Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability.

A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 µΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, ßCys241, ßLys254 and ßLys352 in the colchicine-binding site of the tubulin.

Design, synthesis and biological evaluation of new ß-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors.

A series of new ß-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 µM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV-Visible, fluorescence, circular dichroism and molecular docking studies revealed that the ß-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.

European and Mediterranean hydroclimate responses to tropical volcanic forcing over the last millennium.

Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated from multiple datasets, and seasonal paleoclimate reconstructions (soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in post-eruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April-July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.

Synthesis and biological evaluation of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles as potent tubulin polymerization inhibitors.

A series of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti-proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)-5-fluoro-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), 11 ((E)-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), and 15 ((E)-6-chloro-3-((6-phenyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one) exhibited potent anti-proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G2 /M phase, inhibition of tubulin assembly, and increased cyclin-B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC50 range of 1.1-1.6 µM, and inhibited tubulin polymerization with an IC50 value (0.15 µM) lower than that of combretastatin A-4 (1.16 µM). Docking studies reveal that compounds 7 and 11 bind with αAsn101, ßThr179, and ßCys241 in the colchicine binding site of tubulin.

Synthesis of ß-carboline-benzimidazole conjugates using lanthanum nitrate as a catalyst and their biological evaluation.

A series of ß-carboline-benzimidazole conjugates bearing a substituted benzimidazole and an aryl ring at C3 and C1 respectively were designed and synthesized. The key step of their preparation was determined to involve condensation of substituted o-phenylenediamines with 1-(substituted phenyl)-9H-pyrido[3,4-b]indole-3-carbaldehyde using La(NO3)3·6H2O as a catalyst and their cytotoxic potential was evaluated. Conjugates 5a, 5d, 5h and 5r showed enhanced cytotoxic activity (GI50 values range from 0.3 to 7.1 µM in most of the human cancer cell lines) in comparison to some of the previously reported ß-carboline derivatives. To substantiate the cytotoxic activity and to understand the nature of interaction of these conjugates with DNA, spectroscopy, DNA photocleavage and DNA topoisomerase I inhibition (topo-I) studies were performed. These conjugates (5a, 5d and 5r) effectively cleave pBR322 plasmid DNA in the presence of UV light. In addition, the effect of these conjugates on DNA Topo I inhibition was studied. The mode of binding of these new conjugates with DNA was also examined by using both biophysical as well as molecular docking studies, which supported their multiple modes of interaction with DNA. Moreover, an in silico study of these ß-carboline-benzimidazole conjugates reveals that they possess drug-like properties.

Synthesis and biological evaluation of imidazopyridine-oxindole conjugates as microtubule-targeting agents.

A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31 µM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin.

Anti-tubercular agents. Part 7: a new class of diarylpyrrole-oxazolidinone conjugates as antimycobacterial agents.

In an effort to discover new anti-tubercular agents, a series of new diarylpyrrole-oxazolidinone conjugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4a-n and 5a-d) against Mycobacterium tuberculosis H37Rv and drug resistance strains such as M. tuberculosis Rif(R) and M. tuberculosis XDR are discussed, wherein compound 4i has been found to be the most potent amongst the series. MTT assay was performed on the active conjugates of the series (4b-f, 4i and 5c) against mouse macrophage (J-774) cells to evaluate cytotoxic effects and selective index values. In addition, these conjugates (4a-n and 5a-d) are also tested against a panel of Gram-positive and Gram-negative bacterial strains. The docking studies have been carried out to provide some insight into the mechanism of action for this class of compounds.

Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents.

A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 µg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 µg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented.

Health insurance as a requirement to undergo cardiac transplantation: a national survey of transplant program practices.

BACKGROUND: Recent limitations in Medicaid coverage of transplantation in Arizona jeopardized transplantation of potential recipients in that state and called attention to financial barriers inherent in the present organ allocation system. Policies of cardiac transplant centers regarding insurance requirements for transplantation have not been previously assessed. We sought to determine the policies of adult cardiac transplant programs nationwide regarding insurance requirements for evaluation and listing for cardiac transplantation. METHODS: From December 15, 2008 to November 16, 2010, all active adult cardiac transplant programs in the United States were surveyed regarding insurance requirements for evaluation and listing for cardiac transplantation. RESULTS: Surveys were completed by 62 of 101 programs, accounting for 71% of adult cardiac transplants in 2007. Only 2% of recipients were uninsured. Insurance was required by 48% of programs to evaluate and 84% to list for transplantation. For uninsured patients, 81% of programs required a large amount of money upfront (median, $200,000; interquartile range, $10,000-$300,000) to list for transplantation and often (84%) educated patients about fundraising to acquire these resources. CONCLUSIONS: Adult cardiac transplant programs generally require candidates to have adequate health insurance to undergo transplantation. Uninsured patients typically need a significant amount of money upfront to be listed for transplantation and often are advised to fundraise to gather such resources.

Simultaneous recording of rat auditory cortex and thalamus via a titanium-based, microfabricated, microelectrode device.

Direct recording from sequential processing stations within the brain has provided opportunity for enhancing understanding of important neural circuits, such as the corticothalamic loops underlying auditory, visual, and somatosensory processing. However, the common reliance upon microwire-based electrodes to perform such recordings often necessitates complex surgeries and increases trauma to neural tissues. This paper reports the development of titanium-based, microfabricated, microelectrode devices designed to address these limitations by allowing acute recording from the thalamic nuclei and associated cortical sites simultaneously in a minimally invasive manner. In particular, devices were designed to simultaneously probe rat auditory cortex and auditory thalamus, with the intent of recording auditory response latencies and isolated action potentials within the separate anatomical sites. Details regarding the design, fabrication, and characterization of these devices are presented, as are preliminary results from acute in vivo recording.