The regulation of αvβ6-dependent functions in carcinoma cell migration

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Dimethylammonium 5,5-dimethyl-3-oxo-2-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)cyclohex-1-enolate 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione n-hexane hemisolvate monohydrate

The main molecule of the title compound, C2H8N+·C25H31O5−·C25H32O5·0.5C6H14·H2O, exists as two crystallographically independent molecules, the hydroxy group of one being deprotonated. The pyran rings of both independent units adopt boat conformations. One of the two cyclohexene rings of the xanthene unit adopts an envelope conformation whereas the other is in a half-chair conformation. The cyclohexene ring attached to the xanthene unit adopts an envelope conformation. The n-hexane solvent molecule is disordered about a crystallographic glide plane and the symmetry-independent components are again disordered over two positions, each with an occupancy of 0.25. In the crystal structure, the xanthene derivatives are linked by O—H...O, N—H...O and C—H...O hydrogen bonds, forming a three-dimensional network with channels along the a axis. The dimethylammonium cations and water molecules lie in small channels and are linked to the framework via O—H.·O and N—H...O hydrogen bonds. The n-hexane solvent molecules occupy large channels

Synthesis, molecular docking and antiproliferative activity of upper rim modified Azo Calix[4]arene derivatives

Azo derivatives of calixarenes are mostly reported for the extraction of transition metal ions and as switchable receptors or sensors for Na+ and K+ ions to mimic the biological Na+/K+ ion pump. Only a few reports describe the drug-like potential of azo calixarenes. The current work is an attempt to explore the anticancer potential of three upper rims modifed azo derivatives of calix[4]arene. Sulfaguanidine (SGC), sulfanilamide (SCM), and 4-amino-2-methylbenzoic acid (COX) groups were linked with calix[4]arene via azo linkage and their antiproliferative efect was evaluated against breast (MCF7 and MDA-MB-231), colon (HCT-116), and lung (A549) cancer cell lines using MTT assay. SGC showed antiproliferative efect on MCF7 and MDA-MB-231 breast cancer cells with IC50 values of 32.2 and 27.3 µM, respectively. SCM exerted an antiproliferative activity against MCF7, MDA-MB-231, and HCT-116 cells with IC50 values of 31.8, 50.1, and 28.03 µM, respectively, while COX did not show an antiproliferative efect against all the tested cell lines. The compounds were docked against Cyclin-Dependent Kinase-2 (CDK2) receptor (PDB ID 1FVT) for their possible interactions followed by in vitro analysis by MTT assay. CDK2 was selected as the target enzyme because of the structural similarities of the synthesized compounds with previously reported CDK2 potential inhibitors. The docking results supported the in vitro results for the two compounds. A proposed scheme for using the azo derivatives of calix[4]arene as prodrugs is suggested for further investigation

Design and synthesis of 1-sec/tert-Butyl-2-Chloro/Nitrophenylbenzimidazole derivatives: molecular docking and in vitro evaluation against MDA-MB-231 and MCF-7 cell lines

Breast cancer is the most common type of cancer among women and the increasing cases of drug resistance pose a great challenge in the development of new anticancer drugs. Benzimidazole derivatives containing various functional groups have been reported to exhibit excellent anticancer activity. Previous studies revealed that some of the synthesized 2‑chloro/nitrophenylbenzimidazole derivatives showed unexpected selective inhibition towards MDA-MB-231. In continuing efforts toward the development of a more selective anticancer drug, two series of N-sec and tert-butyl-2-phenylbenzimidazoles were designed and synthesized by substitution of chloro‑ and nitro- groups at various positions of the phenyl group. The derivatives were characterized by 1H NMR, 13C NMR, and mass spectrometry. The antiproliferative activity of the synthesized compounds was evaluated against MDA-MB-231 and MCF-7. In both cell lines, chloro‑substituted benzimidazoles generally showed better inhibitory effect compared to those with nitro-substituent. The most potent compound was 4b3 (IC50 = 54.62 µM for MCF-7), and the most potent derivative on MDA-MB-231 cells was 4a7 (IC50 = 62.3 µM). ortho-Chloro-substituted derivatives 4a7 and 4b1 exhibited good selectivity towards MDA-MB-231 cells, although the additional chloro‑substituent and the presence of the less bulky sec-butyl group in 4a7 slightly increased its selectivity. Benzimidazoles 4b6, 4b8, 4b9, and 4b10 were found to show selectivity towards the estrogen receptor-positive cell line, MCF-7, and inactive against the MDA-MB-231 cell line. Molecular dockings of 4a7 and 4b3 in the Epidermal Growth Factor Receptor (EGFR) (PDB ID: 1M17) active sites showed similar binding poses, while gefitinib bound slightly further inside the binding sites

Comparative proteomic analysis of different stages of breast cancer tissues using ultra high performance liquid chromatography tandem mass spectrometer.

BACKGROUND:Breast cancer is the fifth most prevalent cause of death among women worldwide. It is also one of the most common types of cancer among Malaysian women. This study aimed to characterize and differentiate the proteomics profiles of different stages of breast cancer and its matched adjacent normal tissues in Malaysian breast cancer patients. Also, this study aimed to construct a pertinent protein pathway involved in each stage of cancer. METHODS:In total, 80 samples of tumor and matched adjacent normal tissues were collected from breast cancer patients at Seberang Jaya Hospital (SJH) and Kepala Batas Hospital (KBH), both in Penang, Malaysia. The protein expression profiles of breast cancer and normal tissues were mapped by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The Gel-Eluted Liquid Fractionation Entrapment Electrophoresis (GELFREE) Technology System was used for the separation and fractionation of extracted proteins, which also were analyzed to maximize protein detection. The protein fractions were then analyzed by tandem mass spectrometry (LC-MS/MS) analysis using LC/MS LTQ-Orbitrap Fusion and Elite. This study identified the proteins contained within the tissue samples using de novo sequencing and database matching via PEAKS software. We performed two different pathway analyses, DAVID and STRING, in the sets of proteins from stage 2 and stage 3 breast cancer samples. The lists of molecules were generated by the REACTOME-FI plugin, part of the CYTOSCAPE tool, and linker nodes were added in order to generate a connected network. Then, pathway enrichment was obtained, and a graphical model was created to depict the participation of the input proteins as well as the linker nodes. RESULTS:This study identified 12 proteins that were detected in stage 2 tumor tissues, and 17 proteins that were detected in stage 3 tumor tissues, related to their normal counterparts. It also identified some proteins that were present in stage 2 but not stage 3 and vice versa. Based on these results, this study clarified unique proteins pathways involved in carcinogenesis within stage 2 and stage 3 breast cancers. CONCLUSIONS:This study provided some useful insights about the proteins associated with breast cancer carcinogenesis and could establish an important foundation for future cancer-related discoveries using differential proteomics profiling. Beyond protein identification, this study considered the interaction, function, network, signaling pathway, and protein pathway involved in each profile. These results suggest that knowledge of protein expression, especially in stage 2 and stage 3 breast cancer, can provide important clues that may enable the discovery of novel biomarkers in carcinogenesis

Microwave-assisted synthesis of sec/tert-butyl 2-arylbenzimidazoles and their unexpected antiproliferative activity towards ER negative breast cancer cells

A new series of N-sec/tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85–96% yields within 2–3.5 min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using 1H NMR, 13C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a