Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus.

This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.

Sensitization of Hep3B hepatoma cells to cisplatin and doxorubicin by corilagin.

The anticancer action of gallotannins is a well-developed topic. We have demonstrated the in vivo antitumour activity of corilagin on Hep3B hepatoma using the xenograft athymic nude mice model. Here, we further report the potential sensitization of Hep3B hepatoma cells to cisplatin and doxorubicin by corilagin. Our results showed that corilagin is able to enhance the cytotoxicity of both cisplatin and doxorubicin on the Hep3B hepatoma cells. We speculate the possible use of corilagin in combination with low dosages of the anticancer chemotherapeutic standard drugs like cisplatin and doxorubicin, with the aim of obtaining an increment in the anticancer effect.

The puzzling issue of 'vehicle-treated control' when using ethanol as drug carrier for MCF-7 cells.

Ethanol has been commonly used as a vehicle for drug discovery purpose in vitro. The human breast cancer MCF-7 estrogen dependent cell line is a common in vitro model used for hormonal therapy study. However, special precaution is suggested when ethanol is used in pharmacological tests as solvent in order to evaluate the biological activity of potential drugs especially concerning about the MCF-7. Ethanol was shown to stimulate the proliferation of this estrogen receptor positive cell line. Here, we have further demonstrated that the dose responsive stimulatory effect of ethanol on the MCF-7 cells after pre-incubating the breast carcinoma cells with phenol red-free medium and stripped fetal bovine serum. Our findings open a discussion for the evaluation of ethanol as solvent for drug discovery and screening when using MCF-7 cells as a testing model.

In vivo antitumour activity of amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B.

We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified.

Development of phyllanthin containing microcapsules and their improved biological activity towards skin cells and Staphylococcus aureus.

Chitosan based microcapsule which encapsulated with phyllanthin was developed by simple coacervation. The composition and surface morphology of phyllanthin containing microcapsules were analyzed by Fourier Transform Infrared spectroscopy and Scanning Electron Microscopy, respectively. The release of phyllanthin from the microcapsules was found to be more than 60% after 120 h. In vitro biological assays demonstrated that these phyllanthin containing microcapsules showed a stronger anti-oxidation potential on both human fibroblasts and keratinocytes as well as a better growth inhibitory activity towards Staphylococcus aureus.

Development of hydrocortisone succinic acid/and 5-fluorouracil/chitosan microcapsules for oral and topical drug deliveries.

Recently, we demonstrated the safety use of calendula oil/chitosan microcapsules as a carrier for both oral and topical deliveries. We also reported the improved biological activity towards skin cells and Staphylococcus aureus of phyllanthin containing chitosan microcapsules. However, the possibility of both oral and topical applications was still necessary to be further studied. Here we investigated that both oral and topical applications of chitosan-based microcapsules were tested using hydrocortisone succinic acid (HSA) and 5-fluorouracil (5-FU), respectively. The drug loading efficiency, particle size, surface morphology and chemical compositions of both drug loaded microcapsules were confirmed by UV-vis spectrophotometer, particle size analyzer, scanning electron microscope and Fourier transform infrared spectroscopy. The in vitro release studies revealed that both HSA and 5-FU could be released form chitosan microcapsules. The mean adrenocorticotropic hormone concentration in HSA loaded microcapsule mice plasma was detected to be lower than that of water control. One hundred micrograms per milliliter of 5-FU containing microcapsules exhibited a stronger growth inhibition towards skin keratinocytes than that of free 5-FU. In vitro drug delivery model demonstrated the delivery of 5-FU from microcapsule treated textiles into nude mice skin. Further uses of the drug loaded microcapsules may provide an efficiency deliverable tool for both oral and topical applications.

Tuning the donor-acceptor strength of low-bandgap platinum-acetylide polymers for near-infrared photovoltaic applications.

Two near-infrared (NIR) absorbing metallopolyynes of platinum (P1 and P2) functionalized with a weakly electron-donating fluorene unit and two strong electron acceptors (viz. benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) and [1,2,5]thiadiazolo[3,4-i]dibenzo[a,c]phenazine) were synthesized and applied for NIR photovoltaic applications. With these designed weak donor-strong acceptor electronic traits, these metallopolymers possess narrow bandgaps of 1.54 and 1.65 eV and a low HOMO level of about 5.50 eV, thus inducing a power conversion efficiency up to 1% for bulk heterojunction solar cells at the NIR wavelength.

Synthesis, characterization and preliminary analysis of in vivo biological activity of chitosan/celecoxib microcapsules.

The use of chitosan as the wall of microcapsule designed for delivery of encapsulated celecoxib is reported. Microcapsules were characterised with respect to size and encapsulation efficiency of celecoxib. In vivo animals demonstrated that both free celecoxib administration and chitosan/celecoxib microcapsules administration lead to a significant inhibition of cyclooxygenase-2 protein expression in the hepatocytes when compared with vehicle control mice. Interestingly, microcapsule containing celecoxib showed a better inhibition of cyclooxygenase-2 protein expression when compared with a simple oral administration of free celecoxib. Gas-chromatography-mass-spectrometry analysis showed that in mice treated with free celecoxib or chitosan/celecoxib microcapsules, their plasma concentration of celecoxib was similar. Microcapsules-based biomaterials as oral drug delivery vehicles may help to improve the absorption efficiency of therapeutic drugs.

The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents.

A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.

Antitumor activity of diethynylfluorene derivatives of gold(I).

A list of diethynylfluorenes and their gold(I) derivatives have been studied for their antitumor activity as a function of their structure-activity relationships. End-capping the fluoren-9-one unit with gold(I) moieties could significantly strengthen the cytotoxic activity in vitro on three human cancer cell lines with induction of reactive oxygen species generation on Hep3B hepatocellular carcinoma cells and exhibit attractive antitumor activity from in vivo nude mice Hep3B xenograft model with limited adverse effects on vital organs including liver and kidney.

Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells.

Multidrug resistance (MDR) is one of conventional cancer chemotherapy's limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a's MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a's inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a's MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.

In vitro cytotoxicity of (-)-EGCG octaacetate on MDAMB-231 and SKHep-1 human carcinoma cells: a pharmacological consideration on prodrug design.

Esterification of acetate with generic pharmaceutical compound has been commonly employed to produce ester prodrug for improving its potency when compared with the mother compound. Acetate, on the other hand, has been recognized to have inhibitory effect on the respiratory biochemistry. Here we demonstrate that acetate at a concentration of 400 microM exhibited significant growth inhibitory activity on two human cancer cell lines, the MDAMB-231 breast cancer and the SKHep-1 hepatoma cell lines. To establish the ester prodrug with multi-acetate ester conjugates as our experimental model, one molecule of (-)-epigallocatechin gallate was required to conjugate with eight molecules of acetate forming the corresponding (-)-epigallocatechin gallate octaacetate prodrug. Chemical structure of this epigallocatechin gallate octaacetate ester prodrug was confirmed by both 13C and 1H nuclear magnetic resonance spectra and mass spectrometry. Further cytotoxic assay using both MDAMB-231 and SKHep-1 human carcinoma cell lines showed that acetate at a concentration of 400 microM exhibits an additional cytotoxic effect with (-)-epigallocatechin gallate at a concentration of 50 microM, although the additional effect was not as high as (-)-epigallocatechin gallate octaacetate ester prodrug alone at a concentration of 50 microM. Our results thus raise a pharmacological consideration of using multi-acetate conjugate as the ester prodrug where the release of free acetate by esterase could be part of the explanation for the improved in vitro cytotoxicity.

Synthesis and anti-cancer activity of benzothiazole containing phthalimide on human carcinoma cell lines.

Phthalic anhydride is a highly toxic substance, facing, however, the problem of hydrolysis. In fact, it is rapidly hydrolyzed in aqueous medium, generating phthalic acid as the final product, which is almost harmless to viable cells. Here we describe the 'one pot' condensation reaction for the synthesis of phthalic imide derivative (benzothiazole containing phthalimide), exhibiting in vitro cytotoxic potential on human cancer cell lines. We further demonstrated that both caspase-dependent and -independent pathways are involved in our novel benzothiazole containing phthalimide induced apoptosis on cancer cells.

Corilagin Induces High Levels of Apoptosis in the Temozolomide-Resistant T98G Glioma Cell Line.

Glioblastoma multiforme (GBM), a malignant tumor of the central nervous system, has a high mortality rate. No curative treatment is presently available, and the most commonly used chemotherapeutic drug, the alkylating agent temozolomide (TMZ), is only able to increase life expectancy and is often associated with drug resistance. Therefore, an urgent need does exist for novel drugs aimed at treating gliomas. In the present study, we obtained three major results using corilagin: (a) demonstrated that it inhibits the growth of U251 glioma cells through activation of the apoptotic pathway; (b) demonstrated that it is also active on TMZ-resistant T98G glioma cells; and (c) demonstrated that when used in combination with TMZ on T98G glioma cells, a higher level of proapototic and antiproliferative effects is observed. Our study indicates that corilagin should be investigated in more detail to determine whether it can be developed as a potential therapeutic agent. In addition, our results suggest that corilagin could be used in combination with low doses of other standard anticancer chemotherapeutic drugs against gliomas (such as TMZ) with the aim of obtaining enhanced anticancer effects.

Expression of Insulin-Like Growth Factor Binding Protein-5 (IGFBP5) Reverses Cisplatin-Resistance in Esophageal Carcinoma.

Cisplatin (CDDP) is one of the front-line chemotherapeutic drugs used in the treatment of esophageal squamous cell carcinoma (ESCC). Occurrence of resistance to CDDP has become one of the main challenges in cancer therapy. In this study, the gene expression profile of CDDP-resistant ESCC cells was investigated and molecular approaches were explored in an attempt to reverse the CDDP resistance. A CDDP-resistant SLMT-1/CDDP1R cell line was established from SLMT-1 cells by subculturing in the medium containing an increasing concentration of CDDP (0.1⁻1µg/mL). Mitochondrial (MTS) cytotoxicity assay, cell proliferation assay and cell morphology were used to assess the acquisition of cisplatin-resistance. The most differentially expressed gene in SLMT-1/CDDP1R cells was identified by cDNA microarray analysis compared with the parental SLMT-1 cells and validated by quantitative real-time polymerase chain reaction (qPCR). Association between expression of the most differentially expressed target gene to cisplatin-resistance was verified by RNA interference. An attempt to reversecisplatin-resistance phenotypes was made by using the vector expressing the most downregulated target gene in the CDDP-resistant cells. A CDDP-resistant ESCC cell line, SLMT-1/CDDP1R, was established with 2.8-fold increase CDDP-resistance (MTS50 = 25.8 µg/mL) compared with the parental SLMT-1 cells. cDNA microarray analysis revealed that IGFBP5 showed the highest level of downregulation in SLMT-1/CDDP1R cells compared with the parental SLMT-1 cells. Suppression of IGFBP5 mediated by IGFBP5-targeting siRNA in parental SLMT-1 cells confirmed that IGFBP5 suppression in ESCC cells would induce CDDP-resistance. More importantly, upregulation of IGFBP5 using IGFBP5 expression vector reduced cisplatin-resistance in SLMT-1/CDDP1R cells by 41%. Thus, our results demonstrated that IGFBP5 suppression is one of the mechanisms for the acquisition of cisplatin-resistance in ESCC cells. Cisplatin-resistance phenotype can be reversed by increasing the expression level of IGFBP5. The overall findings of this study thus offered a new direction for reversing the CDDP resistance in ESCC and possibly in other cancer types with further investigations in future.

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma.

Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone.

BACKGROUND: The role of high-dose dexamethasone in the treatment of immune thrombocytopenic purpura in adults is controversial. We assessed the effectiveness of high-dose dexamethasone as initial treatment in a series of consecutive adults with immune thrombocytopenic purpura. METHODS: Consecutive patients with newly diagnosed immune thrombocytopenic purpura and a platelet count of less than 20,000 per cubic millimeter or a platelet count of less than 50,000 per cubic millimeter and clinically significant bleeding were enrolled between January 1997 and December 2000. Oral dexamethasone at a dose of 40 mg per day for four consecutive days was the initial treatment. A response was defined as an increase in the platelet count of at least 30,000 per cubic millimeter and a platelet count of more than 50,000 per cubic millimeter by day 10 after the initiation of treatment. A sustained response was defined as a platelet count of more than 50,000 per cubic millimeter six months after the initial treatment. RESULTS: Of 157 consecutive patients, 125 were eligible. The mean (+/-SD) platelet count before treatment was 12,200+/-11,300 per cubic millimeter. A good initial response to high-dose dexamethasone occurred in 106 of the 125 patients (85 percent): the platelet count increased by at least 20,000 per cubic millimeter by the third day of treatment, and the mean platelet count was 101,400+/-53,200 per cubic millimeter (range, 50,000 to 260,000 per cubic millimeter) one week after the initiation of treatment. Among the 106 patients with a response, 53 (50 percent) had a sustained response; the other 53 (50 percent) had a relapse within six months, most of them (94 percent) within the first three months. A platelet count of less than 90,000 per cubic millimeter on day 10 was associated with a high risk of relapse. The treatment was well tolerated. CONCLUSIONS: A four-day course of high-dose dexamethasone is effective initial therapy for adults with immune thrombocytopenic purpura.

Paradoxical proliferative potential of iron (II) sulphate on cancer cells after the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay.

There are several scientific approaches for the determination of cellular growth influences of known or novel substances under in vitro conditions, among which colourimetric absorption measurement is considered to be one of the convenient methods. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay is one of the commonly used colourimetric absorption assays based on the ability of dehydrogenase from viable cells to produce the brown soluble formazan detectable at 490 nm. Here we have tested the possible growth influence of iron (II) sulphate on two human cancer cell lines, the K562 chronic myelogenous leukaemia and T47D breast carcinoma cells, based on the MTS assay. We found that iron (II) sulphate possessed an inhibitory effect when added at 16- to 125-microM concentrations, but iron (II) sulphate became growth stimulatory when its concentration was further increased to 1000 microM. In addition, a dose-dependent increase in absorbance at the same wavelength was observed when we repeated the experiments without the addition of MTS and phenazine methosulfate. When we further repeated the cell growth determinations using adenosine triphosphate content assay for K562 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for T47D, iron (II) sulphate showed a consistent dose-dependent growth inhibitory effect. Morphological investigation after methylene blue staining clearly demonstrated that iron (II) sulphate, at a concentration of 1000 microM, is cytotoxic to T47D cells. Interestingly, a consistent increment for the absorbance at 490 nm was further observed with increased iron (II) sulphate concentration either in the presence or absence of MTS even in a cell-free environment. Thus we conclude that iron (II) sulphate is actually growth inhibitory and even cytotoxic at high concentrations towards the K562 and T47D cancer cells and the paradoxical proliferative activity of iron (II) sulphate on these two cancer cell lines using the MTS assay was solely due to the oxidation of initial pale green iron (II) to brownish iron (III) during incubation in the aqueous condition.

Recent advances in green nanoparticulate systems for drug delivery: efficient delivery and safety concern.

Nanotechnology manipulates therapeutic agents at the nanoscale for the development of nanomedicines. However, there are current concerns over nanomedicines, mainly related to the possible toxicity of nanomaterials used for health medications. Due to their small size, they can enter the human body more readily than larger sized particles. Green chemistry encompasses the green synthesis of drug-loaded nanoparticles by reducing the use of hazardous materials in the synthesis process, thus reducing the adverse health impacts of pharmaceutics. This would greatly expand their potential in biomedical treatments. This review highlights the potential risks of nanomedicine formulations to health, delivery routes of green nanomedicines, recent advances in the development of green nanoscale systems for biomedical applications and future perspectives for the green development of nanomedicines.