Nitasha Suri

Pharmacophore, QSAR, and ADME based semisynthesis and in vitro evaluation of ursolic acid analogs for anticancer activity

In the present work, QSAR models for predicting the activities of ursolic acid analogs against human lung (A-549) and CNS (SF-295) cancer cell lines were developed by a forward stepwise multiple linear regression method using a leave-one-out approach. The regression coefficient (r2) and the cross-validation regression coefficient (rCV2) of the QSAR model for cytotoxic activity against the human lung cancer cell line (A-549) were 0.85 and 0.80, respectively. The QSAR study indicated that the LUMO energy, ring count, and solvent-accessible surface area were strongly correlated with anticancer activity. Similarly, the QSAR model for cytotoxic activity against the human CNS cancer cell line (SF-295) also showed a high correlation (r2 = 0.99 and rCV2 = 0.96), and indicated that dipole vector and solvent-accessible surface area were strongly correlated with activity. Ursolic acid analogs that were predicted to be active against these cancer cell lines by the QSAR models were semisynthesized and characterized on the basis of their 1H and 13C NMR spectroscopic data, and were then tested in vitro against the human lung (A-549) and CNS (SF-295) cancer cell lines. The experimental results obtained agreed well with the predicted values.

2-Anilinonicotinyl linked 2-aminobenzothiazoles and [1,2,4]triazolo[1,5-b] [1,2,4]benzothiadiazine conjugates as potential mitochondrial apoptotic inducers

A series of N-(2-anilino-pyridyl) linked 2-amino benzothiazoles (4a-n) and [1,2,4]triazolo [1,5-b]benzothiadiazine conjugates (5a-j) have been designed, synthesized and evaluated for their antiproliferative activity. Some of these compounds (4h-k, 4n, and 5e) have exhibited potent cytotoxicity specifically against human leukemia HL-60 cell lines with IC(50) values in the range of 0.08-0.70 μM. All these compounds were tested for their effects on the cell cycle perturbations and induction of apoptosis. Morphological evidences of apoptosis, including fragmentation of nuclei and inter nucleosomal DNA laddering formation were clearly observed after 24h exposure to compound 4i. Flow cytometry analysis revealed that compound 4i showed drastic cell cycle perturbations due to concentration dependant increase in the sub-G0 region which comprises of both the apoptotic and debris fraction, thus implying the extent of cell death. These compounds trigger the mitochondrial apoptotic pathway that results in the loss of mitochondrial membrane potential through activation of multiple caspases followed by activation of caspase-3, and finally cleavage of PARP. Further the mechanism of cell death was analysed by fluorescent microscopic analysis and also by scanning electron microscopy. The cytotoxicity of 4i correlated with induction of apoptosis, caspases activation and DNA damage and thus indicating the apoptotic pathway of anticancer effect of these compounds.

Sphaeranthus indicus Induces Apoptosis Through Mitochondrial-Dependent Pathway in HL-60 Cells and Exerts Cytotoxic Potential on Several Human Cancer Cell Lines

Purpose. The study was designed to screen Sphaeranthus indicus, Ganoderma lucidum, and Urtica dioica for their anticancer activity against human cancer cell lines. Phytochemical screening of active extracts was also planned. Methods. Petroleum ether, ethanolic, and aqueous extracts of S indicus Linn, G lucidum P Karst, and U dioica Linn were subjected to cytotoxicity studies using 7 different cancer cell lines. Potent cytotoxicity was noted in petroleum ether extract of S indicus (SIP), which inhibited proliferation of various cancer cell lines. Growth inhibition was determined by sulforhodamine B assay. Two biochemical markers, namely β-sitosterol and 7-hydroxyfrullanolide were isolated and characterized using high-performance thin layer chromatography, melting point, Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass analysis. Cytotoxicity of isolated β-sitosterol and 7-hydroxyfrullanolide were also determined. The IC50 of SIP was calculated in the HL-60 cells and was found to be 53 µg/mL. Furthermore, SIP induced apoptosis in human leukemia HL-60 cells as measured by several biological end points. Cell cycle analysis and change in mitochondrial membrane potential was quantified by flow cytometry. Subsequently, using annexin V/PI assay, proportion of cells actively undergoing apoptosis was determined. Changes in DNA were observed by DNA ladder assay. Results. SIP induced apoptotic bodies formation, induced DNA laddering, enhanced annexin-V-FITC binding of the cells, increased sub-G0 DNA fraction, and induced loss of mitochondrial membrane potential (ΔΨm) in HL-60 cells. SIP also elevated the caspase 3 and caspase 9 levels in the HL-60 cells, which clearly indicates the involvement of the intrinsic proteins in inducing apoptosis. Discussion. All the above parameters revealed that SIP induced apoptosis through the mitochondrial-dependent pathway in HL-60 cells. The criterion for anticancer activity in cytotoxicity assay was ≥70% growth inhibition at 100 µg/mL against at least 4 cell lines. As G lucidum and U dioica did not exhibit appreciable inhibitory activity against human cancer cell lines (less than 50%), they were not included in the study thereafter. The results established that SIP has apoptosis-inducing effect against HL-60 cells in vitro and is a promising candidate for further anticancer study. β-Sitosterol and 7-hydroxyfrullanolide can be considered to be potent anticancer compounds isolated from SIP on the basis of present studies.

Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashira cross-coupling reaction.

A series of C-10 acetal artemisinin dimers were synthesized using Sonogashira cross-coupling reaction. All these novel semisynthetic artemisinin dimers exhibited excellent growth inhibitory activity against Lung A-549 human cancer cell line.

Tool life and surface integrity issues in continuous and interrupted finish hard turning with coated carbide and CBN tools

In this paper, turning experiments on hardened steel were carried out with three kinds of cylindrical workpiece surfaces – continuous, interrupted, and fully interrupted – using coated carbide and cubic boron nitride (CBN) tools. The objective of this work was to investigate the conditions under which coated carbide tools give optimum results in terms of both tool life and surface integrity of the machined surface in comparison to costly CBN tools. The turning performance was evaluated in terms of maximum flank wear of the inserts and issues related to surface integrity like white layer formation, microhardness variation, residual stress generated, and surface roughness of the machined surface. The results indicated that the longest tool life was achieved with CBN tools, but the accumulated machining time of all the four cutting edges in coated carbide tools was comparable to that of CBN. The surface integrity achieved with carbide tools was also comparable to that achieved with CBN. The performance of carbide tools deteriorated at higher cutting speeds. The surface roughness value with all inserts under all cutting conditions was below 1.6 µm. The thickness of the white layer only varied from 0.4 to 1 µm, and no white layer was observed with interrupted and fully interrupted surfaces. Compressive residual stress was observed on the machined surface with a selected tool life criterion.

Synthesis and in vitro anticancer activity of brevifoliol derivatives substantiated by in silico approach

Five novel derivatives 1a, 1b, 1c, 2 and 3 of brevifoliol were synthesized. The structures of all the synthesized derivatives were established on the basis of IR, 1H NMR, 13C NMR and mass spectral data. All the five derivatives were tested for in vitro cytotoxicity against four human cancer cell lines. The result showed that compound 1a, 1b and 1c exhibited significant inhibition of cell growth. The mechanism of action of novel glucosidated derivatives have been explored by in silico molecular docking for anticancer activity against human lung, prostate and cervix cancer cell lines. Based on reported experimental activities on human cancer cell lines, specific molecular targets (e.g. microtubule in case of human lung cancer cell line A-549; indoleamine 2,3-dioxygenase in case of prostate cancer cell lines PC-3 and DU-145 and uridine phosphorylase 1 in case of Hela cell line) have been selected for docking studies and successfully validated for anticancer activity of brevifoliol derivatives.

Discovery of novel small molecule EGFR inhibitory leads by structure and ligand-based virtual screening

In modern drug discovery, virtual screening is an attractive and cost-effective approach, which is widely applied to filter chemical compound libraries for the identification of novel inhibitors. Epidermal growth factor receptor protein is a well reported anticancer molecular target due to its over expression and mutation in many solid tumours. The decline in epidermal growth factor receptor activity by small molecules has proved to be an effective treatment for cancer. To design inhibitors for this target, the crystal structures information of epidermal growth factor receptors, co-crystallized with its inhibitors, provide a gateway to perform receptor-based drug designing studies, whereas the inhibitors with their biological activity reported in literature provide information to carry out ligand-based drug designing studies. In the present study, the drug designing methods were strategically combined and used parallely on a library of 50,000 drug-like compounds from ChemDiv and ChemBridge database, for the selection of potential inhibitors of epidermal growth factor receptor. This resulted in the identification of 200 common hits, which were further pruned down to 87, based on the knowledge about the key interaction of known epidermal growth factor receptor inhibitors with Met793. These 87 hits were clustered into 12 different structural moieties. In vitro studies of some of these hits were also carried out in order to validate the screening approach. Further, the lead optimization studies were performed by analyzing the binding poses of all the identified structural moieties in order to ascertain the scope of modifications around these moieties. Molecular dynamics simulation studies further revealed some important residues of the target which may be helpful for providing stability to the enzyme-inhibitor complex. These findings could be very much helpful for a medicinal chemist to design a novel potent inhibitor of epidermal growth factor receptor.

Surface integrity a key issue in hard turning – a review

Hard turning is an attractive alternative to grinding for steel parts, which are often loaded to their physical limits. But in comparison to grinding, the issue of surface integrity in hard turning is not yet clearly established in context of its adaptability for industrial use. This paper presents a survey of recent research progress in regard of surface integrity issues related to hard turning of hardened steel. A significant pool of hard turning studies has been surveyed in an attempt to achieve better understanding of surface issues, i.e., surface roughness, residual stress, white layer formation and microhardness variations. Further important modelling techniques based on finite element, soft computing and other mathematical approaches used in hard turning are reviewed.

Synthesis and anticancer activities of new Benzothiadiazinyl Hydrazinecarboxamides and Anilino[1,2,4]triazolo[1,5-b][1,2,4]thiadiazine 5,5-diones.

Two series of compounds (5-14 and 15-23) based on the scaffolds of 2-(1,1-dioxido-4-phenyl-4Hbenzo[e][1,2,4]thiadiazin-3-yl)-N-(4-methoxyphenyl)hydrazinecarboxamide (5) and 2-((4-methoxyphenyl)amino)-10-phenyl-10H-benzo[e][1,2,4]triazolo[1,5-b][1,2,4]thiadiazine 5,5-dioxide (15) respectively, were designed and synthesized. These compounds were tested for anticancer activity against various cancer cell lines including lung, ovary, prostate, breast and colon cancers. They exhibited moderate to good inhibitory activity against the above cell lines and compound 9 was found to be the most active one from these two series. Further studies showed that cancer cell growth inhibition by compounds 22 and 23 could be in part due to the inhibition of tubulin polymerization, with the IC50 values of 4.70 and 5.25 µM, respectively.