SYNTHESIS, CHARACTERIZATION, AND ANTICANCER ACTIVITY OF SOME NOVEL ACRIDINE DERIVATIVES

Objective: The objective of the study was to synthesize and evaluate the anticancer activity of some novel acridine derivatives. Methods: The present works involve condensation of acridine and various 2, 4-Thiazolidine-2,4-dione derivatives (2a–2h) with chloroacetyl chloride to give a novel acridine derivatives (5a–5l), respectively. Results: All the newly synthesized molecules (5a–5l) were characterized by FTIR, H1-NMR, and mass spectral analysis along with physical data. The biological potentials of the new synthesized compounds are evaluated for their in vitro anticancer activity by MTT assay. Conclusion: The synthesized compounds 5a, 5f, and 5h exhibited good anticancer activity against MCF-7 and SKVO3 cancer cell lines at a concentration of 0.5 mg/mL-1

2,4-SUBSTITUTED QUINAZOLINE AS JAK2 INHIBITOR: DOCKING AND MOLECULAR DYNAMICS STUDY

Objective: The involvement of Janus kinase2/signal transducer and activator of transcription (JAK2/STAT3) pathway reported in various solid tumors made authors study the conformational changes of JAK2-3e complex which was previously reported with a moderate percentage of In-vitro JAK2 inhibition. Methods: In this present study Compound 3e was reported with a moderate percentage of inhibition of JAK2 protein selected for performing molecular docking and molecular dynamics studies to elucidate the conformational changes with JAK2-3e complex. Docking studies were performed using ChemSketch to draw the structure of the compound and optimized/energy minimized using the Ligprep module of Schrodinger suite, employing optimized potentials for liquid simulations (OPLS-2005) force field. Molecular dynamics simulations were performed for 10 ns for complex using TIP4PEW water solvent model and neutralized by adding sodium ions. Results: Docking studies of Compound 3e which has been reported as one of the effective cytotoxic agents and a moderate percentage of In-vitro JAK2 inhibition among the series, showed H-bond interaction with leucine 855, serine936, aspartine994. Dock score and Ligand binding energy with protein suggested compound 3e has shown-4.049,-66.003 kcal/mol respectively. Molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition. The Root means square deviation (RMSD) pattern of both protein and ligands in the JAK2-3e complex observed to be different over 10 ns simulation. In the JAK2-3e complex, an exponential increase in RMSD of Cα and side-chain amino acids is observed during the first 1-3 ns simulation and is stabilized till 10 ns. During the 10 ns simulation, ligand 3e seems to be stable in the complex with an overall deviation<1 Å, despite a drastic increase between 1-3 ns. The ligand RMSD plot suggests that the ligand 3e remained intact within the binding site of the protein and longer time period simulation may elucidate the binding pattern and fate of ligand 3e. Conclusion: Results from molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition by 2, 4 disubstituted quinazoline compound that is N’(2-(4-nitrophenyl)quinazoline-4-yl) isonicotinohydrazide) and their binding phenomenon. Molecular docking studies further supported the elucidation of binding patterns of the molecules in the JAK-2 protein environment. Further simulations with a longer time period may provide deeper insights into ligand interactions in the protein environment. It is noteworthy to use compound 3e as a new scaffold for further development of multifunctional compounds

DESIGN SYNTHESIS OF NOVEL ACRIDINE TAGGED PYRAZOLE DERIVATIVES AS AURORA KINASE INHIBITORS

Objective: A series of novel synthesis of 5-Substituted-3-phenyl-4,5-dihydro-pyrazole-1-carbothioic acid [4-(9, 10-dihydro-acridin-9-yl)-phenyl]- amide (IV) were synthesized using standard procedures and evaluated for cytotoxic studies. Methods: 9-(4-Chloro-phenyl)-9 and 10-dihydro-acridine (I) were formed by cyclization of diphenylamine with substituted acids in the prescience of zinc chloride and synthesis of 5-substituted-3-phenyl-4, 5-dihydro-pyrazole-1-carbothioic acid amide (3) by the cyclization of different chalcones (II) and final compounds were synthesized by fusion of 5-substituted-3-phenyl-4, 5-dihydro-pyrazole-1-carbothioic acid amide (III) with 9-(4-Chloro-phenyl)-9, 10-dihydro-acridine (I) by microwave irradiation method. Characterization of synthesized compounds by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectroscopic methods. Obtained compounds were evaluated for their cytotoxicity against human breast cancer cell lines (MCF/wt) by sulforhodamine-B assay. Docking studies with Aurora kinase protein were performed to elucidate the possible mechanistic insights of these novel acridine tagged pyrazole derivatives. Results: Moderate to good in vitro cytotoxic potentials of the newly synthesized molecules was reported against selected human breast cancer cell lines. Among the tested molecules, compound C6 showed good cytotoxic activity against MCF/wt (08.2±0.4 μM). The dock scores of the tested compounds were ranged between −8.926 and −5.139. Compound C6 which has been reported as the most effective cytotoxic agent among the series also reported the highest dock score of -8.926 and showed hydrogen bond interaction with GLU-211, LYS-162, and LYS-143. Ligand binding energy with protein suggested compound C6 has shown the highest binding energy of −86.32133 kcal/mol. Conclusion: The in vitro studies of the newly synthesized acridine tagged pyrazole derivatives reported considerable cytotoxic potentials against human breast cancer cell lines and structure-activity relationship studies to suggest that acridine tagged pyrazole derivatives with hydroxy group present on phenyl ring at fifth position of pyrazole ring could probably increase the cytotoxic potentials. With the reported bioactivities of these derivatives, further studies on the derivatization could elucidate the broader cytotoxic potentials

An Artificial Neural Network (ANN) Model for Predicting Instability Regimes in Copper-Aluminum Alloys

Materials workability is one of the important aspects for any process design to achieve quality products. Identifying optimum process parameters like temperature, strain rate, and strain are normally done by trial and error. In recent years, processing maps are used in choosing these parameters for hot working of materials. Identification of these parameters requires certain high-level expertise as well as detailed microstructural evidences. In this study, using the available copper-aluminum alloy data, an Artificial Neural Network (ANN) model has been developed to classify the hot-working process parameters, like temperature, strain rate, flow stress for instability regime, directly from the corrected flow stress data without applying the Dynamic Materials Model (DMM). This model uses four compositions of Cu-Al system, ranging from 0.5% to 6% Aluminum. Details about the ANN architecture, and the training and testing of these models are explained. The results obtained using the ANN model are compared and validated with those obtained from the processing maps using DMM. It is further shown that even with smaller data set the development of an ANN model is possible as long as the data has some pattern in it

DESIGN AND SYNTHESIS OF NOVEL 2, 3-DISUBSTITUTED QUINAZOLINES: EVALUATION OF IN VITRO ANTICANCER ACTIVITY AND IN SILICO STUDIES

Objective: In this study, a series of novel 2,3-disubstituted quinazolines (4a-4l) were synthesized using standard procedures and elucidated through different spectroscopic techniques. Methods: Obtained compounds were evaluated for their cytotoxicity against human breast cancer (MDA-MB-231) and ovarian cancer (SK-O-V3) cell lines using MTT assay. Docking studies with JAK2 protein were performed to elucidate the possible mechanistic insights into these novel quinazoline derivatives. Results: Moderate-to-good in vitro cytotoxic potentials of the newly synthesized molecules were reported against selected human cancer cell lines. Among the tested molecules, compound 4e showed good cytotoxic activity against MD-AMB-231 (14.2 ± 0.86 μM) and against SK-O-V3 (17.7 ± 0.62 μM). Conclusion: The in vitro studies of the newly synthesized quinazoline derivatives reported considerable cytotoxic potentials against both breast and ovarian cancer cell lines and SAR studies suggest that quinazoline derivatives with heterocyclic benzothiazole nucleus with hydrophilic acetamide linkage at the 3rd position could probably increase the cytotoxic potentials and the presence of chlorine substitution could add more benefit. With the reported bioactivities of these derivatives, further studies on the derivatization could elucidate the broader cytotoxic potentials

Effect of tungsten and zirconium on structure and properties of niobium

The individual and combined effects of W and Zr additions on macrostructure, microstructure and mechanical properties of Nb have been investigated. Nb, Nb-10 wt% W, Nb-2.5 wt% Zr and Nb-10 wt% W-2.5 wt% Zr alloy ingots were prepared by electron beam drip melting using high purity Nb, W and Zr rods. Additions of W and Zr resulted in significant improvement in hardness and room temperature tensile strength. It is seen that the effect of 10 wt% W addition is more than that of 2.5 wt% Zr addition in improving room temperature strength of Nb, although on 'per wt% addition' basis, Zr is a more effective strengthener than W. It is also observed that the cumulative effects of 10 wt% Wand 2.5 wt% Zr on grain refinement and strengthening are more than their respective individual effects

Electro slag crucible melting for recycling of low oxygen high conductivity copper scrap

Recycling of oxygen free high conductivity (OFHC) copper scrap was carried out through a modified electro slag melting technique using a graphite electrode and graphite crucible. Of the three slags used, a cryolite based slag was found to yield copper ingots with low (2 to 40 ppm) oxygen content and high (up to 98% IACS) conductivity. A slag as well as graphite of high purity are essential since the impurities present in the slag and graphite may contaminate the copper during melting. Possible mechanisms of impurity (Fe, Si, Mg, Ca and S) pick-up by copper are discussed. Identical results were obtained using cathode copper instead of OFHC copper scrap indicating that the process may be used to produce low oxygen high conductivity copper ingots directly from cathode copper

Artificial neural network model for predicting stable and unstable regions in Cu-Zn alloys

Processing maps are developed using the Dynamic Materials Model (DMM) and instability criterion, which help in choosing optimum process parameters for hot-working of materials. Certain high-level expertise is required to interpret and extract the information on instability regimes to be avoided during processing. In recent years, Artificial Neural Network (ANN) models have been developed to predict flow stress by using the input vector; namely, temperature, strain rate and strain. In this study, using the available Cu-Zn alloy data, ANN model has been developed to classify the hot-working process parameters, such as temperature, strain rate and flow stress for instability regime, directly from the corrected flow stress data without applying the DMM. This model uses 10 compositions of Cu-Zn system, ranging from 3% Zn to 51% Zn. The developed ANN model has been able to leam the nonlinear classifier, which separates unstable region from the stable region in the Cu-Zn alloy system with zinc content less than 40%

Effect of TiB2 and ZrB2 additions on structure and properties of Fe-7Al based light weight steel

Microstructural modifications and their effect on tensile properties in an Fe-7 wt.% Al alloy by additions of 0.5% TiB2, 0.5% ZrB2 or both has been studied. Alloys are examined in the as-cast as well as in the hot-rolled and annealed conditions. Solidification structure of the Vacuum Arc Remelted pancake ingots was columnar dendritic. Further, boride modified alloys are found to have finer grains in as-cast as well as in hot-rolled and annealed conditions. In the annealed condition, boride containing alloys were found to have superior tensile yield strength, ductility and strain hardening behaviour. These property improvements are attributed to boride aided grain refinement during casting as well as during thermo-mechanical processing of the steels