ABSTRACT
On-site sanitation has emerged as a preferred mode of sanitation in cities experiencing rapid urbanization due to the high cost involved in off-site sanitation which requires conventional sewerages. However, this practice has put severe stress on groundwater especially its quality. Under the above backdrop, a study has been undertaken to investigate the impact of on-site sanitation on quality of groundwater sources in two mega cities namely Indore and Kolkata which are situated in two different geological settings. The parameters for the studies are distance of groundwater source from place of sanitation, effect of summer and monsoon seasons, local hydro-geological conditions, and physico-chemical parameters. NO(3) and fecal coliform concentrations are considered as main indexes of pollution in water. Out of many conclusions which can be made from this studies, one major conclusion is about the influence of on-site sanitation on groundwater quality is minimal in Kolkata, whereas it is significant in Indore. This difference is due to the difference in hydrogeological parameters of these two cities, Kolkata being on alluvium quaternary and Indore being on Deccan trap of Cretaceous to Paleogene age.
Subject(s)
Environmental Monitoring/methods , Geological Phenomena , Groundwater/analysis , Water Pollutants/chemistry , Water Pollution, Chemical/prevention & control , India , Nitrates/chemistry , Seasons , Soil/chemistry , Surveys and QuestionnairesABSTRACT
BACKGROUND & OBJECTIVE: India has a high prevalence of HIV-1, hapatitis C and B virus (HCV and HBV) in the blood donors but has yet to implement nucleic acid testing (NAT) in blood screening. We undertook a multicentre evaluation of blood donor testing by NAT for simultaneous detection of HIV-1, HBV and HCV in a single tube and also to determine the feasibility of NAT implementation in India's low volume setting. METHODS: A total of 12,224 unlinked samples along with their serological results were obtained from representative eight blood banks in India and were individually manually tested by the Procleix Ultrio Assay (Chiron Corp. Emeryville, CA) for simultaneous detection of HIV-1, HCV, and HBV. RESULTS: Of the 12,224 samples tested, 209 (1.71%) were seroreactive. One hundred thirty three samples (1.09%) were reactive by Ultrio assay, 84 samples were seroreactive but NAT non reactive. There were eight NAT yield cases: 1 HIV, 1 HIV-HCV co-infection, and 6 HBV. INTERPRETATION & CONCLUSION: Our observed NAT yield for all three viruses was 1 in 1528 (0.065%). We estimate NAT could interdict 3272 infectious donations a year among our approximate 5 million annual donations.
Subject(s)
Blood Donors , HIV Infections/diagnosis , HIV-1/metabolism , Hepacivirus/metabolism , Hepatitis B virus/metabolism , Hepatitis B/diagnosis , Hepatitis C/diagnosis , Mass Screening/methods , Nucleic Acid Amplification Techniques/standards , RNA, Viral/analysis , Blood Banks , Female , HIV Infections/epidemiology , HIV Infections/transmission , Hepatitis B/epidemiology , Hepatitis B/transmission , Hepatitis C/epidemiology , Hepatitis C/transmission , Humans , India , Male , Serologic Tests/standardsABSTRACT
We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
Subject(s)
Hepacivirus/chemistry , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Molecular Structure , Protein Binding , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
Conformational and stereochemical analysis of six new symmetrical dimers was performed using proton-proton vicinal coupling measured from (1)H NMR and (13)C satellites of (1)H NMR signals, natural abundance (13)C-edited nuclear overhauser effect (NOE) experiments, comprehensive NOE analysis and molecular modeling. The (13)C satellite analysis and (13)C-edited NOE experiments were carried out to extract spectral information between equivalent protons. Molecular modeling was applied for estimations of three-dimensional parameters of the studied dimers, which were subsequently used to generate a set of theoretical NOE for each possible conformation. The J-coupling, (13)C-edited NOE and quantitative NOE analyses showed the predominance of gauche conformation for three dimers, whereas a mixture of gauche and anti conformations (45:55) for three other dimers was established by quantitative NOE analysis. X-ray crystallographic study confirmed the stereochemistry of one of the dimers and revealed a discrepancy in conformation stability between liquid and solid states.
Subject(s)
Crystallography/methods , Hydrocarbons/chemistry , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Carbon Isotopes , Computer Simulation , Dimerization , Hydrocarbons/analysis , Molecular Conformation , ProtonsABSTRACT
First experimental observations are reported on stimulated coherent synchrotron radiation from highly relativistic electrons in a strong magnetic field. The experiment employed a quasioptical millimeter-wave resonator and a 6-MeV electron beam gyrating in a field of up to 25 kG. Coherent radiation at 54 GHz, corresponding to the 11th gyroharmonic, was observed and characterized. These observations demonstrate the possibility of a synchrotron resonance maser.
ABSTRACT
Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to non-cytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are currently in clinical evaluation. This review focuses on FPT inhibitors in clinical trials and concentrates on the benzocycloheptapyridine class, with details on the discovery and development of SCH 66336, currently in Phase II clinical trials.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Neoplasms/therapy , Piperidines/therapeutic use , Pyridines/therapeutic use , Animals , Binding Sites , Clinical Trials as Topic , Farnesyltranstransferase , Humans , Molecular Structure , Neoplasms/enzymology , Protein ConformationABSTRACT
High-resolution mass spectrometry has been routinely used for structural confirmation and identification; however, it has mostly been applied to relatively pure samples. Exact mass measurement of minor components such as impurities, degradation products or metabolites in complex mixtures has been difficult without prior separation and isolation. Here we report the utilization of on-line liquid chromatography in combination with high-resolution mass spectrometry for the identification of impurities and base degradation products of Sch 27899, a member of the everninomicin class of antibiotics. Nine Sch 27899-related impurities and degradation products were detected by negative ion electrospray ionization using a magnetic sector mass spectrometer. Exact mass measurements were obtained at a resolution of 5000 using polyethylene glycol (PEG) sulfates as internal standards. Corresponding elemental compositions were determined within a 2 ppm error tolerance and structures were proposed for all components.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Chromatography, Liquid/methods , Oligosaccharides/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Anti-Bacterial Agents/analysis , Calibration , Carbohydrate Sequence , Micromonospora/chemistry , Molecular Sequence Data , Molecular Structure , Oligosaccharides/chemistry , Oligosaccharides/metabolism , Sensitivity and SpecificityABSTRACT
AIMS: To find out the status of DNA, RNA and protein in human uterine, ovarian, breast and rectal carcinoma. MATERIAL AND METHODS: In this prospective study, patients of age group between late thirties and late fifties suffering from uterine, ovarian, breast and rectal cancer were taken as subjects of the present study. The total number of cases studied for each cases was ten. Pieces of human carcinomatous tissues of above mentioned cases were taken along with surrounding normal tissues. From the tissue samples, putrescine is separated by the method of Herbst et al, DNA analysed by Diphenylamine method, RNA by Orcinol method and protein by Biuret method. RESULTS: Tissue content of putrescine rises simultaneously with that of DNA, RNA and protein in carcinomatous growths as above in comparison to their respective adjacent normal tissue, the differences being statistically highly significant. CONCLUSIONS: Increase in DNA, RNA and protein concentration may be a pre-requisite for increased synthesis of putrescine in carcinomatous tissue and thereby the concentration of other di- and poly-amines.
Subject(s)
Biomarkers, Tumor/analysis , DNA, Neoplasm/analysis , Oncogene Proteins/analysis , Putrescine/analysis , RNA, Neoplasm/analysis , Adult , Biopsy, Needle , Breast Neoplasms/chemistry , Culture Techniques , Female , Humans , Male , Middle Aged , Ovarian Neoplasms/chemistry , Probability , Prospective Studies , Rectal Neoplasms/chemistry , Sensitivity and Specificity , Spectrophotometry , Uterine Neoplasms/chemistryABSTRACT
Ziracin is produced by Micromonospora carbonacea and is highly active against Gram-positive bacteria. In particular it is highly active against methicillin resistant staphylococci and vancomycin resistant enterococci. Ziracin, C71H97NO38Cl2, contains two orthoester linkages, a nitro sugar, a methylene dioxy group, two aromatic ester residues and thirty five centres of assymmetries. In this paper a brief description of the structural elucidation of ziracin is presented along with the chemical modification of the antibiotic which has led to the identification of several potent antibacterials.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Cocci/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Molecular Structure , Oligosaccharides/chemistry , Structure-Activity RelationshipABSTRACT
Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Sulfonamides/chemical synthesis , Sulfonylurea Compounds/chemical synthesis , Administration, Oral , Animals , Biological Availability , COS Cells , Cell Division/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Mice , Mice, Nude , Piperidines/chemistry , Piperidines/pharmacokinetics , Protein Prenylation , Proto-Oncogene Proteins p21(ras)/metabolism , Pyridines/chemistry , Pyridines/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/pharmacokineticsABSTRACT
Introduction of bromine at the 10-position of 3-bromo-8-chloro-benzocycloheptapyridine analogues of type 3 results in formation of atropisomeric compounds of type (+/-)-1 and (+/-)-2 that are easily separable at room temperature on a ChiralPak AD column providing pure atropisomers, (+)-1, (-)-1, and (+)-2, (-)-2, respectively. Evaluation of the FPT activity of these atropisomers revealed that compounds (+)-1 and (+)-2 were more potent in the FPT enzyme and cellular assay than their (-)-isomer counterparts. Compounds (+)-1 and (+)-2 were found to inhibit FPT processing in COS cells at low micro molar range. They were also found to have excellent cellular antitumor activity. Evaluation of compound (+)-1 and (+)-2 in DLD-tumor model in nude mice revealed that they were efficacious, inhibiting tumor growth by 55 and 63% at 50 mpk, respectively.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyridines/pharmacokinetics , Animals , COS Cells , Dose-Response Relationship, Drug , Female , Humans , Macaca fascicularis , Male , Mice , Mice, Nude , Models, Chemical , Time Factors , Tumor Cells, CulturedABSTRACT
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Cyclic N-Oxides/chemistry , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Piperidines/chemistry , Protein Prenylation , Pyridines/chemistry , Binding Sites , Calorimetry , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , ThermodynamicsABSTRACT
Chemical modifications of eveminomicin antibiotics, particularly ziracin (1), were carried out to study the SARs as well as the chemical properties of this class of compounds. Use of allyl ether group for protection and selective deprotection of phenolic groups provided access to a variety of novel analogs of the title compounds, some of which exhibited the same high in vitro potency as the parent compounds.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Structure-Activity Relationship , Enterococcus/drug effects , Staphylococcus/drug effectsABSTRACT
This paper presents a comparison of Gaussian and Bessel beam driven laser accelerators. The emphasis is on the vacuum beat wave accelerator (VBWA), employing two laser beams of differing wavelengths to impart a net acceleration to particles. Generation of Bessel beams by means of circular slits, holographic optical elements, and axicons is outlined and the image space fields are determined by making use of Huygens' principle. Bessel beams-like Gaussian beams-experience a Guoy phase shift in the vicinity of a focal region, resulting in a phase velocity that exceeds c, the speed of light in vacuo. In the VBWA, by appropriate choice of parameters, the Guoy phases of the laser beams cancel out and the beat wave phase velocity equals c. The particle energy gain and beam quality are determined by making use of an analytical model as well as simulations. The analytical model--including the v x B interaction--predicts that for equal laser powers Gaussian and Bessel beams lead to identical energy gains. However, three-dimensional, finite-emittance simulations, allowing for detuning, transverse displacements, and including all the electromagnetic field components, show that the energy gain of a Gaussian beam driven VBWA exceeds that of a Bessel beam driven VBWA by a factor of 2-3. The particle beam emerging from the interaction is azimuthally symmetric and collimated, with a relatively small angular divergence. A table summarizing the ratios of final energies, acceleration lengths, and gradients for a number of acceleration mechanisms is given.
ABSTRACT
[formula: see text] Synthesis of C-11 methyl-substituted benzocycloheptylpyridine tricyclic compounds has been achieved via two different methods. Methylation of C-11 has been effected by treatment of amine 4 with BuLi followed by Mel quenching. In a similar procedure, introduction of a C-11 substituent with concomitant rearrangement of the exocyclic double bond has been carried out. Potent farnesyl protein transferase inhibitors have been synthesized using the above methodologies.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyridines/pharmacologyABSTRACT
There is controversy about the relationship between thymic secretion and secretion of gonadotrophins and testosterone. One group of scientists reported that thymus is stimulatory to gonadotrophins and testosterone secretion, and according to other group thymic secretion is inhibitory to gonadotrophins and testosterone secretion. So we tried to observe what exactly happens to serum gonadotrophins and testosterone level following thymectomy. Thymectomy was performed in prepubertal animals and after 45 days of their operation serum gonadotrophins were measured by ELISA technique and serum testosterone was measured by RIA technique. The present study reveals a significant fall in serum FSH level along with significant rise in serum LH and testosterone level in male albino rats following thymectomy in comparison to that of sham thymectomized rats. It appears that thymus has an inhibitory influence on LH secreting gonadotrophs which has been withdrawn following thymectomy and as a result there occurs an increase in serum LH level. This LH stimulates interstitial cells of leydig and cause thereby an increase in serum testosterone level. The result also gives an indication that among the gonadotrophs in pituitary, one type is concerned with the secretion of LH while some gonadotrophs are concerned with secretion of FSH only; and the thymus possibly maintains the FSH secreting gonadotrophs intact at least till the age of puberty. Thymectomy may cause some disorganization of FSH secreting gonadotrophs which results in the fall in serum FSH level in thymectomized animals in comparison to that of sham thymectomized animal group.
Subject(s)
Gonadotropins/blood , Testosterone/blood , Thymectomy , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Follicle Stimulating Hormone/analysis , Follicle Stimulating Hormone/blood , Gonadotropins/analysis , Luteinizing Hormone/analysis , Luteinizing Hormone/blood , Male , Probability , Radioimmunoassay , Rats , Rats, Inbred Strains , Reference Values , Testosterone/analysis , Thymectomy/adverse effectsABSTRACT
Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.
Subject(s)
Glucosides/metabolism , Guanosine Diphosphate/metabolism , Proteins/antagonists & inhibitors , Sulfonamides/metabolism , ras Proteins/metabolism , Amino Acid Sequence , Binding Sites , Computer Simulation , Glucosides/chemistry , Guanine Nucleotide Exchange Factors , Humans , Macromolecular Substances , Magnesium/metabolism , Models, Molecular , Molecular Sequence Data , Monte Carlo Method , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Conformation , Proteins/chemistry , Sulfonamides/chemistry , ras Guanine Nucleotide Exchange FactorsABSTRACT
The detection of non-covalent complexes in the mass range 19,000-34,000 Da, using electrospray ionization mass spectrometry (ESI-MS), is reviewed. The examples discussed include (1) a protein-ligand interaction (ras-GDP), (2) an inhibitor-protein-ligand interaction (SCH 54292/SCH 54341-ras-GDP), (3) a protein-protein interaction (gamma-IFN homodimer) and (4) a protein-metal complex [HCV (1-181)-Zn]. In each case, the ESI-MS method is capable of releasing the intact non-covalent complex from its native solution state into the gas phase in the form of multiply-charge ions. The molecular masses of these complexes were determined with a mass accuracy of better than 0.01%, which is far superior to the traditional methods of sodium dodecyl sulfate polyacrylamide gel electrophoresis and gel permeation chromatography. The method provides the researcher with a quick, reliable and reproducible method for probing difficult biological problems. The key to success in the study of non-covalent complexes depends on careful understanding and manipulation of ESI source parameters and sample solution conditions; special care must be taken with the source orifice potential and the solution pH and organic co-solvents must be avoided. This paper also illustrates the usefulness of ESI-MS for addressing biological problems leading to the discovery of new therapeutics; the approach involves the rapid screening of potential drug candidates, such as weakly bound inhibitors.