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In this study, the physicochemical properties and solubility of inclusion complexes of ground mixtures (GMs) of piperine (PP), a pungent ingredient of pepper, with α- and γ-cyclodextrin (CD) were studied. From the solubility results, the PP/αCD inclusion molar ratio was determined to be 1/2, while that of PP/γCD was 1/1, according to the AP-type phase diagram of PP/αCD and the BS-type one of PP/γCD. The powder X-ray diffraction and differential scanning calorimetry analyses confirmed the formation of GM complexes with molar ratios of PP/αCD = 1/2 and PP/γCD = 1/1. The Raman analysis revealed the disappearance of the bands corresponding to the C=C, O–CH2–O, −CH, and aliphatic C=C moieties of the methylene dioxyphenyl fragment of PP in the spectra of the inclusion complexes. In the dissolution tests, GM (PP/αCD = 1/2) and GM (PP/γCD = 1/1) showed higher solubility than free PP and the analogous physical mixtures. Furthermore, after 60 min, GM (PP/αCD = 1/2) exhibited higher solubility than GM (PP/γCD = 1/1). In the 1H-1H nuclear Overhauser effect spectroscopy measurements, GM (PP/αCD = 1/2) was found to present a head-to-head inclusion structure via the aliphatic C=C and methylene dioxyphenyl groups of PP and the two αCD molecules. In contrast, it was confirmed that γCD interacts with the O–CH2–O functionality of the methylene dioxyphenyl group of PP in a molar ratio of 1/1. It was thus concluded that the differences in the PP/CD structures influence the solubility of the inclusion complexes. [ABSTRACT FROM AUTHOR]

Polyamine uptake by the polyamine transport system (PTS) in HTC cells was studied without the use of radioisotope-labeled polyamines. N1-Dansylspermine (DNS343) was selected as a candidate probe to examine the PTS. DNS343 was incorporated into HTC cells, and its distribution in the cells was confirmed by fluorescence microscopy. The incorporation of DNS343 via PTS was confirmed by a competition study with bis(3-aminopropyl)amine, which is incorporated into cells via the PTS. In addition, the temperature dependency of DNS343 uptake and studies with inhibitors of ornithine decarboxylase and proteoglycan synthesis supported the use of DNS343 as a fluorescent probe for the PTS. The kinetics studies for HTC cells treated with or without an ornithine decarboxylase inhibitor indicated that DNS343 uptake was saturable and that the apparent Km values for the PTS were approximately 1.5 μM in both types of cells at 37°C. Thus, we developed an assay method for the PTS by high-performance liquid-chromatography with DNS343. The inhibitory effect of polyamine analogs and related compounds on DNS343 uptake was then examined and discussed. [ABSTRACT FROM AUTHOR]

Abstract: We developed a nonradioactive assay to measure spermidine/spermine N 1-acetyltransferase (SSAT) activity by high-performance liquid chromatography (HPLC). N 1-dansylnorspermine was prepared and evaluated as a substrate of acetylation with acetyl-CoA by SSAT in rat hepatoma (HTC) cells. Kinetic studies revealed that the Km values of N 1-dansylnorspermine and acetyl-CoA were approximately 11 and 13μM, respectively. When the assay method was applied to HTC cell samples, the SSAT activity, even at the control level, could easily be detected in as few as 20μg protein of cell extract corresponding to 1×105 cells per determination, and 100 samples could be analyzed overnight. Thus, our HPLC method is a rapid and sensitive assay for the measurement of SSAT activity. [Copyright &y& Elsevier]

Twenty natural-product-like 2,8-dioxabicyclo[3.3.1]nonane derivatives were synthesized and their neuroprotective activities were tested using human monoamine oxidases (MAO) A and B and acetyl and butyryl cholinesterases (ChE). Compound 1s showed inhibitory activity for MAO-A, MAO-B and acetylcholinesterase (AChE) (IC 50 values 34.0, 2.3 and 11.0 µM, respectively). The inhibition mode of (-)-1s for MAO-B was investigated. Chiral HPLC of (±)-1s separated the enantiomers and (-)-1s showed MAO-B inhibitory activity. Molecular docking simulation of (-)-1s and MAO-B revealed the binding mode.

Background/aim: Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT., Materials and Methods: The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis., Results: Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G 2 /M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG 1 arrest, in a synergistic fashion., Conclusion: The combination G 2 /M blockers and mild-HT can potentially be used for the treatment of OSCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Syntheses of fluorescent substrate and product for arginyltransferase, N-aspartyl-4-dansylamidobutylamine (Asp4DNS) and N-arginylaspartyl-4-dansylamidobutylamine (ArgAsp4DNS), respectively, including their precursor 4-dansylamidobutylamine (4DNS), are described. Then, HPLC conditions are summarized for a baseline separation of the three compounds in 10 min. The present method, which permits the simultaneous determination of Asp4DNS, 4DNS, and ArgAsp4DNS (in eluting order), is advantageous in measuring arginyltransferase activity and detecting the unfavorable enzyme(s) in 105,000 × g supernatant of tissues to ensure accurate determination., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aim: Very few studies are available about the biological activity of 3-styrylchromones. Our previous study demonstrated the importance of methoxy group at 6-position of the chromone ring and hydroxyl group at 4'-position of phenyl group in styryl moiety. As a sequel of this study, we synthesized fourteen compounds that include eight 3-styrylchromones where methoxy group was introduced at 7-position of chromone rings, and then evaluated their tumor-specificity., Materials and Methods: Tumor-specificity (TS) was calculated by relative cytotoxicity against human oral squamous cell carcinoma cell lines versus human normal oral cells. Apoptosis induction and growth arrest were monitored by cell-cycle analysis. Quantitative structure-activity relationship analysis of TS was performed with 3,167 chemical descriptors., Results and Discussion: Two compounds, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one [ 7 ] and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one [ 14 ] showed higher tumor-specificity than doxorubicin and 5-FU, suggesting the importance of methoxy group in 7-position of the chromone ring. These compounds induced the apoptosis and mitotic arrest in HSC-2 cells. The tumor-specificity of 3-styrylchromone derivatives were most correlated with descriptors for molecule shape and electronic charge. The present study suggested that modification by introducing methoxy group at 7-position, instead at 6-position, further increased the tumor-specificity of 3-styrylchromone., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Inhibitors for polyamine oxidizing enzymes, spermine oxidase (SMOX) and N 1 -acetylpolyamine oxidase (PAOX), were designed and evaluated for their effectiveness in a photochemically induced thrombosis (PIT) mouse model. N 1 -Nonyl-1,4-diaminobutane (C9-4) and N 1 -tridecyl-1,4-diaminobutane (C13-4) competitively inhibited the activity of PAOX and SMOX in a manner comparable to N 1 ,N 4 -bis(2,3-butadienyl)-1,4-butanediamine (MDL72527), an irreversible inhibitor of both enzymes. The two compounds were then tested for their effects in the PIT model. Both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of C9-4 decreased infarct volumes significantly. By contrast, C13-4 reduced the volume of brain infarction by i.c.v. administration, but no reduction was observed after i.p. administration. C9-4 administered by i.p. injection reduced the volume of brain infarction significantly at doses of more than 3 mg/kg, and the dosage of 5 mg/kg or 10 mg/kg demonstrated the most potent effect and were more effective than equivalent doses of the other inhibitors such as MDL72527 and N-benzylhydroxylamine. I.P. injection of 5 mg/kg of C9-4 provided a therapeutic time window of longer than 12 h. This report demonstrates that C9-4 is a potent inhibitor of the polyamine oxidizing enzymes and is useful lead compound for candidate drugs with a long therapeutic time window, to be used in the treatment of ischemic stroke., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/aim: Twenty-four 2-azolylchromones were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor specificity, in order to find their new biological activities., Materials and Methods: Cytotoxicity against two human oral squamous cell carcinoma cell lines and two human normal oral mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC 50 ) against oral cells to that against oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC 50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization., Results: Three sets of 4H-1-benzopyran-4-ones with indole ring showed much higher TS values than those with pyrrole, pyrazole, imidazole, 1,2,4-triazole, 1,2,3-triazole, indazole and benzimidazole rings. Among those with an indole ring, the compound having a 6-methoxy group, that exhibited the highest cytotoxicity, yielded one to three-order higher PSE values to compared with other groups of compounds. Western blot analysis demonstrated that this compound stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. QSAR analysis demonstrated that TS values were correlated with 3D shape, polarizability, ionization potential and lipophilicity., Conclusion: Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drug., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Many phenolic acid phenethyl esters possess diverse biological effects including antioxidant, cytoprotective, anti-inflammation and anti-tumor activities. However, most previous antitumor studies have not considered the cytotoxicity against normal cells. Ten cinnamic acid phenetyl esters were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity and tumor-specificity, in order to find their new biological activities., Materials and Methods: Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC 50 ) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC 50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization., Results: Western blot analysis demonstrated that [ 9 ] stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. QSAR analysis demonstrated that TS values were correlated with shape, size and ionization potential., Conclusion: Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A method for determining spermine oxidase activity is described using the pentamine 1,16-diamino-4,8,13-triazahexadecane (3343) as the substrate, coupled with o-phthalaldehyde-post-label ion-exchange HPLC. The synthesis of 3343 is also described.

Background/aim: Eleven piperic acid esters were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor-specificity, in order to find their new biological activities., Materials and Methods: Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC 50 ) against normal cells to that against tumor cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC 50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization., Results: One phenylmethyl ester and five phenylethyl esters showed relatively higher cytotoxicity and tumor specificity, that were significantly modified by introduction of hydroxyl and methoxy groups. On the other hand, phenylpropyl ester, phenylbutyl ester and decyl ester were essentially inactive. (2E,4E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienoic acid 2-(3,4-dihydroxyphenyl)ethyl ester [ 4 ] had the highest TS and PSE values. This compound also stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. TS values were correlated with molecular size, ionization potential, molecular shape, ionization potential and electronegativity. None of the compounds had any anti-HIV activity., Conclusion: Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)