Sm(III)nitrate-catalyzed one-pot synthesis of furano3,2c]-1,2,3,4-tetrahydroquinolines and DNA photocleavage studies

The synthesis and DNA photocleavage studies of furano3,2-c]-1,2,3,4-tetrahydroquinolines have been reported. Sm(III)nitrate was found to be an efficient for the Diels-Alder reaction of aryl amines with 2,3-dihydrofuran to offer the corresponding furano3,2-c]-1,2,3,4-tetrahydroquinolines derivatives as a mixture of cis/trans stereoisomers in moderate yields. The aqueous solubility of acid catalyst can be recycled without significant loss of activity. The DNA photocleavage studies shows that, the cis/trans stereoisomers are good DNA cleavage mimic in terms of molecular structure. (C) 2012 Elsevier B.V. All rights reserved.

2,3-Unsaturated enoses. A Pummerer rearrangement route to sugar vinyl sulfides and synthesis of 3-deoxy-3-alkyl/arylsulfinyl pyranosides

A Pummerer rearrangement of 2,3-dideoxy-3-alkyl/arylsulfinyl-arabino-hexopyranosides is reported. Treatment of sulfinyl-arabino-hexopyranoside derivatives, obtained through oxidation of the corresponding thio-derivatives, with trifluoroacetic anhydride (TFAA)/pyridine led to a facile formation of 2,3-dideoxy-3-alkyl/arylthio-hex-2-enopyranosides. Upon conversion of sugar vinyl sulfides to vinyl sulfoxides, conjugate addition reactions were conducted with alkoxides, to afford 3-deoxy-3-alkyl/arylsulfinyl pyranosides, in the manno-configuration exclusively. Whereas the conjugate addition reaction did not proceed with ether protecting groups, ester protecting groups and free hydroxyl groups in the sugar vinyl sulfoxide permitted the reaction. (C) 2012 Elsevier Ltd. All rights reserved.

A novel DNA intercalator, 8-methoxy pyrimido4 `,5 `:4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent.

A Novel Anticancer Agent, 8-Methoxypyrimido4 `,5 `: 4,5]thieno(2,3-b) Quinoline-4(3H)-One Induces Neuro 2a Neuroblastoma Cell Death through p53-Dependent, Caspase-Dependent and Independent Apoptotic Pathways

Neuroblastoma is the most common cancer in infants and fourth most common cancer in children. Despite recent advances in cancer treatments, the prognosis of stage-IV neuroblastoma patients continues to be dismal which warrant new pharmacotherapy. A novel tetracyclic condensed quinoline compound, 8-methoxypyrimido 4 `,5 `: 4,5] thieno(2,3-b) quinoline-4(3H)-one (MPTQ) is a structural analogue of an anticancer drug ellipticine and has been reported to posses anticancer property. Study on MPTQ on neuroblastoma cells is very limited and mechanisms related to its cytotoxicity on neuroblastoma cells are completely unknown. Here, we evaluated the anticancer property of MPTQ on mouse neuro 2a and human SH-SY5Y neuroblastoma cells and investigated the mechanisms underlying MPTQ-mediated neuro 2a cell death. MPTQ-mediated neuro 2a and SH-SY5Y cell deaths were found to be dose and time dependent. Moreover, MPTQ induced cell death reached approximately 99.8% and 90% in neuro 2a and SH-SY5Y cells respectively. Nuclear oligonucleosomal DNA fragmentation and Terminal dUTP Nick End Labelling assays indicated MPTQ-mediated neuro 2a cell death involved apoptosis. MPTQ-mediated apoptosis is associated with increased phosphorylation of p53 at Ser15 and Ser20 which correlates with the hyperphosphorylation of Ataxia-Telangiectasia mutated protein (ATM). Immunocytochemical analysis demonstrated the increased level of Bax protein in MPTQ treated neuro 2a cells. MPTQ-mediated apoptosis is also associated with increased activation of caspase-9, -3 and -7 but not caspase-2 and -8. Furthermore, increased level of caspase-3 and cleaved Poly ( ADP Ribose) polymerase were observed in the nucleus of MPTQ treated neuro 2a cells, suggesting the involvement of caspase-dependent intrinsic but not extrinsic apoptotic pathway. Increased nuclear translocation of apoptosis inducing factor suggests additional involvement of caspase-independent apoptosis pathway in MPTQ treated neuro 2a cells. Collectively, MPTQ-induced neuro 2a cell death is mediated by ATM and p53 activation, and Bax-mediated activation of caspase-dependent and caspase-independent mitochondrial apoptosis pathways.

Facial selectivities in the nucleophilic additions of 2,3-unsaturated 3-arylsulfinyl pyranosides

2,3-Unsaturated 3-arylsulfinyl pyranosides undergo nucleophilic additions at C-2, with facial selectivities depending on the nucleophile and the substituent on sulfinyl sulfur. The reactions of such sugar vinyl sulfoxides lead to the addition of nucleophile preferring an axial orientation at C-2, with concomitant formation of an allylic bond at C-3 to C-4. This trend in the addition pattern is observed for primary amine, carbon and sulfur nucleophiles, whereas secondary amines prefer an equatorial addition at C-2. The effect of p-tolylthio-versus (p-isopropylphenyl)thio vinyl sulfoxide is that the equatorial nucleophilic addition is preferred even more with the latter vinyl sulfoxide. (C) 2013 Published by Elsevier Ltd.

The exploration of Kemp's triacid (KTA) as the core for the synthesis of 3-fold symmetric 2(3)-cyclophane, 2(2)-cyclophane and novel linker directed designs

For the first time, two units of KTA have been linked to three units of cyst-di-OMe. The reaction is noteworthy since it involves the formation of six amide bonds leading to a three-fold symmetric 23-cyclophane (3) harboring a cluster of three S-S bridges. The major product is a di-imide (4), arising from the interaction of a cystine NH with a neighbouring activated ester. A third reaction of tethering KTA with a single cyst-di-OMe unit afforded the flexible compound 6 and, with benzidine, the novel linker directed 7 with orthogonally disposed anchor modules.

DNA intercalative 4-butylaminopyrimido4',5':4,5]thieno(2,3-b)quinoline induces cell cycle arrest and apoptosis in leukemia cells

DNA intercalators are one of the interesting groups in cancer chemotherapy. The development of novel anticancer small molecule has gained remarkable interest over the last decade. In this study, we synthesized and investigated the ability of a tetracyclic-condensed quinoline compound, 4-butylaminopyrimido4',5':4,5]thieno(2,3-b)quinoline (BPTQ), to interact with double-stranded DNA and inhibit cancer cell proliferation. Circular dichroism, topological studies, molecular docking, absorbance, and fluorescence spectral titrations were employed to study the interaction of BPTQ with DNA. Cytotoxicity was studied by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Further, cell cycle analysis by flow cytometry, annexin V staining, mitochondrial membrane potential assay, DNA fragmentation, and western blot analysis were used to elucidate the mechanism of action of BPTQ at the cellular level. Spectral, topological, and docking studies confirmed that BPTQ is a typical intercalator of DNA. BPTQ induces dose-dependent inhibitory effect on the proliferation of cancer cells by arresting cells at S and G2/M phase. Further, BPTQ activates the mitochondria-mediated apoptosis pathway, as explicated by a decrease in mitochondrial membrane potential, increase in the Bax:Bcl-2 ratio, and activation of caspases. These results confirmed that BPTQ is a DNA intercalative anticancer molecule, which could aid in the development of future cancer therapeutic agents.

A novel DNA intercalator, 8-methoxy pyrimido4 `,5 `:4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent. (c) 2011 Wiley Periodicals, Inc.

Antiproliferative and tumor inhibitory studies of 2,3 disubstituted 4-thiazolidinone derivatives

4-Thiazolidinone derivatives were synthesized using T3P (R)-DMSO media as a cyclodehydrating agent. All the molecules were tested for their cytotoxicity against leukemic cell lines. The compound 3-(4-bromophenyl)-2-(4-(dimethylamino)phenyl)thiazolidin-4-one (4e) with electron donating substituent at para position of phenyl ring displayed considerable cytotoxicity against Reh and Nalm6 cells with an IC50 value of 11.9 and 13.5 mu M, respectively. Furthermore, the compound 4e tested for tumor regression studies induced by EAC in Swiss albino mouse. Both in vitro and in vivo results suggested significant antiproliferative activity of compound 4e in Reh cells and mouse tumor tissue treated with compound 4e showed multifocal areas of necrosis and numerous number of apoptotic cells. (C) 2015 Elsevier Ltd. All rights reserved.

Report of the Sea Turtle Health Assessment Workshop, 2-3 February 1998, Part I: Background and information needs

A two day workshop was convened on February 2-3, 1998 in Charleston, SC with 20 invited experts in various areas of sea turtle research. The goal of this workshop was to review current information on sea turtles with repect to health and identify data gaps. The use of a suite of health assessment indicators will provide insight on the health status of sea turtle populations. Since the relationship of health factors of sea turtles is limited, a seconde workshop was planned. Using a tiered approach, the first workshop we identified and reviewed the available, pertinent baseline information and data gaps. The second workshop will focus on developing the framework for the research plan. The workshops will address the use of integrated set of health parameters; specific objectives are: 1) Identify reliable indicators of health in sea turtles: assess advantages and disadvantages; determine new indicators/biomarkers which may be useful; 2) Review existing sea turtle field sampling projects; 3) Identify field projects suitable for inclusion for health assessment sampling; 4) Identify data gaps, particularly environmental characterization; 5) Identify new health assessment sampling sites, including reference site(s); and 6) Develop integrated five-year research plan, with focus on health assessment of environmental characterization. (PDF contains 174 pages)

A measurement of the proton elastic form factors for 1 ≤ Q^2 ≤ 3 (GeV/c)^2

We report measurements of the proton form factors, G^p_E and G^p_M, extracted from elastic electron scattering in the range 1 ≤ Q^2 ≤ 3 (GeV/c)^2 with uncertainties of <15% in G^p_E and <3% in G^p_M. The results for G^p_E are somewhat larger than indicated by most theoretical parameterizations. The ratio of Pauli and Dirac form factors, Q^2(F^p_2/F^p_1), is lower in value and demonstrates less Q^2 dependence than these parameterizations have indicated. Comparisons are made to theoretical models, including those based on perturbative QCD, vector-meson dominance, QCD sum rules, and diquark constituents to the proton. A global extraction of the form factors, including previous elastic scattering measurements, is also presented.

Catechol 2,3-dioxygenase-assisted cleavage of aromatics by “anaerobic” termite gut spirochetes and genomic evidence of a complete meta-pathway

The termite hindgut microbial ecosystem functions like a miniature lignocellulose-metabolizing natural bioreactor, has significant implications to nutrient cycling in the terrestrial environment, and represents an array of microbial metabolic diversity. Deciphering the intricacies of this microbial community to obtain as complete a picture as possible of how it functions as a whole, requires a combination of various traditional and cutting-edge bioinformatic, molecular, physiological, and culturing approaches. Isolates from this ecosystem, including Treponema primitia str. ZAS-1 and ZAS-2 as well as T. azotonutricium str. ZAS-9, have been significant resources for better understanding the termite system. While not all functions predicted by the genomes of these three isolates are demonstrated in vitro, these isolates do have the capacity for several metabolisms unique to spirochetes and critical to the termite system’s reliance upon lignocellulose. In this thesis, work culturing, enriching for, and isolating diverse microorganisms from the termite hindgut is discussed. Additionally, strategies of members of the termite hindgut microbial community to defend against O₂-stress and to generate acetate, the “biofuel” of the termite system, are proposed. In particular, catechol 2,3-dioxygenase and other meta-cleavage catabolic pathway genes are described in the “anaerobic” termite hindgut spirochetes T. primitia str. ZAS-1 and ZAS-2, and the first evidence for aromatic ring cleavage in the phylum (division) Spirochetes is also presented. These results suggest that the potential for O₂-dependent, yet nonrespiratory, metabolisms of plant-derived aromatics should be re-evaluated in termite hindgut communities. Potential future work is also illustrated.

Synthesis and matrix isolated photolysis of 2,3-dimethylbicyclo [2.2.0]hexa-2,5-diene-1,4-dicarboxylic acid anhydride: a potential percursor to 2,3-dimethyl-1,4-dehydrobenzene

The synthesis of the first member of a new class of Dewar benzenes has been achieved. The synthesis of 2,3- dimethylbicyclo[2.2.0]hexa-2,5-diene-1, 4-dicarboxylic acid and its anhydride are described. Dibromomaleic anhydride and dichloroethylene were found to add efficiently in a photochemical [2+2] cycloaddition to produce 1,2-dibromo- 3,4-dichlorocyclobutane-1,2-dicarboxylic acid. Removal of the bromines with tin/copper couple yielded dichloro- cyclobutenes which added to 2-butyne under photochemical conditions to yield 5,6-dichloro-2,3-dimethylbicyclo [2.2.0] hex-2-ene dicarboxylic acids. One of the three possible isomers yielded a stable anhydride which could be dechlorinated using triphenyltin radicals generated by the photolysis of hexaphenylditin.

Photolysis of argon matrix isolated 2,3-dimethylbicyclo [2.2.0]hexa-2, 5-diene-1,4-dicarboxylic acid anhydride produced traces whose strongest bands in the infrared were at 3350 and 600 cm^(-1). This suggested the formation of terminal acetylenes. The spectra of argon matrix isolated E- and Z- 3,4-dimethylhexa-1,5-diyne-3-ene and cis-and trans-octa- 2,6-diyne-4-ene were compared with the spectrum of the photolysis products. Possibly all four diethynylethylenes were present in the anhydride photolysis products. Gas chromatograph-mass spectral analysis of the volatiles from the anhydride photolysis again suggested, but did not confirm, the presence of the diethynylethylenes.

The streaming of 1.3-2.3 MeV cosmic-ray protons during periods between prompt solar particle events

The anisotropy of 1.3 - 2.3 MeV protons in interplanetary space has been measured using the Caltech Electron/Isotope Spectrometer aboard IMP-7 for 317 6-hour periods from 72/273 to 74/2. Periods dominated by prompt solar particle events are not included. The convective and diffusive anisotropies are determined from the observed anisotropy using concurrent solar wind speed measurements and observed energy spectra. The diffusive flow of particles is found to be typically toward the sun, indicating a positive radial gradient in the particle density. This anisotropy is inconsistent with previously proposed sources of low-energy proton increases seen at 1 AU which involve continual solar acceleration.

The typical properties of this new component of low-energy cosmic rays have been determine d for this period which is near solar minimum. The particles have a median intensity of 0.06 protons/ cm^(2)-sec-sr-MeV and a mean spectral index of -3.15.The amplitude of the diffusive anisotropy is approximately proportional to the solar wind speed. The rate at which particles are diffusing toward the sun is larger than the rate at which the solar wind is convecting the particles away from the sun. The 20 to 1 proton to alpha ratio typical of this new component has been reported by Mewaldt, et al. (1975b).

A propagation model with κ_(rr) assumed independent of radius and energy is used to show that the anisotropy could be due to increases similar to those found by McDonald, et al. (1975) at ~3 AU. The interplanetary Fermi-acceleration model proposed by Fisk (1976) to explain the increases seen near 3 AU is not consistent with the ~12 per cent diffusive anisotropy found.

The dependence of the diffusive anisotropy on various parameters is shown. A strong dependence of the direction of the diffusive anisotropy on the concurrently measured magnetic field direction is found, indicating a κ_⊥ less than κ_∥ to be typical for this large data set.