Triethylated chromones with substituted naphthalenes as tubulin inhibitors

Previously synthesized 2-(benzo[]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (, TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B () showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (–) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound , a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC 0.2–5.7 μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin

Red thermoluminescence of enstatite from the Chainpur meteorite

For most ordinary chondrites feldspar is mainly responsible for thermoluminescence [TL], but in type 3 ordinary chondrites, especially those which are most primitive, other minerals are important. We observed red TL with a ∿660nm spectral peak in an ordinary chondrite, Chainpur (LL3.4). The mineral responsible for the red TL was identified as iron-free enstatite. Spatial distribution of TL and cathodoluminescence [CL] for the same specimen was also investigated, and it was found that the red TL areas corresponded to the high-sensitivity areas of red CL

1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, a novel compound class with potent chemoreversal activity

1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, which share a fragment from (±)-3′-O-4′-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and 3′R,4′R-disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP), exhibited remarkable chemoreversal activity on multi-drug resistant human nasopharyngeal carcinoma (KB) when combined with three anti-cancer drugs, paclitaxel, vincristine and doxorubicin. Among 15 novel synthesized analogs, bis-trimethoxybenzoyl derivative 15 was the most active (340-fold more active than verapamil when used with vincristine) followed by two di-cinnamoyl derivatives, 10 and 11, and then di-cyclohexanecarbonyl derivative 9. All aliphatic chain derivatives, 3–5, showed no activity. Structure-activity relationship study indicated that a di-ester structure was critical to enhance the activity resulting from the maintenance of the spatial arrangement proposed by the pharmacophore based on the verapamil-binding site. Further mechanism of action study showed 15 inhibited mainly P-glycoprotein efflux pump function, while 13 exhibited an additional multidrug resistance-associated protein efflux pump function

Acetophenone Monomers from Acronychia trifoliolata

Seven new [acronyculatins I-O (1-7)] and four known acetophenone monomers were isolated from a CH 3 OH/CH 2 Cl 2 (1:1) extract (N089419) of Acronychia trifoliolata provided by the U.S. National Cancer Institute (NCI, Frederick, MD, USA). Their structures were characterized by using various NMR and HRMS techniques. Among the known compounds, the structure of acronyculatin B (8) was revised. Some of the isolated compounds were evaluated for antiproliferative activity against human cancer cell lines. While most of the tested compounds were not cytotoxic, acronyculatins I (1) and J (2) showed moderate antiproliferative activity

Antitumor Agents. 293. Nontoxic Dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) Analogues Chemosensitize Multidrug-Resistant Cancer Cells to Clinical Anticancer Drugs

Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogs were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine resistant nasopharyngeal carcinoma) cells, a multi-drug resistant cell line over-expressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2′-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 16 and 23 showed 5–10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analog 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogs against both non-MDR and MDR cells, suggesting that DDB analogs serve as the novel lead compounds for the development of chemosensitizers to overcome MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogs dramatically elevated cellular concentration of anticancer drugs

マルチチャネル フォトンカウンティング システム ニヨル キュウチャク ルミネッセンス ノ ケイソク

放射線照射されていない固体において, 表面へのガス吸着に起因する熱ルミネッセンスを生じる現象(吸着ルミネッセンス)について調べた。BaSO_4 : Eu粉末への水, エタノール, アセトン等の蒸気の吸着によるルミネッセンスは, Eu^の励起準位からの緩和発光による615nmの線スペクトルと可視全域に広がる帯スペクトルとから成り, 線スペクトルと帯スペクトルの強度比および帯スペクトルの形状は吸着種に依存して異なる。吸着ルミネッセンスにおよぼす履歴効果と, ルミネッセンススペクトルの温度依存, 雰囲気変化に対する過渡応答等について計測した。The thermoluminescence of unirradiated solids originated from adsorption of gases (adsorption thermoluminescence) has been examined. The luminescence of BaSO_4 : Eu phosphors results from the adsorption of water, ethanol and acetone vapor. The luminescence has a main line spectrum at 615nm and a sub band spectrum ranging from 400 to 700nm. The main line spectrum corresponds to the de-exitation emission of Eu^, whereas the sub band spectrum does not appear in normal thermoluminescence. The ratio of the intensity of the main and sub spectrum and/or the structure of the band spectrum are dependent on adspecies. Sustained emission is observed when the vapor of these organic solvents are introduced into synthesized air. These observations suggest that the measurement of adsoption luminescence spectrum may realize the analysis of environmental gases. The effect of the sample history on adsorption thermoluminescence, the temperature dependence of the luminescence spectrum and the transient response of the luminescence to alterations in the gas environment are measured. It may be concluded that the adsorption thermoluminescence which appeared for samples stored in the atmosphere results from the recombination radiation between electrons trapped into the surface states originated from chemisorbed water and free holes released from the surface states originated from chemisorbed oxygen

Antitumor Agents. 284. New Desmosdumotin B Analogues with Bicyclic B-Ring as Cytotoxic and Antitubulin Agents

We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI50 values of 0.8–2.1 μM. In contrast, 1-analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistance cell line. We have now prepared and evaluated 1-analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI50 values of 0.06–0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC 50 value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation

Antitumor agents 283. Further elaboration of Desmosdumotin C analogs as potent antitumor agents: Activation of spindle assembly checkpoint as possible mode of action

In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21–32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4′-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED50 values of 1.1–2.8 μM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED50 1.7 μM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase