Thiosemicarbazone and thiazolylhydrazones of 1-indanone: as a new class of nonacidic anti-inflammatory and antiplatelet aggregation agents

This research based on the anti-inflammatory and antiplatelet aggregation properties of some new thiazolyl hydrazone derivatives of 1-indanone. In this regard a thiosemicabazone and twelve thiazolyl derivatives of 1-indanone have been synthesized. Out of these synthetic compounds seven derivatives 1-3, 6, 11-13 exhibited varying degree of anti-inflammatory action with IC50 esteems going from 5.1+/-1.3 - 78.8+/-4.6µM/mL. Compound 1 [IC50 =5.1+/-1.9µM] displayed potent result than standard ibuprofen [IC50 = 11.2+/-1.9 µM]. In antiplatelet aggregation assay, five compounds 1, 5, 6, 8 and 11 were observed to be dynamic with IC50 esteems observed in the range of 38.34-255.7+/-4.1µM, whereas, aspirin [IC50 = 30.3+/-2.6 µM] was used as standard. However, compound 11 was found to be good active for both anti-inflammatory and antiplatelet aggregation activities [IC50 = 13.9+/-4.9µg/mL] [IC50 = 38.60+/-3.1µM], respectively

Synthesis of drug metal complexes and their influence on human platelet aggregation

During the past few decades the emergence of inorganic medicinal chemistry has been developed novel therapeutic agents. Researcher's perseverance in this branch of chemistry has led them to explore further valuable chemical spaces by synthesizing metal complexes already known pharmacological agents for their potential use. However, it is in its early stage, this methodology has demonstrated metal complexes with better bioactivities than the parent ligand molecules. In this study, transition metal complexes of pyrazinamide [PZ], isoniazid [INH], fluconazole [FCZ], metformin [dimethylbiguanide, DMBG] and losartan potassium [LS-K] were selected to evaluate for their possible anti-platelets aggregation in the light of reports on divalent and trivalent cations like calcium, copper, manganese, magnesium, and cadmium may influence the process of thrombocytic activity and aggregation. The required evaluation was carried out on human plasma through an APACT 4004 platelet aggregation analyzer. Arachidonic acid [ADP] was used to gauge any alteration in platelet shape and aggregation process. The parent drugs showed some antiplatelets aggregation, however, their metal complexes demonstrated better efficacy

Development of an analytical method for dibutyl phthalate determination using surrogate analyte approach

Dibutyl phthalate [DBP] is a phthalic acid ester and is widely used in polymeric products to make them more flexible. DBP is found in almost every plastic material and is believed to be persistent in the environment. Various analytical methods have been used to measure DBP in different matrices. Considering the ubiquitous nature of DBP, the most important challenge in DBP analyses is the contamination of even analytical grade organic solvents with this compound and lack of availability of a true blank matrix to construct the calibration line. Standard addition method or using artificial matrices reduce the precision and accuracy of the results. In this study a surrogate analyte approach that is based on using deuterium labeled analyte [DBP-d4] to construct the calibration line was applied to determine DBP in hexane samples

Validation of an analytical method for determination of 13 priority polycyclic aromatic hydrocarbons in mineral water using dispersive liquid-liquid microextraction and GC-MS

Dispersive liquid-liquid microextraction [DLLME] combined with gas chromatography-mass spectrometry [GC-MS] was used for the extraction and determination of 13 polycyclic aromatic hydrocarbons [PAHs] in mineral water samples. In this procedure, the suitable combination of extraction solvent [500 microL chloroform] and disperser solvent [1000 microL acetone] were quickly injected into the water sample [10.00 mL] by Hamilton syringe. After centrifugation, 500 microL of the lower organic phase was dried under a gentle stream of nitrogen, re-dissolved in chloroform and injected into GC-MS. Chloroform and acetone were found to be the best extraction and disperser solvent, respectively. Validation of the method was performed using spiked calibration curves. The enrichment factor ranged from 93 to 129 and the recovery ranged from 71 to 90%. The linear ranges for all the PAHs were 0.10-2.80 ngmL-1. The relative standard deviations [RSDs] of PAHs in water by using anthracene-d[10] as internal standard, were in the range of 4-11% for most of the analytes [n=3]. Limit of detection [LOD] for different PAHs were between 0.03 and 0.1 ngmL-1. The method was successfully applied to the analyze of PAHs in mineral water samples collected from Tehran

FTIR biospectroscopy investigation on cisplatin cytotoxicity in three pairs of sensitive and resistant cell line

Fourier Transformed Infrared Spectroscopy [FTIR] has extensively been used for biological applications. Cisplatin is one the most useful antineoplastic chemotherapy drugs for a variety of different human cancers. One of the clinical problems in its application, which would consequently affect the therapeutic outcome of its application, is the occurrence of resistance to this agent. In this project three different pairs of sensitive and resistant cell lines of human ovarian A2780 and its resistant pair of A2780-CP, human ovarian OV2008 and its resistant pair of C13, and finally human lung carcinoma of HTB56 and its resistant pair of HTB56-CP were grown in the laboratory under the standard procedure. Saline was exposed to control cells, whereas 1, 5 and 10 microg/ml of cisplatin was exposed to experimental cells, for one hour. Cells were then collected and lyophilized from which spectra were taken. According to our results, we could not trigger a well-recognized cells biomolecular band at 1015 cm[-1], being modified after exposure to cisplatin in all cell lines. On the other hand, there was a clear dose-dependent increase in protein beta-sheet structure related peaks shift in resistant cell lines after exposure to cisplatin. This would probably indicate an easier protein interaction site for cisplatin in the resistant cell lines, which would probably inhibit cisplatin from binding to DNA, as the cytotoxic target. As a conclusion, FTIR biospectroscopy has proven its potency to identify the interactions, as well as the false engagement cellular sites for cisplatin in sensitive and resistant cell lines

Optimization of RGD-modified nano-liposomes encapsulating eptifibatide

Background: Eptifibatide [Integrilin] is an intravenous [IV] peptide drug that selectively inhibits ligand binding to the platelet GP IIb/IIIa receptor. It is an efficient peptide drug, however has a short half-life. Therefore, antithrombotic agents like eptifibatide are required to become improved with a protected and targeted delivery system such as using nano-liposomes to the site of thrombus

Objectives: The goal in the present report was to optimize encapsulation efficiency of the eptifibatide into Arg-Gly-Asp [RGD]-modified nano-liposomes [RMNL]. As well, it was intended to evaluate the effect of sodium lauryl sulfate [SLS] on drug release

Materials and Methods: The effect of five independent variables including number of freeze/thawing cycles, concentration of eptifibatide, 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC], cholesterol, and dipalmitoyl-GRGDSPA peptide on drug entrapment efficiency [DEE] was investigated using response surface methodology [RSM]. The effect of different concentrations of SLS on encapsulation and drug release from RMNL was also investigated. The size and morphology of RMNL were characterized using transmission electron microscopy [TEM]

Results: The maximum DEE [38%] was obtained with 7 freeze/thawing cycles, 3.65 micro moL eptifibatide, 7 mM DSPC, 3 mM cholesterol, and 1 mM dipalmitoyl- GRGDSPApeptide. SLS has significantly increased the drug release from RMNL, although its effect on encapsulation efficiency was not significant

Conclusions: The optimization of the formulations for valuable and expensive peptide drugs is essential to have the maximum encapsulation efficiency and the minimum experiments

Design, synthesis and cytotoxicity evaluation of new 1,2-diaryl-4, 5, 6, 7-tetrahydro-1H-benzo[d] imidazolesas tubulin inhibitors

A new series of 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d]imidazoles, possessing trimethoxyphenyl pharmacophore, were synthesized to evaluate their biological activities as tubulin inhibitors. Cytotoxic activity of the synthesized compounds 7a-f was assessed against several human cancer cell lines, including MCF-7 [breast cancer cell], HEPG2 [liver hepatocellular cells], A549 [adenocarcinomic human alveolar basal epithelial cells], T47D [Human ductal breast epithelial tumor cell line] and fibroblast. According to our results, HEPG2 seems to be the most sensitive, while MCF7 was the most resistant cell line to the compounds. All the compounds expect 7b, possessed satisfactory activity against HEPG2 with mean IC[50] values ranging from 15.60 to 43.81 micro M

Synthesis and preliminary evaluation of a new[99m]Tc labeled substance P analogue as a potential tumor imaging agent

Neurokinin 1 receptors [NK[1]R] are overexpressed on several types of important human cancer cells. Substance P [SP] is the most specific endogenous ligand known for NK1Rs. Accordingly,a new SP analogue was synthesized and evaluated for detection of NK[1]R positive tumors.[6-hydrazinopyridine-3-carboxylic acid [HYNIC]-Tyr[8]-Met[O][11]-SP] was synthesized and radiolabeled with 99mTc using ethylenediamine-N,N-diacetic acid [EDDA]and Tricine as coligands. Common physicochemical properties of radioconjugate were studied and in-vitro cell line biological tests were accomplished to determine the receptor mediated characteristics. In-vivo biodistribution in normal and tumor bearingnude mice was also assessed. The cold peptide was prepared in high purity [>99%] and radiolabeled with [99m]Tc at high specific activities [84-112GBq/ micro mol] with an acceptable labeling yield [>95%]. The radioconjugate was stable in-vitro in the presence of human serum and showed 44% protein binding to human serumalbumin. In-vitro cell line studies on U373MG cells showed an acceptable uptake up to 4.91 +/- 0.22% with the ratio of 60.21 +/- 1.19% for its specific fraction and increasing specific internalization during 4 h. Receptor binding assays on U373MG cells indicated a mean Kd of 2.46 +/- 0.43 nM and Bmax of 128925 +/- 8145 sites/cell. In-vivo investigations determined the specific tumor uptake in 3.36 percent of injected dose per gram [%ID/g] for U373MG cells and noticeable accumulations of activity in the intestines and lung. Predominant renal excretion pathway was demonstrated. Therefore, this new radiolabeled peptide could be a promising radiotracer for detection of NK[1]R positive primary or secondary tumors

Synthesis and antiplatelet aggregation activity evaluation of some 2-aminopyrimidine and 2-substituted-4,6-diaminopyrimidine derivatives

A series of novel 2-aminopyrimidine and 2-Substituted-4,6-diaminopyrimidine derivatives have been synthesized and their antiplatelet aggregation activities were assessed against ADP and arachidonic acid-induced platelet aggregation in human plasma using light transmission aggregometry. Among the tested derivatives, compounds Ia, I[b], I[B] and II[16] exhibited the highest antiplatelet aggregation activity [36.75, 72.4, 62.5 and 80 microM]. None of the compounds showed satisfactory activity against the aggregation induced by ADP but acceptable activities were observed against the aggregation induced by arachidonic acid. 2- aminopyrimidines were more active than 4,6- diaminopyrimidines in this respect

Evaluation of emerging Fusarium mycotoxins beauvericin, Enniatins, Fusaproliferin and Moniliformin in domestic rice in Iran

The occurrence of emerging Fusarium mycotoxins beauvericin [BEA], enniatins [ENNs] [A, A1, B, B1], Fusaproliferin and moniliformin was evaluated by a liquid chromatography/ electrospray ionization-tandem mass spectrometric [LC/ESI-MS/MS] technique in 65 domestic rice samples produced in Gilan and Mazandaran Provinces in Iran. The results showed that 46% of the samples were contaminated with at least one of the emerging mycotoxins. BEA was the most prevalent mycotoxin, which was found in 26 out of 65 rice samples at the concentrations up to 0.47 microg/Kg. Enniatin A1 which was the only member of ENNs was detected in the samples, occurred in 7.7% of samples with an average level of 0.06 microg/Kg. No detectable level of Fusaproliferin and moniliformin was found. This is the first report concerning the contamination of Iranian domestic rice samples with the emerging Fusarium mycotoxins

Synthesis and antimycobacterial activity of some triazole derivatives - new route to functionalized triazolopyridazines

A series of cyclic analogues of bioactive thiosemicarbazide derivatives have been synthesized as potential antimycobacterial agents. The 4-amino-1,2,4-triazole-5-thione analogues [Ia-f] were prepared by heating a mixture of thiocarbohydrzide and appropriate carboxylic acids. Reaction of thiocarbohydrazide with gamma-ketoesters in the presence of sodium methoxide furnished triazolopyridazine derivatives IIa-b. Finally, condensation of 4-amino-1,2,4-triazole-5-thione with some aldehydes gave Schiff bases IIIa-e. After characterization by different spectroscopic and analytical methods, the derivatives were tested for their inhibitory activity against Mycobacterium bovis BCG. Among the derivatives, compound Ib proved to be the most potent derivatives with MIC value of 31.25 microg/mL. Given the fact that 4-amino-1,2,4-triazole-5-thiones Ia-f were the most active derivatives, it could be suggested that this group of derivatives have the potential to be considered as lead compounds for future optimization efforts

Synthesis and evaluation of new fluorinated anti-tubercular compounds

Treatment of tuberculosis [TB] and the discovery of effective new anti tubercular drugs is one of the most urgent priorities in health organizations all around the world. In the present study, fluorinated analogs of some of the most important anti-TB agents such as p-aminosalicylic acid [PAS], thiacetazone and pyrazinamide were synthesized and tested against TB. The fluorinated analog of thiacetazone was 20 times more potent than the parent compound against M.tuberculosis H37-RV, while the fluorinated PAS was almost three times less potent than PAS. A few other halogenated analogs of thioacetazone were also synthesized and subjected to anti-TB screening tests. The best halogen substituent was found to be fluorine which has the smallest size from one hand and the strongest electronegativity from the other hand among the halogen atoms. This fact reemphasizes the unique nature of fluorine as a golden substituent in medicinal chemistry

[Rapid screening for synthetic adulterant drugs in herbal slimming products]

In recent years the use of herbal slimming supplements has increased in Iran. One problem may be the illegal inclusion of synthetic drugs by some manufacturers in these products. The aim of this study is to determine four undeclared synthetic adulterants in some herbal slimming products present in the Iranian market. This survey study researched six common herbal slimming supplements that were obtained from the market. Supplements were purchased from Persian language advertising sites on satellite channels and the Internet. These products were analyzed by GC-MS for the detection of sibutramine, phenolphthalein, phenytoin and LC-MS for bumetanide. Three products contained phenolphthalein. Fast Slim and Original Super Slim carried the highest content of sibutramine - 57 microg per capsule for Fast Slim and 78 microg per capsule for Original Super Slim. Bumetanide was found in Herbaceous Essence, Green Lean Super Slim, Magic Slim and Fat loss. Other undisclosed components such as caffeine and pseudoephedrine were detected by GC-MS library search. All herbal slimming products have been shown to contain undeclared synthetic adulterants. Increased public awareness of the risks of taking herbal weight-loss supplements is necessary

Synthesis of N-arylmethyl substituted indole derivatives as new antiplatelet aggregation agents

A number of N-arylmethyl substituted indole derivatives have been synthesized and their effectiveness against ADP and arachidonic acid induced platelet aggregation in human plasma was determined. The desired compounds were synthesized by reacting the appropriate aniline derivative with isatin [or substituted isatin] to form the corresponding imine structures. The so formed compound was then activated using sodium hydride and reacted with the proper substituted benzyl halides. Among the tested compounds, derivatives 4a, 4c, 4d, 4f-i and 4k were the most potent compounds with satisfactory IC[50] values [under 38.5 micro M] for inhibition of platelet aggregation induced by arachidonic acid. All indole derivatives without substitution on position 1 of the indole ring, exhibited either weaker activities or were not active at all

Development and validation of a reversed-phase HPLC method for assay of the decapeptide cetrorelix acetate in bulk and pharmaceutical dosage forms

A gradient reversed-phase high performance liquid chromatography [HPLC] method was developed for the assay of cetrorelix acetate, a synthetic decapeptide with gonadotropin-releasing hormone [GnRH] antagonistic activity used in infertility treatment. The HPLC method, which is used to determine cetrorelix in bulk and pharmaceutical dosage forms, was validated per ICH guidelines. The chromatographic separation was achieved on a C18 reversed-phase column using acetonitrile, water and trifluoroacetic acid [TFA] as mobile phase and wavelength was set at 275 nm. The calibration curve was linear [r[2] = 0.999] over cetrorelix concentrations ranging from 62.50 to 12.50 micro g/mL [n = 6]. The limits of detection [LOD] and quantification [LOQ] were calculated from the peak-to-noise ratio as 15.6 and 62.5 micro g/mL, respectively. The method had an accuracy of > 97% and intra- and inter-day RSD of < 0.3% and < 1.6%, respectively and was validated with excellent specificity, sensitivity, and stability. The validated method was successfully applied for determination of cetrorelix in bulk and pharmaceutical dosage forms

Method development for simultaneous determination of 41 pesticides in rice using LC-MS/MS technique and its application for the analysis of 60 rice samples collected from Tehran market

For the first time, a multi-residue method for simultaneous determination of 41LC-amenable pesticides in rice, belonging to different chemical classes has been developed in Iran by LC-MS/MS. The pesticides were analyzed simultaneously in a single run using positive electrospray ionization with multiple reaction monitoring [MRM] after extraction with slightly modified QuEChERS method. The calibration curves for each analyte were linear in the concentration range 0.02-1.0 microg/g with a correlation coefficient range between 0.993 and 0.999. The LOQ and LOD were0.025 microg/g and 0.008 microg/g respectively, for all 41 pesticides and the mean recoveries obtained for three fortification levels [0.025, 0.08 and 0.250 microg/g ] were71-119% with satisfactory precision [RSD<20%]. The developed method was used to investigate the occurrence of pesticides in 30domestic and 30 imported rice samples collected from Tehran market. Five compounds were detected in 11 domestic and 9 imported positive samples in concentration range from 0.032 microg/g to 0.081 microg/g and 0.028 microg/g to 0.074microg/g, respectively. With the exception of prohibited pesticides, phosphmidon and TCMTB, three permitted pesticides, cinosulfuron, triadimenol and tricyclazole, found in positive rice samples were below MRLs established by Institute of Standards and Industrial Research of Iran [ISIRI]

Phytochemical investigations on chemical constituents of Achillea tenuifolia lam

Achillea tenuifolia Lam [Asteraceae] afforded a methanolic extract from which after fractionation in solvents with different polarities two known flavones 3', 5- dihydroxy- 4', 6, 7- trimethoxy flavone [eupatorine, compound 3], 5- hydroxy- 3', 4', 6, 7- tetramethoxyflavone [compound 4], besides stearic acid [compound 1 ], lupeol [compound 2], daucosterol [beta- sitosterol 3-O- beta- D- glucopyranoside, compound 5], 2, 4- dihydroxy methyl benzoate [compound 6] were isolated for the first time. The structure of isolated compounds was elucidated by means of different spectroscopic methods such as UV, IR, Mass and [1]H- NMR [1D and 2D] and [13]C-NMR. For further confirming of structures of isolated compounds, comparison of the spectral data of them with those reported in the litratures have been done

Anticancer Activity of Cobra Venom Polypeptide, Cytotoxin-II, against Human Breast Adenocarcinoma Cell Line (MCF-7) via the Induction of Apoptosis / 한국유방암학회지

PURPOSE: Breast cancer is a significant health problem worldwide, accounting for a quarter of all cancer diagnoses in women. Current strategies for breast cancer treatment are not fully effective, and there is substantial interest in the identification of novel anticancer agents especially from natural products including toxins. Cytotoxins are polypeptides found in the venom of cobras and have various physiological effects. In the present study, the anticancer potential of cytotoxin-II against the human breast adenocarcinoma cell line (MCF-7) was investigated. METHODS: The cytotoxic effects of cytotoxin-II were determined by morphological analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The mode and mechanism of cell death were investigated via acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis of cell death, detection of mitochondrial membrane potential, measurement of intracellular reactive oxygen species (ROS), annexin V/propidium iodide staining, and caspase-9 activity assays. RESULTS: The half maximal inhibitory concentration (IC50) of cytotoxin-II in MCF-7 cells was 4.18+/-1.23 microg/mL, while the value for cisplatin was approximately 28.02+/-1.87 microg/mL. Morphological analysis and AO/EtBr double staining showed typical manifestations of apoptotic cell death (in doses lower than 8 microg/mL). Dose- and time-dependent ROS generation, loss of mitochondrial membrane potential, caspase-9 activation, and cell cycle arrest were observed in their respective tests. CONCLUSION: In conclusion, cytotoxin-II has potent anticancer effects in the MCF-7 cell line, which are induced via the intrinsic pathways of apoptosis. Based on these findings, cytotoxin-II is a suitable choice for breast cancer treatment.

Synthesis, evaluation of anticancer activity and QSAR study of heterocyclic esters of caffeic acid

Caffeic acid phenethyl ester [CAPE] suppresses the growth of transformed cells such as human breast cancer cells, hepatocarcinoma, myeloid leukemia, colorectal cancer cells, fibrosarcoma, glioma and melanoma. A group of heterocyclic esters of caffeic acid was synthesized using Mitsunobu reaction and the esters were subjected to further structural modification by electrooxidation of the catechol ring of caffeic acid esters in the presence of sodium benzenesulfinate and sodium toluensulfinate as nucleophiles. Both heterocyclic esters of caffeic acid and their arylsulfonyl derivatives were evaluated for their cytotoxic activity against HeLa, SK-OV-3, and HT-29 cancer cell lines. HeLa cells showed the highest sensitivity to the compounds and heterocyclic esters with no substituent on catechol ring showed better activity compared to their substituted counterparts. QSAR studies reemphasized the importance of molecular shape of the compounds for their cytotoxic activity

Simultaneous determination of 17 pesticide residues in rice by GC/MS using a direct sample introduction procedure and spiked calibration curves

A reliable, rapid and accurate method based on spiked calibration curves and direct sample introduction was developed for determination of 17 pesticide residues in rice by gas chromatography-mass spectrometry single quadrupole selected ion monitoring GC/MS-SQ-SIM. Sample preparation is based on extraction with acetonitrile without clean up. The use of spiked calibration curves for constructing the calibration curve substantially reduced adverse matrix-related effects. The average recovery of pesticides at 6 concentration levels was in range of 97.5-102.1%. The method was proved to be repeatable with RSDr in range of 0.7%-19.8%for all of the concentration levels. The limits of detection and limit of quantifications for all the pesticides were < 10 ng/g and < 25 ng/g, respectively. The developed method was applied for simultaneous determination of the selected pesticides in 23 rice samples collected from Tehran retail market in March 2009. Although many studies have been conducted regarding the determination of pesticides by using GC-MS, this is the first attempt in Iran using GC-MS-SIM technique that successfully can determine 17 pesticides with difference in physicochemical properties in rice