molecule and the stabilizing orbital interactions. UV irradiation of 5-MH isolated in argon matrix resulted in its photofragmentation through a single photochemical pathway, yielding isocyanic acid, ethanimine, and carbon monoxide, thus following a pattern already observed before for the parent hydantoin and 1-Methylhydantoin molecules. The investigation of the thermal properties of 5-MH was undertaken by differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM) and Raman spectroscopy. Four different polymorphs of 5-MH were identified. The crystal structure of one of the polymorphs, for which it was possible to grow up suitable crystals, was determined by X-ray diffraction (XRD). Two of the additional polymorphs were characterized by powder XRD, which confirmed the molecules pack in different crystallographic arrangements.

KLK1 and ZG16B proteins and arginine-proline metabolism identified as novel targets to monitor atherosclerosis, acute coronary syndrome and recovery.[Pubmed:26413039]

Metabolomics. 2015;11(5):1056-1067.

We pursued here the identification of specific signatures of proteins and metabolites in urine which respond to atherosclerosis development, acute event and/or recovery. An animal model (rabbit) of atherosclerosis was developed and molecules responding to atherosclerosis silent development were identified. Those molecules were investigated in human urine from patients suffering an acute coronary syndrome (ACS), at onset and discharge. Kallikrein1 (KLK1) and zymogen granule protein16B (ZG16B) proteins, and l-alanine, l-arabitol, scyllo-inositol, 2-hydroxyphenilacetic acid, 3-hydroxybutyric acid and N-acetylneuraminic acid metabolites were found altered in response to atherosclerosis progression and the acute event, composing a molecular panel related to cardiovascular risk. KLK1 and ZG16B together with 3-hydroxybutyric acid, putrescine and 1-Methylhydantoin responded at onset but also showed normalized levels at discharge, constituting a molecular panel to monitor recovery. The observed decreased of KLK1 is in alignment with the protective mechanism of the kallikrein-kinin system. The connection between KLK1 and ZG16B shown by pathway analysis explains reduced levels of toll-like receptor 2 described in atherosclerosis. Metabolomic analysis revealed arginine and proline metabolism, glutathione metabolism and degradation of ketone bodies as the three main pathways altered. In conclusion, two novel urinary panels of proteins and metabolites are here for the first time shown related to atherosclerosis, ACS and patient's recovery.

Anti-leukemia activity of semi-synthetic phenolic derivatives from Polygonum limbatum Meisn.[Pubmed:26155305]

Chem Cent J. 2015 Jun 24;9:40.

BACKGROUND: The present report describes the semi-synthesis of a few O-prenylated phenolic derivatives and their in vitro antitumor activities. These compounds were prepared by modifying two naturally occurring antitumor phenols, 5,7-dihydroxy-3-(1'-hydroxy-1'-phenyl-methyl)-6-methoxy-chroman-4-one (A) and 2',4'-dihydroxy-3',6'-dimethoxychalcone (B), previously isolated from Polygonum limbatum Meisn. (Polygonaceae). The structures were elucidated by spectroscopic means and comparison with published data. The cytotoxicity of compounds was determined by using the resazurin assay in the parental drug-sensitive CCRF-CEM cell line and its multidrug-resistant P-glycoprotein-over-expressing subline, CEM/ADR5000. RESULTS: We describe in the present paper four new semi-synthetic derivatives of A and B: 5-hydroxy-6-methoxy-7-O-(3'-methylbut-2'-enyl)chroman-4-one (1), trivially named metapchromone, 5-acetoxy-6-methoxy-7-O-[3'-methylbut-2'enyl]chroman-4-one (2), trivially named sargisin, 2'-hydroxy-3',6'-dimethoxy-4'-O-(3''-methylbut-2''-enyl)chalcone (3) trivially named limbachalcone A, and 2'-acetoxy-3',6'-dimethoxy-4'-O-(3''-methylbut-2''-enyl)chalcone (4) trivially named tsedengchalcone. Their preliminary cytotoxic activities have been determined. We also report herein the isolation of 1-Methylhydantoin (C) and betulinic acid (D) from Polygonum limbatum for the first time. CONCLUSIONS: The study clearly suggests that semi-synthesis involving O-prenylation and acetylation of chalcones or other chromanones should be avoided in a search for anticancer drugs. This conclusion should be helpful when selecting substituents for the synthesis of potential anticancer drugs.

[Preventive effects of 5-hydroxy-1-methylhydantoin on paraquat-induced nephrotoxicity in rat].[Pubmed:25891451]

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015 Apr;27(4):246-9.

OBJECTIVE: To investigate the protective effects of 5-hydroxy-1-methylhyantoin (HM ) on paraquat (PQ)-induced nephrotoxicity in rat and its possible mechanism. METHODS: Twenty-four male Sprague-Dawley (SD) rats were randomly divided into four groups: namely control, PQ, vitamin C and HMH groups, with 6 rats in each group. The rats in control group were given an injection of 2 mg/kg of normal saline intraperitoneally. The rats in PQ group were given an injection of 50 mg/kg of PQ intraperitoneally. The rats in vitamin C and HMH groups were given 1 mmol/kg of vitamin C or HMH through gastric tube right after PQ injection. The hydroxyl free radical scavenging ability of HMH and vitamin C was determined by Fenton method. Blood sample was collected after 24 hours of PQ treatment, then the animals were sacrificed and renal tissues were harvested. Blood urea nitrogen (BUN), serum creatinine (SCr), protein content of renal cortex, blood malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD) activity were determined. RESULTS: Both vitamin C and HMH showed a very good ability to scavenge hydroxyl radicals, and the 50% inhibiting concentration (IC(5)(0)) was both 4.02 mg/mL. Compared with control group, serum BUN, SCr and MDA in renal tissue were significantly increased in PQ group, and the protein, GSH contents and SOD activity were significantly decreased [BUN (mmol/L): 40.80 +/- 2.49 vs. 13.67 +/- 1.58, SCr (mumol/L): 163.46 +/- 8.67 vs. 51.80 +/- 4.37, MDA (nmol/g): 7.51 +/- 0.23 vs. 4.52 +/- 0.33, protein (mumol/L): 0.94 +/- 0.14 vs. 1.35 +/- 0.10, GSH (mg/g): 1.08 +/- 0.48 vs. 3.30 +/- 0.44, SOD (kU/L): 70.74 +/- 6.42 vs. 112.89 +/- 8.72, all P < 0.01 ]. Compared with PQ group, serum BUN and SCr and MDA in kidney tissue in vitamin C and HMH groups were significantly decreased, and GSH content and SOD activity in kidney tissue were significantly elevated [BUN mmol/L): 22.64 +/- 2.36, 18.71 +/- 5.23 vs. 40.80 +/- 2.49, SCr (mumol/L): 97.28 +/- 4.81, 89.20 +/- 6.72 vs. 163.46 +/- 8.67, MDA (nmol/g): 4.67 +/- 0.31, 4.21 +/- 0.42 vs. 7.51 +/- 0.23, GSH (mg/g): 1.78 +/- 0.10, 1.86 +/- 0.39 vs. 1.08 +/- 0.48, SOD (kU/L): 98.69 +/- 5.43, 103.76 +/- 4.45 vs. 70.74 +/- 6.42, all P < 0.01]. Compared with vitamin C group, HMH could significantly reduce SCr contents P < 0.05). There were no differences in reduction PQ-induced BUN, MDA content, and effect on GSH content and SOD activity between vitamin C group and HMH group (all P > 0.05). CONCLUSIONS: HMH can protect the kidney against PQ-induced nephrotoxicity, and the mechanism of which maybe attributed to its anti-oxidation property and ability to scavenge hydroxyl radical.

Molecular structure, infrared spectra, photochemistry, and thermal properties of 1-methylhydantoin.[Pubmed:25029485]

J Phys Chem A. 2014 Aug 7;118(31):5994-6008.

The structural, vibrational, and photochemical study of 1-Methylhydantoin (1-MH, C4H6N2O2) was undertaken by matrix isolation infrared spectroscopy (in argon matrix; 10 K), complemented by quantum chemical calculations performed at the DFT(B3LYP)/6-311++G(d,p) level of approximation. The theoretical calculations yielded the Cs symmetry structure, with planar heavy atom skeleton, as the minimum energy structure on the potential energy surface of the molecule. The electronic structure of this minimum energy structure of 1-MH was then studied in detail by means of the natural bond orbital (NBO) and atoms in molecules (AIM) approaches, allowing for the elucidation of specific characteristics of the molecule's sigma and pi electronic systems. The infrared spectrum of the matrix-isolated 1-MH was fully assigned, also with the help of the theoretically predicted spectrum of the compound, and its UV-induced unimolecular photochemistry (lambda >/= 230 nm) was investigated. The compound was found to fragment to CO, isocyanic acid, methylenimine, and N-methyl-methylenimine. Finally, a thermal behavior investigation on 1-MH samples was carried out using infrared spectroscopy (10 K until melting), differential scanning calorimetry and polarized light thermal microscopy. A new polymorph of 1-MH was identified. The IR spectra of the different observed phases were recorded and interpreted.

Creatinine metabolite, HMH (5-hydroxy-1-methylhydantoin; NZ-419), modulates bradykinin-induced changes in vascular smooth muscle cells.[Pubmed:24641698]

J Recept Signal Transduct Res. 2014 Jun;34(3):195-200.

A creatinine metabolite, 5-hydroxy-1-Methylhydantoin (HMH: NZ-419), a hydroxyl radical scavenger, has previously been shown to confer renoprotection by inhibiting the progression of chronic kidney disease in rats. In the current study, we demonstrate that HMH modulates the effects of glucose and bradykinin (BK) in vascular smooth muscle cell (VSMC). HMH a novel anti-oxidant drug completely suppressed the expression of B2-kinin receptors (B2KR) in response to high glucose (25 mM) stimulation in VSMC and was also shown to attenuate the effects of BK on VSMC remodeling. HMH inhibited the BK-induced increase in MAPK phosphorylation and attenuated the increase in connective tissue growth factor (CTGF) protein levels in VSMC. These findings suggest that HMH may confer vascular protection against high glucose concentrations and BK-stimulation to ameliorate vascular injury and remodeling through its anti-oxidant properties.

Monodisperse, molecularly imprinted polymers for creatinine by modified precipitation polymerization and their applications to creatinine assays for human serum and urine.[Pubmed:23973759]

J Pharm Biomed Anal. 2013 Nov;85:288-94.

Molecularly imprinted polymers (MIPs) for creatinine were prepared by modified precipitation polymerization using methacrylic acid as a functional monomer and divinylbenzene as a crosslinker. The prepared MIPs were monodispersed with a narrow particle size distribution. Binding experiments and Scatchard analyses revealed that two classes of binding sites, high- and low-affinity sites, were formed on the MIPs. The retention and molecular-recognition properties of the MIPs were evaluated by hydrophilic interaction chromatography using a mixture of ammonium acetate buffer and acetonitrile as a mobile phase. With an increase of acetonitrile content, the retention factor of creatinine was increased on the MIP. In addition to shape recognition, hydrophilic interactions seemed to enhance the recognition of creatinine on the MIP. The MIPs' molecular-recognition ability was specific for creatinine; the structurally related compounds such as hydantoin, 1-Methylhydantoin, 2-pyrrolidone, N-hydroxysuccinimide and creatine were not recognized. Furthermore, the creatinine concentrations in human serum and urine were successfully determined by direct injection of the deproteinized serum and diluted urine samples onto the MIP.