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At least 91 records · Page 5Linked to original sources
PubMed2002

Synthesis and biological evaluation of N-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents.

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.

Animals↗
PubMed2001

Antitumor activity- and gene expression-based profiling of ecteinascidin Et 743 and phthalascidin Pt 650.

BACKGROUND: Ecteinascidin 743 (Et 743) is a potent antitumor marine alkaloid currently undergoing phase II clinical trials. The synthetic analog phthalascidin (Pt 650), a designed structural analog of Et 743 displays in vitro potency comparable to Et 743. In this study, we used a panel of 36 human cancer cell lines, flow cytometry and oligonucleotide microarrays to analyze further these two compounds in a parallel fashion with regard to both antitumor activity (phenotype) and gene expression (genotype) bases. RESULTS: The cancer panel experiment established that activity patterns of Et 743 and Pt 650 were essentially the same with their IC(50) values ranging from pM to low nM. By means of flow cytometric cell cycle analysis using HCT116 cells, they were shown to disrupt S phase progression after a 12-h treatment at 2.0 nM, eventually resulting in the late S and G2/M accumulation at the 24-h time point. Array-based gene expression monitoring also demonstrated that the Et 743 and Pt 650 profiles were highly similar in two distinct cancer cell lines, HCT116 colon and MDA-MB-435 breast. Characteristic changes were observed in subsets of genes involved in DNA damage response, transcription and signal transduction. In HCT116 carrying the wild-type p53 tumor suppressor gene, the up-regulation of several p53-responsive genes was evident. Furthermore, a subset of genes encoding DNA-binding proteins to specific promoter regions (e.g. the CCAAT box) was down-regulated in both cell lines, suggesting one potential mode of action of this series of antitumor agents. CONCLUSION: A combination of gene expression analysis using oligonucleotide microarrays and flow cytometry confirms an earlier finding that Et 743 and Pt 650 have remarkably similar biological activities.

Antineoplastic Agents, Alkylating↗
PubMed1995

Metastatic adenocarcinoma of the ethmoids in a patient with previous gastric adenocarcinoma: a case report.

Metastatic carcinoma of the ethmoids is very rare. Of the few cases reported in the literature, the majority are renal in origin. Although metastases from the gastrointestinal tract have been reported, there are no known cases of metastases from the stomach. We present a rare case of metastatic adenocarcinoma of the ethmoids in a patient previously treated for adenocarcinoma of the stomach and describe the possible mechanisms of spread. The patient had a craniofacial resection of the tumour but unfortunately died four weeks post-operatively from acute liver failure probably caused by a liver metastasis.

Adenocarcinoma↗
PubMed1998

Simple model for teaching myringotomy and aural ventilation tube insertion.

Aural ventilation tube insertion is the most common otological operation and is usually the first operation learnt by trainees. The limited supply of temporal bones as well as expensive commercial models hampers training in the procedure. This paper describes a simple solution making a model of the ear canal and drum out of materials available on an ENT ward.

Education, Medical, Continuing↗
PubMed2003

Quantitative chemical proteomics for identifying candidate drug targets.

We have developed a systematic strategy for drug target identification. This consists of the following sequential steps: (1) enrichment of total binding proteins using two differential affinity matrixes upon which are immobilized positive and negative chemical structures for drug activity, respectively; (2) covalent labeling of the proteins with a new cleavable isotope-coded affinity tag (ICAT) reagent, followed by proteolysis of the combined proteins; (3) isolation, identification, and relative quantification of the tagged peptides by liquid chromatography-mass spectrometry; (4) array-based transcription profiling to select candidate proteins; and (5) confirmation of direct interaction between the activity-associated structure and the selected proteins by using surface plasmon resonance. We present a typical application to identify the primary binding protein of a novel class of anticancer agents exemplified by E7070. Our results suggest that this approach provides a new aspect of quantitative proteomics to find specific binding proteins from protein mixture and should be applicable to a wide variety of biologically active small molecules with unidentified target proteins.

Antineoplastic Agents↗
PubMed2006

Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation.

Several sulfonamides have antitumor activities and are currently undergoing clinical evaluation for the treatment of cancer. In this study, we have elucidated the antiproliferative mechanism of action of five indole sulfonamides. The indole sulfonamides inhibited the polymerization of microtubule protein into microtubules in vitro. In addition, three representative derivatives, ER-68378 (2), ER-68384 (4) and ER-68394 (5), suppressed the dynamic instability behavior at the plus ends of individual steady-state microtubules in vitro. The analogues inhibited HeLa cell proliferation with half-maximal inhibitory concentrations in the range of 6-17 microM. The compounds blocked cell cycle progression at mitosis. At their lowest effective antimitotic concentrations, they depolymerized the spindle microtubules and disorganized the chromosomes but did not affect the microtubules in interphase cells. However, at relatively high concentrations, interphase microtubules were also depolymerized by these sulfonamides. Furthermore, all five compounds were found to induce apoptosis in the cells in association with the phosphorylation of bcl-2. The results suggest that the indole sulfonamides inhibit cell proliferation at mitosis by perturbing the assembly dynamics of spindle microtubules and that they can kill cancer cells by inducing apoptosis through the bcl-2-dependent pathway.

Aminophenols↗
PubMed2007

Control of mesoporous silica nanostructures and pore-architectures using a thickener and a gelator.

A chiral cationic thickener l-ValPyBr, which was able to enhance the viscosity of water and form loosely physical gel in mixtures of water and alcohols, was synthesized. Sol-gel polymerization of TEOS was carried out in mixtures of water and alcohols under basic conditions using the self-assemblies of l-ValPyBr as template. The left-handed twisted mesoporous silica nanoribbons, which were constructed by nanotubes in monolayer, were obtained, and they tended to self-assemble into bundle structure. Stirring under the preparation process played an important role in the formation of this bundle structure. The obtained silica nanoribbons were uniform in width, thickness, and helical pitch without combining amorphous particles. The helical pitch and pore size of the mesoporous silica nanoribbons sensitively depended on the volume ratio of alcohols to water in the reaction mixtures. With increasing volume ratio of alcohols to water in the reaction mixture, the morphologies of the obtained silica changed from left-handed twisted ribbon to coiled ribbon, then to tubular structure. A compound l-ValPyPF6, structurally related to thickener l-ValPyBr, was able to form physical gel in ethanol, THF, acetonitrile, and the mixtures of ethanol and water. Left-handed multiple helical mesoporous silica nanofibers were prepared by using the self-assemblies of l-ValPyPF6 as template in mixtures of water and alcohols under basic conditions. By controlling both the volume ratio of ethanol to water and the weight ratio of l-ValPyPF6 to TEOS, two- or three-dimensional pore-architecture constructed by porous chiral nanotubes was obtained.

Journal Article↗
PubMed2002

Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide.

Compounds from sulfonamide-focused libraries have been evaluated in cell-based antitumor screens using the COMPARE analysis with a panel of 39 human cancer cell lines and flow cytometric cell cycle analysis. Thus far, 2 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (E7010)) and 3 (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070)) have been selected from the collections as potent cell cycle inhibitors, which have progressed to clinical trials. Compound 2 is an orally active antimitotic agent disrupting tubulin polymerization, whereas compound 3 belongs to a novel class of antiproliferative agents causing a decrease in the S phase fraction along with G1 and/or G2 accumulation in various cancer cell lines. Because both compounds exhibited preliminary clinical activities in the phase I setting, we decided to examine further this series of oncolytic small molecules, particularly by using high-density oligonucleotide microarray analysis. The array data have enabled us to characterize these two classes of antitumor sulfonamides on the basis of gene expression changes, illuminating the essential pharmacophore structure and drug-sensitive cellular pathways for each class. Moreover, the dual character of 5 (N-(3-chloro-7-indolyl)-4-methoxybenzenesulfonamide (ER-67880)), resembling both 2 and 3, was revealed by array-based transcription profiling, though the 3-type profile of this molecule had not been apparent in the cell-based phenotypic screens. These results provide an example of the utility of structure and gene expression relationship studies in medicinal genomics.

Algorithms↗
PubMed2005

Sulfonamide drugs binding to the colchicine site of tubulin: thermodynamic analysis of the drug-tubulin interactions by isothermal titration calorimetry.

The discovery of several sulfonamide drugs paved the way toward the synthesis of 6 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide, E7010) and 7 (N-(3-fluoro-4-methoxyphenyl)pentafluorobenzenesulfonamide, T138067), both of which inhibit tubulin polymerization and are under clinical development. A series of diarylsulfonamides containing an indole scaffold was also found to have antimitotic properties, but their mode of interactions with tubulin has remained unidentified so far. In this study, we demonstrate that these sulfonamide drugs bind to the colchicine site of tubulin in a reversible manner. They quenched intrinsic tryptophan fluorescence of tubulin presumably due to drug-induced conformational changes in the protein, but were unable to modulate GTPase activity of tubulin in contrast to colchicine that enhances the same enzymatic activity. Further investigation using isothermal titration calorimetry (ITC) revealed that 5 (N-(5-chloro-7-indolyl)-4-methoxybenzenesulfonamide) afforded a large positive value of heat capacity change (DeltaC(p)() = +264 cal mol(-1) K(-1)) on binding to tubulin, suggesting a substantial conformational transition in the protein along with partial enthalpy-entropy compensation. On the other hand, the 2-chloro regioisomer 2 gave a large negative value of DeltaC(p)() (-589 cal mol(-1) K(-1)) along with complete enthalpy-entropy compensation. This thermodynamic profile was thought to be attributable to a prominent contribution of van der Waals interaction and hydrogen bonding between specific groups in the drug-tubulin complex. These results indicate that a mere alteration in the position of a single substituent chlorine on the indole scaffold has a great influence on the drug-tubulin binding thermodynamics.

Antineoplastic Agents↗
PubMed1999

Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle.

Described herein is the discovery of a novel series of antitumor sulfonamides targeting G1 phase of the cell cycle. Cell cycle control in G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). We previously reported our first antitumor sulfonamide E7010 as a novel tubulin polymerization inhibitor. Interestingly enough, continuous research on structurally related compounds led us to the finding of another class of antitumor sulfonamides that block cell cycle progression of P388 murine leukemia cells in G1 phase, but not in M phase. Of the compounds examined, N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) showed significant antitumor activity against HCT116 human colon carcinoma both in vitro (IC(50) 0.11 microg/mL in cell proliferation assay) and in vivo (not only growth suppression but also a marked reduction of tumor size in nude mice). Because of its promising efficacy against human tumor xenografts and its unique mode of action, E7070 is currently undergoing phase I clinical trials in European countries.

Animals↗
PubMed2000

A general method for acylation of indoles at the 3-position with acyl chlorides in the presence of dialkylaluminum chloride.

[reaction--see text] Indoles are selectively acylated at the 3-position in high yields on treatment with a wide variety of acyl chlorides in CH(2)Cl(2) in the presence of diethylaluminum chloride or dimethylaluminum chloride. The reaction proceeds under mild conditions and is applicable to indoles bearing various functional groups without NH protection.

Acylation↗
PubMed2001

Effects of growth hormone following chronic angiotensin-converting enzyme inhibition in chronic heart failure: their relation to infarct size.

Growth hormone (GH) has been attracted as a possible adjunctive treatment for severe heart failure. However, its treatment effects have been still controversial. To assess severity of basal cardiac disease states in which GH might be effective, we analyzed the relation of treatment effects of GH following chronic angiotensin-converting enzyme (ACE) inhibition on cardiac function and structures to infarct size in rat model of chronic heart failure after myocardial infarction. One day after coronary occlusion, rats were randomized to either an ACE inhibitor, temocapril (T) (80 mg/L in drinking water) or placebo for 12 weeks. The animals received concomitant recombinant human (rh) GH (2 mg/kg/day, SC) (T + GH) or vehicle during the final 2 weeks. Compared with the T group, the T + GH group with large MI had smaller increments of left ventricular (LV) dP/dt(max) (0 vs 17%) and cardiac output (9 vs 49%), less improvement of LV relaxation (tau) (-3 vs 29%) and systemic vascular resistance (8 vs 29%), and a greater increase in LV end-diastolic pressure (123 vs -5%) than did the T+GH group with moderate MI. In the T + GH group when compared with the T group, these functional alterations were associated with a 12% reduction in the LV capillary density and a 21% increase in hydroxyproline contents in rats with large MI, whereas a 12% increase in the density and similar collagen contents were found in rats with moderate MI. Thus, prominent beneficial cardiovascular effects of the additive short-term, high-dose GH to chronic high-dose ACE inhibition were obtained in rats with moderate MI, whereas little additional benefit or even detrimental effects of GH were found in rats with large MI. The present study may provide an insight into the therapeutic strategy of GH given late after MI in the presence of chronic ACE inhibition in congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Evaluation of the Herbst Mandibular Advancement Splint in the management of patients with sleep-related breathing disorders.

Sleep-related breathing disorders such as snoring and obstructive sleep apnoea syndrome are the cause of significant social disruption and hypersomnolence. Several intraoral appliances for the treatment of these disorders have been described, especially where nasal continuous positive airway pressure is poorly tolerated. Mandibular Advancement Splints, such as the Herbst splint used in this study can also be offered to patients with mild to moderate sleep apnoea and simple snorers. The success and compliance rate noted in the literature are quite diverse. Few side-effects have been reported. We therefore undertook this study to assess: (1) the compliance; (2) the effectiveness; and (3) the side-effects in the long- and short-term. All patients for whom a Herbst splint had been prescribed in the last 18 months were sent a postal questionnaire regarding the above mentioned issues. In all, 179 questionnaires were posted and on analysis of the 132 returned it was noted that 82% of splints were worn and 88% of patients found the device to be effective. The long-term side-effects were minimal. In addition objective assessment on 10 patients with and without a jaw-retaining device was also obtained. We conclude that the Herbst Mandibular Advancement Splint is a justifiable option in selected subjects with sleep-related breathing disorders.

Female↗
PubMed2003

Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without structural heart disease.

INTRODUCTION: Previous studies have suggested that paroxysmal atrial fibrillation (PAF) of vagal origin often occurs at night and PAF of sympathetic origin occurs during the daytime; however, autonomic tone after spontaneous termination of PAF has not been determined. The aim of this study was to evaluate by heart rate variability (HRV) analysis the relationship between the time of PAF onset and autonomic tone before and after PAF. METHODS AND RESULTS: Twenty-three patients (65 +/- 2 years) who underwent 24-hour ambulatory monitoring, had one or more episodes of PAF (>30 min), and had maintained normal sinus rhythm for >60 min before/after PAF were enrolled in this study. Mean duration of PAF was 6.2 +/- 1.2 hours. HRV parameters were analyzed in a 10-minutes section at 60 minutes, 20 minutes, and immediately before the onset of PAF and after its termination. PAF began at night in 14 patients (group N) and during the daytime in 9 patients (group D). In group N, the high-frequency (HF) component and low-frequency (LF) component showed a significant decrease after PAF; PAF was preceded by a gradual increase in HF and LF. Changes in the LF/HF ratio, however, did not occur before or after PAF. Conversely, group D showed a significant increase in the LF/HF ratio before PAF and a decrease in LF and the LF/HF ratio after PAF, but no changes in HF. These changes in HRV parameters were not influenced by the duration or termination time of PAF. CONCLUSION: This study suggests that the autonomic nervous system plays an important role in both the initiation and termination of PAF. Furthermore, the time of PAF onset influences the autonomic tone at the initiation and termination of PAF.

Aged↗
PubMed2002

Quantification of cardiac stress during EGD without sedation.

BACKGROUND: Although the complication rate of endoscopy is low, EGD may induce cardiac stress. The aim of this study was to quantify cardiac stress during EGD. METHODS: Heart rate, blood pressure, cardiac output, and peripheral oxygen saturation were measured during endoscopy without sedation in 7 volunteers. Cardiac output was measured with an automated echocardiographic technique. Cardiac index, left ventricular work index, and rate-pressure product were calculated. Serum catecholamine concentrations were measured before and after the examination. RESULTS: Heart rate increased significantly when the endoscope was located in the esophagus compared with the rate before insertion (p < 0.05). No significant changes in cardiac index and left ventricular work index were observed during endoscopy. Rate-pressure product increased significantly at the point of esophageal observation compared with that before insertion (p < 0.05). The rate-pressure product was maximally increased during esophageal observation at 66% over baseline (95% CI [45%, 86%]). Serum concentration of norepinephrine rose significantly after the examination (p < 0.05). CONCLUSIONS: Cardiac output did not increase during EGD without sedation in healthy male volunteers. Cardiac stress increased during EGD as indicated by a 66% increase in rate-pressure product. The cardiac stress was approximately equal to that observed in 3.3 to 5 metabolic equivalents of treadmill exercises.

Adult↗