Cytotoxic thiol alkylators containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore

For the last several years curcumin has attracted considerable interest due to its ability to inhibit cancer cell proliferation in vitro and in vivo by targeting a number of different cell signaling and molecular mechanism pathways in cancer cells. These results prove its potential to be considered as a future anticancer drug candidate. However its metabolic instability, low oral bioavailability and high clearance have limited its use as a clinical drug candidate. Subsequently enormous efforts have been expended by medicinal chemists to modify the curcumin structure which has led to the development of novel cytotoxic curcuminoid analogs. The replacement of the β-diketone moiety by a mono carbonyl group led to the discovery of the 1,5-diaryl-3-oxo-1,4- pentadienyl pharmacophore which was found to be metabolically stable and demonstrate high cytotoxic potencies. This class of compounds which possesses multiple alkylating sites are referred to as thiol alkylators based on their ability to interact preferentially with the thiol groups of macromolecules compared to the hydroxy and amino groups present in nucleic acids. The ability of this class of compounds to target multiple biochemical pathways has been considered to be an advantage to overcome multidrug resistance that is shown by many tumours to current anticancer drugs. My current work in this report focuses on the development of novel curcuminoid analogs possessing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore as potent cytotoxic agents with the aspiration of identifying some lead molecules which can further be developed as anticancer drug candidates. In particular, the synthesis of novel curcuminoids based on the 3,5-bis(arylidene)-4-piperidone nucleus is pursued. One of the main objectives was to produce novel cytotoxins which will display selective toxicity towards malignant cells compared to normal cells. In order to obtain tumour-selective cytotoxins, the design of molecules was based on a theory of sequential cytotoxicity which states that an initial chemical attack on cellular constituents followed by a second chemical attack will cause more damaging effects in cancer cells than normal cells. The sequential alkylation reaction was proposed to take place on both of the olefinic carbon atoms of the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore in the molecules at the primary binding site whereas the other part of the molecule would interact at an auxiliary binding site which may confer preferential toxicity to tumours. Efforts have been made to improve the physicochemical properties of the molecules by introducing hydrophilic groups such as phosphates onto the molecules. Bioevaluations of the novel molecules disclosed in the thesis revealed that many of these compounds display potent cytotoxic properties towards a wide range of neoplastic and transformed cells and show greater cytotoxic potencies to neoplasms than normal cells. Most of the molecules demonstrated higher cytotoxic potencies and greater tumour selectivity than melphalan, a reference alkylating anticancer drug. In general, increasing the number of thiol alkylating sites in the molecule has increased cytotoxic potencies and selective toxicities to tumours compared to normal cells. One of the major challenges in cancer treatment is the resistance shown by tumors towards a number of chemotherapeutic agents. The molecules designed in this report are chemically and structurally divergent from established anticancer drugs; therefore they are expected to display different modes of action and may be able to overcome drug resistance shown by tumours to contemporary anticancer agents. The ability of novel cytotoxic agents to modulate P-glycoprotein mediated drug resistance, a major form of drug resistance in cancers, was verified in a neoplastic cell transfected with the mdr1 gene. A number of molecules demonstrate remarkable multidrug resistance reversal properties in a neoplastic cell line and the aspiration is that one or more molecules can be developed as a potent multidrug resistance modulator. A striking feature of many of these curcuminoids is that using a dose level up to and including 300 mg/kg is well tolerated in mice and displays no significant toxicities. The modes of action of a number of representative potent cytotoxic molecules were evaluated which include apoptosis, caspase-3 activation, DNA fragmentation, PARP cleavage and cell cycle arrest. The mitochondrion is emerging as a potential target for anticancer agents and to evaluate this possibility, the effect of a number of potent cytotoxins on mitochondrial functions was verified. The compounds affected respiration and caused swelling in mitochondria. Some guidelines for future development of these molecules are suggested. It is hoped that this eulogy of the importance of the conjugated dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins

Preparation of magnesium aluminate spinel by auto combustion route using glycine as fuel and densification study with Cr2O3 addition

The present work deals with the processing and sintering of phase pure Mag–Al spinel by auto-combustion process by using glycine as fuel. Magnesium and aluminium nitrates have been used as the oxidizers and glycine as the fuel. Addition of glycine to the mixture of magnesium and aluminium nitrates results in a series of redox reactions to form a complex which subsequently crystallizes to form spinel at a lower temperature. Mag-Al spinel has been synthesized by varying metal to glycine ratio as 1:2, 1:2.22 and 1:2.5. Variation of Calcination temperature was done from 600 ̊C to 800 ̊C for 2 hours soaking and their XRD analysis were performed to identify the exact starting temperature for obtaining definite phase for pure spinel. The phase pure Mag-Al spinel was formed at 700 °C, for all the composition.Cr2O3 is added to the spinel and densification effect was studied. The effect is highest in the Composition 3 that is metal to glycine ratio 1: 2.5. The highest Bulk density was achieved is 3.52 that is for composition 3. Apparent porosity and shrinkage value was also calculated

EVALUATION OF ANTIBACTERIAL AND HAEMOLYTIC ACTIVITY OF PHYTOCHEMICALS FROM FRESHWATER MICROALGA, EUGLENA VIRIDIS (EHREN)

Objective: The main aim of this research work was to evaluate the antibacterial and haemolytic activities of different extracts of Euglena viridis (E. viridis), a freshwater microalga.Methods: The solvent extraction has been followed by a preliminary screening of phytochemicals. The ethanolic extract, Eu(EtOH) was chromatographed on a silica gel column. The column was eluted with hexane and then with ethyl acetate/hexane mixtures of increasing polarity, 16 fractions (Ef1-Ef16) were collected and grouped according to their TLC (Thin layer chromatography). Antibacterial activities of different fractions of E. viridis against Pseudomonas putida (P. putida) ATCC49828, P. aeruginosa MTCC 35672, Aeromonas hydrophila (A. hydrophila) MTCC 646, ATCC 49140, eleven strains of Staphylococcus aureus (S. aureus) and thirteen strains of Flavobacterium columnare (F. columnare) was done using disc diffusion methods. Haemolytic activity was carried out by using blood agar plate method. The MIC (Minimum inhibitory concentration) values of active fractions were determined by the broth dilution method.Results: The results showed that the Eu(EtOH) poses significantly (p≤0.5) higher zone of inhibition (14.0±0.28, 13.5±0.28 mm) against FLV8 and FLV9 respectively. Three strains of Flavobacterium (FLV5, FLV6 and FLV10) were highly sensitive (zone size, 17 mm, 17.5 mm) towards 30% EA: Hex chromatographic eluents (Ef11) with lowest MIC values, e. i 60 µg and 30 µg respectively. Two chromatographic fractions, Ef11 and Ef13 were highly effective (zone size, 14.5 mm and 13.5 mm) against S. aureus (SA5) with lowest MIC value (60µg). Haemolytic activities of all the algal extracts were noticed that both Eu(EtOH) and methanolic extract, Eu(MeOH) of Euglena gives negative results.Conclusion: These findings suggest that the extract obtained from E. viridis have active substances contributing to the increasing antibacterial potential

Pleomorphic hyalinizing angiectatic tumor of the mesorectum: a rare case and review of literature

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare tumor of uncertain tissue origin. Although it has been classified as a benign tumor under the WHO classification, it is locally aggressive, and multiple recurrences have been reported. PHAT commonly involves the lower extremities; however, various unusual sites of origin have been reported. We present the case of a 30-year-old female with dysmenorrhea, who presented a presacral mass on imaging. The core biopsy confirmed the diagnosis of PHAT. She underwent laparotomy and excision. Histopathology confirmed the presence of a tumor comprised of aggregates of ectatic vessels with perivascular hyalinization. An immunohistochemical study showed diffuse CD34 positivity, but S100, MDM2, and smooth muscle actin negativity. After surgical procedures, the patient is disease free as at the 12-month follow-up. Only 120 cases have been published in the English literature to date. Our study is only the third case of PHAT arising from the pelvis to be reported. Though considered to be a rare condition, the diagnosis of PHAT should always be considered in the differential diagnosis of well-defined hypervascular soft tissue mass in the pelvis. The typical histopathological findings along with immunohistochemistry should clinch the diagnosis

Evaluation of the New Fluorescent Internal Tag (Soft Visible Implant Alphanumeric Tag) in the Freshwater Prawn, Macrobrachium rosenbergii

The new version of the polyester visible implant alphanumeric tag (VI Alpha tag; Northwest Marine Technology Inc., Shaw Island, Washington, USA) was evaluated in the giant river prawn (Macrobrachium rosenbergii) under laboratory conditions. The new VI Alpha tag is soft and fluorescent with an alphanumeric code designed to identify individual specimens. Two tag sizes - standard (1.0 x 2.5 mm) and large (1.5 x 3.5 mm) - were tested on juve- niles (standard size), subadults (standard size), and adults (large size) for 10 weeks. Retention, readability, and effects on growth and survival were evaluated. Final mean tag retention was 71.25±3.3% in juvenile prawns, 91.3%±2.73 in subadult prawns, and 59.0%±1.65 in adult prawns. Final tag readability was 100.0% in juveniles, 88.6±5.3 in subadults, and 77.8±4.8 in adults. Average daily growth (mg/day) and SGR (%/day) of tagged juvenile prawns (22.4±0.23 and 0.81±0.02, respectively) did not significantly differ (p>0.05) from that of the untagged control (20.5±1.47 and 0.83±0.04). Similar results were observed in subadult and adult M. rosenbergii. Mean final survival did not significantly differ (p>0.05) between tagged and untagged prawns. Results indicate that tagging M. rosenbergii with VI Alpha tags has no adverse effect on survival or growth and can therefore be effec- tively used to identify individuals in selective breeding programs

Protective Effects of <i>Chlorella vulgaris</i> Supplemented Diet on Antibacterial Activity and Immune Responses in Rohu Fingerlings, <i>Labeo rohita</i> (Hamilton), Subjected to <i>Aeromonas hydrophila</i> Infection

The current study focuses on the antibacterial activity and potential efficiency of dietary supplements of Chlorella vulgaris on the immune response, improved growth performance, and disease resistance of Labeo rohita fingerlings against Aeromonas hydrophila infection. Crude ethanolic extract of Chlorella and partially purified fractions of the extract were tested against two selected fish pathogens using the disc diffusion method. A total number of 360 rohu fingerlings (25 ± 2 g) were allocated to 4 treatments for 90 days. They were fed with an experimental diet containing Chlorella powder (0, 0.1, 0.5, and 1.0 g Kg−1 of a basic diet). To evaluate the non-specific immunity parameters including serum bactericidal, lysozyme activity, superoxide anion production, and biochemical and haematological indices, the fish were sampled at day 30, 60, 90, and after bacterial challenge. Mortalities of the fish were observed over 10 days post challenge with A. hydrophila. The protein and globulin levels of the treatment group were significantly higher after being treated with Chlorella than those of the control group. The total blood-cell count and haemoglobin content were also increased in the algal-diet-treated group. Among all the experimental diets, the 0.5 g Kg−1Chlorella fed group of fish showed significantly (p −1 diet fed group on day 30. The Chlorella treated group exhibited a better growth performance of the fish. The maximum survivability (86.5%) was recorded in the 1.0 g Kg−1 diet fed group at the end of the 10-day fish exposure to A. hydrophila. These results suggest that the optimum dietary Chlorella supplementation could be 0.5–1.0 g Kg−1 of the diet, which stimulates immunity and protects L. rohita from A. hydrophila infection

Effect of KNbO3 modification on structural, electrical and magnetic properties of BiFeO3

The polycrystalline samples of (Bi1-x K (x) ) (Fe1-x Nb (x) ) O-3 (BKFN) for x = 0.0, 0.1, 0.2 and 0.3 were synthesized by a solid-state reaction method. The X-ray diffraction patterns of BKFN exhibit that the addition of KNbO3 in BiFeO3 gradually changes its structure from rhombohedral to pseudocubic. The analysis of scanning electron micrograph clearly showed that the sintered samples have well-defined and uniformly distributed grains. Addition of KNbO3 to BiFeO3 enhances the dielectric, ferroelectric and ferromagnetic properties of BiFeO3. Detailed studies of impedance and related parameters of BKFN using the complex impedance spectroscopic technique exhibit the significant contributions of grain and grain boundaries in the resistive and transport properties of the materials. Some oxygen vacancies created in the ceramic samples during high-temperature processing play an important role in the conduction mechanism. The leakage current or tangent loss of BiFeO3 is greatly reduced on addition of KNbO3 to the parent compound BiFeO3. Preliminary studies of ferroelectric and magnetic characteristics of the samples reveal the existence of ferroelectric, and weak ferromagnetic ordered ceramics