ABSTRACT
Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1mg/kg five times every other 2days.
Subject(s)
Antineoplastic Agents/pharmacology , DNA-Binding Proteins/metabolism , Mediator Complex/metabolism , Proto-Oncogene Proteins/metabolism , Receptor, ErbB-2/metabolism , Transcription Factors/metabolism , Xanthones/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Breast Neoplasms/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Female , HEK293 Cells , Humans , Mice , Mice, Nude , Mitogen-Activated Protein Kinases/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Proto-Oncogene Proteins c-ets , Signal Transduction , Tamoxifen/pharmacology , Tumor Burden/drug effects , Xanthones/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
On April 26, 2012, the Korea National Institute of Health officially held the opening ceremony of newly dedicated biobank building, 'NationalBiobank of Korea'. The stocked biospecimens and related information have been distributed for medical and public health researches. The Korea Biobank Project, which was initiated in 2008, constructed the Korea Biobank Network consisting of the National Biobank of Korea (NBK) with 17 regional biobanks in Korea. As of December 2011, a total of 525,416 biospecimens with related information have been secured: 325,952 biospecimens from the general population obtained through cohort studies and 199,464 biospecimens of patients from regional biobanks. A large scale genomic study, Korea Association Resource (KARE) and many researches utilized the biospecimens secured through Korea Genome Epidemiology Study (KoGES) and Korea Biobank Project (KBP). Construction of 'National Biobank of Korea', a dedicated biobank building at Osong means that NBK can manage and check quality of the biospecimens with promising distribution of 26 million vials of biospecimen, which provide the infrastructure for the development of health technology in Korea. The NBK and the National Library of Medicine (to be constructed in 2014) will play a central role in future biomedical research in Korea.
ABSTRACT
We have recently constructed a phenomenological theory that provides a unified explanation for athermal and isothermal martensitic transformation processes. On the basis of this theory, we predict some properties of martensitic transformation and confirm them experimentally using some Fe-based alloys and a Ni-Co-Mn-In magnetic shape memory alloy.
ABSTRACT
In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC(50): 0.49 ± 0.21 µM) and HCT15 (IC(50): 0.23 ± 0.02 µM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 µM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function.
Subject(s)
Antineoplastic Agents/chemical synthesis , Chalcone/chemistry , Chalcones/chemical synthesis , DNA Topoisomerases, Type II/chemistry , Sulfides/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Chalcone/chemical synthesis , Chalcone/toxicity , Chalcones/chemistry , Chalcones/toxicity , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Drug Screening Assays, Antitumor , Humans , Sulfides/chemistry , Sulfides/toxicity , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/toxicityABSTRACT
A series of benzo-annulated rutaecarpines were prepared from anthranilic acid and 3-aminonaphthalene-2-carboxylic acid by Fischer indole synthesis as key reaction. Cytotoxicity was somewhat increased by the introduction of benzo-annulation, which was not directly related to the inhibitory activity against topoisomerases (topo) I and II. Benzo-annulation on ring A led to significant increase of inhibitory activity against topo II while annulations on ring E increased inhibitory activity against topo I.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacology , Plant Extracts/chemical synthesis , Plant Extracts/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Rutaceae/chemistry , Antineoplastic Agents, Phytogenic/therapeutic use , Cell Line, Tumor , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Drug Screening Assays, Antitumor , Humans , Indole Alkaloids/therapeutic use , Neoplasms/drug therapy , Phytotherapy , Plant Extracts/therapeutic use , Quinazolines/therapeutic use , Structure-Activity RelationshipABSTRACT
In order to develop potential anti-cancer agents that act on topoisomerase II and DNA, we have synthesized 12 new xanthone derivatives. In the cytotoxicity test, compounds 17 and 31 exhibited 2- to 7-fold stronger inhibitory activity than adriamycin against most cancer cell lines tested. Halohydrin group-tethered compounds 19, 21 and 27 showed comparable topoisomerase II inhibitory activity to etoposide at 100 microM concentration. In the DNA cross-linking test, compounds 20, 30 and 31 produced DNA cross-linked adducts and compound 30 was the strongest DNA cross-linker. Based on the combined pharmacological results, we suspected that the strong anti-cancer activity of compounds 16, 17, 20, 30 and 31 originated from the DNA mono-alkylation or cross-linking properties of the compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Xanthones/chemical synthesis , Xanthones/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/metabolism , Cross-Linking Reagents/pharmacology , DNA/chemistry , DNA/metabolism , DNA Topoisomerases, Type II/metabolism , Humans , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology , Xanthones/chemistry , Xanthones/metabolismABSTRACT
A new series of 2,4-diphenyl-6-aryl pyridines containing hydroxyl group(s) at the ortho, meta, or para position of the phenyl ring were synthesized, and evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Structure-activity relationship study revealed that the substitution of hydroxyl group(s) increased topoisomerase I and II inhibitory activity in the order of meta > para > ortho position. Substitution of hydroxyl group on the para position showed better cytotoxicity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacology , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyridines/chemistryABSTRACT
A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10-19 showed moderate topoisomerase I and II inhibitory activity and 20-29 showed significant topoisomerase II inhibitory activity. Structure-activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important role in displaying topoisomerase II inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Designed and synthesized 60 2-thienyl-4-furyl-6-aryl pyridine derivatives were evaluated for their topoisomerase I and II inhibitory activities at 20 microM and 100 microM and cytotoxicity against several human cancer cell lines. Compounds 8, 9, 11-29 showed significant topoisomerase II inhibitory activity and compounds 10 and 11 showed significant topoisomerase I inhibitory activity. Most of the compounds (7-21) possessing 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety showed higher or similar cytotoxicity against HCT15 cell line as compared to standards. Most of the selected compounds displayed moderate cytotoxicity against MCF-7, HeLa, DU145, and K562 cell lines. Structure-activity relationship study revealed that 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety has an important role in displaying biological activities.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Neoplasms/drug therapy , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Microstructures and deformation behaviour of Ti-45Ni-5Cu and Ti-46Ni-5Cu alloy ribbons prepared by melt spinning were investigated by transmission electron microscopy, thermal cycling tests under constant load and tensile tests. Spherical Ti2Ni particles coherent with the B2 parent phase were observed in the alloy ribbons when the melt spinning temperature was higher than 1773 K. Average size of Ti2Ni particles in the ribbons obtained at 1873 K was 8 nm, which was smaller than that (10 nm) in the ribbons obtained at 1773 K. Volume fraction of Ti2Ni phase in the ribbons obtained at 1873 K was 40%, which was larger than that (20%) in the ribbons obtained at 1773 K. The stress required at temperatures of Af + 10 K for the stress-induced martensitic transformation increased from 93 MPa to 229 MPa and apparent elastic modulus of the B2 parent phase increased from 56 GPa to 250 GPa with increasing the melt spinning temperature from 1673 K to 1873 K in Ti-45Ni-5Cu alloy ribbons. The critical stress for slip deformation of the ribbons increased by coherent Ti2Ni particles, and thus residual elongation did not occur even at 160 MPa, while considerable plastic deformation occurred at 60 MPa in the ribbons without Ti2Ni particles. Almost perfect superelastic recovery was found in the ribbons with coherent Ti2Ni particles, while only partial superelastic recovery was observed in the ribbons without coherent Ti2Ni particles.
