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Enhanced Oral Bioavailability of the Pharmacologically Active Lignin Magnolol via Zr-Based Metal Organic Framework Impregnation
(2020-05-01)
Santos, Joshua H.
;
Quimque, Mark Tristan J.
;
Macabeo, Allan Patrick G.
;
Corpuz, Mary Jho-Anne T.
;
Wang, Yun-Ming
Bioavailability plays an important role in drug activity in the human body, as certain drug amounts should be present to elicit activity. However, low bioavailability of drugs leads to negligible use for human benefit. In this study, the diversely active neolignan, magnolol, was impregnated onto a Zr-based organometallic framework [Uio-66(Zr)] to increase its low bioavailability (4-5%) and to test its potential acute oral toxicity. Synthesis of Uio-66(Zr) was done through the solvothermal method while simple impregnation at different time points was used to incorporate magnolol. The loading capacity of Uio-66(Zr) at 36 h was found to be significantly higher at 72.16 +/- 2.15% magnolol than in other incubation time. Based on the OECD 425 (limit test), toxicity was not observed at 2000 mg kg(-1) dose of mag@Uio-66(Zr) in female Sprague Dawley rats. The area under the curve (AUC) at 0-720 min of mag@Uio-66(Zr) was significantly higher than the AUC of free magnolol. Moreover, relative bioavailability increased almost two-folds using Uio-66(Zr). Unconjugated magnolol was found in the liver, kidney, and brain of rats in all treatment groups. Collectively, Uio-66(Zr) provided a higher magnolol bioavailability when used as drug carrier. Thus, utilization of Uio-66(Zr) as drug carrier is of importance for maximal use for poorly soluble and lowly bioavailable drugs.
抑制血管內皮細胞生長因子作用的先導藥物最佳化和新穎藥物傳輸配方設計
(2009)
孫仲銘
;
SUN CHUNG-MING
;
國立交通大學應用化學系(所)
基於先前實驗的結果，我們發現編號194的化合物對於VEGFR-3的抑制能力較編號1250的化合物為佳。因此先導藥物從#1250更改為#194，並且開始了各式各樣的評估實驗。然上述先導化合物均顯示低或難溶於水的性質，因此、持續修飾化合物結構或利用適當配方技術可以解決低溶解度相關問題。此外，治療腫瘤的小分子藥物可由適當的藥物傳輸及配方技術提高藥物功能。光田醫院吳世冠博士所做的新配方可增加 #194的水溶性至6 mg/mL，並且利用此新的配方進行藥物動力學和毒理實驗。此外，郭明良教授和他的同僚目前也致力於#194新配方在生物活體上的腫瘤研究。除了使用新配方來增加溶解度之外，我們也試著改變化合物的結構來提高抑制血管新生因子的活性和溶解度。藉由更改benzimidazole的取代基，我們已經合成一系列的#194衍生物，當benzimidazole的取代基為2-phenyl ethyl時所得到的抑制效果最佳 (#376)。但是#376溶解度比#194差，我們可以利用其他取代基來增加溶解度及抑制活性。我們已經設計了一系列的雜環取代基包含pyridinyl取代基 (可做成鹽類) 來提高抑制活性和溶解度性。此外，我們也將benzimidazole部分更改為其他的雜環分子來提高#194的抑制效果。同時我們也將繼續利用微波式組合化學合成新穎的化學分子庫並將這些分子送給郭教授篩選。化合物201， 355， 368和440是最近發現的新化合物，他們比194有更好的VEGFR-3抑制能力且這些化合物的核心結構與194不同。最近，曾宇鳳博士利用了VEGFR-2的蛋白質結構及VEGFR-3蛋白質序列模擬出VEGFR-3的蛋白質結構，我們將之前篩選過的化合物整理後送給曾博士計算他們與VEGFR-3結合的情形，這些訊息及我們的經驗都是在未來開發更具活性的VEGFR-3抑制劑重要的依據。
抑制腫瘤細胞轉移和成長的分子靶向性先導藥物研發(Ⅳ)---先導抗癌標靶藥物nstpbp253和355的最佳化設計和新穎奈米化抑制腫瘤藥物傳輸配方
(2010)
孫仲銘
;
SUN CHUNG-MING
;
國立交通大學應用化學系（所）
我們從先導藥物#1250更改為#194延續實驗至今，持續修飾化合物結構以及利用適當配方技術增加溶解度以及提高藥物功能。終於在今年我們在改變#194結構之衍生物NCTU-Sun-253的生物活性上得到突破性的結果，#253類的衍生物尤其是在溶解度以及對tumor size的影響都有顯著的提昇，且抑制活性趨近於以上市藥物sutent以及Sorafenib。在溶解度方面253類的衍生物幾乎是194的100倍，我們也試著改變化合物的結構來提高抑制血管新生因子的活性和溶解度。藉由更改R1、R2、R3、R4的取代基以及雜原子，我們已經利用微波式組合化學合成一系列的253衍生物，並將這些分子送給郭教授篩選。並且曾宇鳳博士利用了VEGFR-2的蛋白質結構及VEGFR-3蛋白質序列模擬出VEGFR-3的蛋白質結構，我們將NCTU-Sun-253之結構送給曾博士計算與VEGFR-3結合的情形，運用曾博士的計算結果及預測，合成出一系列可能具有活性的化合物，並將NCTU-Sun-253化學結構優化到最佳的結果，成為未來開發更具活性的VEGFR-3抑制劑重要的依據; 由於這些令人振奮結果，我們預計很快的就可以完成臨床前的實驗。
登革熱抑制劑快速篩選系統之建構
(2003)
楊進木
;
Jinn-Moon, Yang
;
國立交通大學生物科技研究所
登革病毒(Dengue virus)屬於黃質病毒科( Flaviviridae )中黃質病毒屬( Flavivirus)內的登革病毒亞屬，目前世界上尚無穩定、安全的疫苗可供防治登革熱，亦無有效的治療藥物。登革病毒基因體(genome)為單一正股RNA鏈(single-stranded RNA，+ strand )，約含10700個鹼基。其RNA經轉譯後，所得的單一多蛋白聚合鏈(single polyprotein chain)將被宿主細胞或病毒的酵素切割出10個蛋白質，包括3個結構性蛋白(structural protein)和7個非結構性蛋白(non-structural protein)。結構性蛋白主要功能是構成病毒的外殼，而非結構性蛋白則與病毒RNA分子的複製有關。 10種蛋白質中，已知其立體結構及功能的有二：套膜蛋白Ｅ(major envelope protein E，PDB code:1K4R)以及非結構性蛋白NS3 (PDB code:1BEF)。套膜蛋白E為構成病毒外殼的主要蛋白，是主要的抗原決定部位，宿主的免疫系統即針對此蛋白質產生抗體。目前研究顯示，virus-　antibody complex進入細胞的能力遠高於單獨存在的病毒，這亦是不同血清型登革熱交叉感染後會引發登革出血熱的可能機制之一。NS3為一蛋白質水解?(protease)，與胰蛋白?(trypsin)同屬絲胺酸催化蛋白?(serine protease)，負責切割RNA轉譯後所得的單一多蛋白鏈，以產生其他非結構性蛋白。此兩種蛋白質結構已知，且為登革病毒感染與成熟過程中不可缺少的重要環節，因此若能利用我們已發展完成的軟體並配合現有的藥物資料庫，針對此二蛋白質的結構，搜尋可與其嵌合的化學物質，即有可能從中揀選出具備藥物潛力的化合物分子。本計畫將提出一個能辨識藥物、預測藥物副作用以及毒性的雛形系統，暫稱為DockGEM，此系統可與傳統的藥物開發方式互補，組合成一個更完善的藥物開發體系，並極有可能大大壓縮臨床實驗所需的時間與經費。此系統包含三個主要元素: Docking知識庫、工具庫及發現藥物之系統步驟(drug discovery roadmap)。Docking知識庫包含藥物資料庫(drug database)、活性區域知識庫(binding-site information database)、蛋白質與其副作用及毒性的關聯資料庫；而工具庫則以演化式方法(evolutionary approaches)及類神經網路(neural networks)為基礎，可自動整合ligand-protein docking及ligand-protein inverse docking運算程式，並具備資料庫搜索(database search)功能，以自動化流程揀選出具有藥物潛力的小分子化學物質；發現藥物的系統步驟包含rapid ligand docking, flexible ligand docking與ligand optimization，並希望達到下列目標: 1. 建立能自動整合ligand-protein docking 及 ligand-protein inverse docking的系統，此系統能辨識潛在藥物，同時也可預測這些藥物的副作用以及毒性。 2. 開發登革熱已知蛋白質抑制劑之專屬快速篩選系統。 3. 建立藥物庫、活性區域知識庫、蛋白質與其副作用及毒性的整合性關聯資料庫。 4. 整合知識為基及物理為基的方法，建立更準確的scoring functions及更有效率的ligand-protein docking及ligand-protein inverse docking的程式，以提高系統準確度。過去幾年我們在整合演化式方法、結構生物、及protein docking上已獲得一些成果，我們認為以知識為基礎的演化式計算是以自然的演化方式解決生物資訊問題，我們希望此系統能應用於預防登革熱之相關藥物開發上。
Statistical comparisons of the no-observed-effect concentration and the effective concentration at 10% inhibition (EC10) in algal toxicity tests
(2001)
Shieh, JN
;
Chao, MR
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
Batch-type algal toxicity tests were conducted to evaluate the low toxic effects of metal toxicants. Both the no-observed-effect concentration (NOEC) and the effective concentration at 10% inhibition (EC10) were calculated and compared. The results of this study indicate that, for algal toxicity tests, NOEC. offers better protection to the test organisms than EC10. In addition, the consistency of NOEC is found to depend on the response endpoints measured. A cut-off-value approach is proposed to determine whether NOEC or EC10 should be chosen for estimating low toxic effects. For a specific toxicity test, the average cut-off value directly indicates the magnitude of the square root of the within-group-variance. A precise test associated with small within-group-variances also produces relatively small average cut-off value (say, less than 10% of the growth reduction). This average value provides useful information on the minimum protection that can be offered by the NOEC.
Discrepancies between different response parameters in batch and continuous algal toxicity tests
(2001-03-30)
Chao, MR
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
The test sensitivities and reproducibilities based on different response endpoints (cell density and total cell volume) were compared using both bath and continuous algal toxicity tests. Parameters related to algal cell density are found to be more sensitive and reproducible than total cell volume which bears a direct correlation to algal biomass or dry weight. The magnitude of differences in the median effective concentration values could be upto six folds. The main cause for the above discrepancies is because the cell density and total cell volume are two response endpoints reflecting the degree of inhibition on the binary fission mechanism and overall photosynthesis, respectively. At low toxicant concentrations, the inhibitory effect is primarily on the cell division rather than on the cellular photosynthesis. Thus, more severe toxic effects are expected to be observed based on the cell density than the total cell volume. The results of this study clearly demonstrate that sensitivity and reproducibility can be significantly improved if response parameters are calculated based on the cell density. Traditionally, cell density data are often converted into biomass before assessing the effects of toxicants. This procedure may not be necessary and may reduce the test sensitivity. (C) 2001 Elsevier Science B.V. All rights reserved.
Toxicity of nitriles and their derivatives on Raphidocelis subcapitata (Algae)
(2005)
Huang, Chun-Pin
;
Chen, Chung-Yuan
;
環境工程研究所
;
Institute of Environmental Engineering
Algae are ecologically important organisms in the aquatic food chain and are frequently used in environmental studies for assessing the relative toxicity of various chemicals and/or waste discharges. Currently, however, most standard algal test protocols are based on conventional batch technique (ASTM, 1994; ISO, 1987; US EPA, 1996; OECD; 1984). The European Centre for Ecotoxicology and Toxicology of Chemicals (1996) has concluded that current algal toxicity test protocols are unsuitable for assessing the effects of volatile compounds because the experimental design for these methods may cause considerable losses of volatile organic toxicants and, consequently, underestimations of the toxicity of volatile organic chemicals. Nitriles and their derivatives are common intermediate products from plastic and resin manufactories. Their toxic effects to phytoplankton have rarely been investigated. This study evaluated the toxicity of 12 kinds of nitriles and halogen-substituted nitriles using a closed-system algal toxicity test with no head-space. Raphidocelis subcapitata was selected as the test alga. Toxicity testing was conducted by transferring adequate amounts of algal suspension, dilution water (with growth medium), and toxicants into 300-ml BOD bottles. The BOD bottles were completely filled up with no head-space left. The initial cell density and the exposure time were 15,000 cells/mL and 48 hours, respectively. Light intensity and temperature were kept at 65 mu EM(-2)s(-1) (+/- 10%) and 24 +/- 1 square. The DO level at the beginning of the test was approximately 1 to 3 mg/L. Two response endpoints, i.e., dissolved oxygen production and algal growth rate, were employed to assess the toxicity of the test chemicals. The median effective concentration (EC50) was defined as the toxicant concentration that resulted in 50% reduction with respect to the response endpoints (i.e., ADO, or growth rate). The median effective concentrations (EC50) range from 0.051 to 5843 mg/L. In general, the DO endpoint revealed higher inhibition than that from algal growth rate. The above phenomenon indicates that certain nitrils and their derivatives have stronger toxic effects to algal photosynthesis reactions. Furthermore, halogen-substituted nitriles were found to be extremely toxic to Raphidocefis subcapitata. With increasing numbers of the halogen molecules, stronger toxicity was observed. The bromine substitutent also seems to be more toxic than chlorine substitutent. Quantitative structure-activity relationships (QSARs) were established based on the chemicals'ELUMO values with R 2 values equal to 0.85. Such relationships can thus be used to predict the toxicity of other nitrile compounds.
A novel algal toxicity testing technique for assessing the toxicity of both metallic and organic toxicants
(2005-05-01)
Lin, JH
;
Kao, WC
;
Tsai, KP
;
Chen, CY
;
環境工程研究所
This study presents a closed-system algal toxicity test technique that is capable of detecting the effects of both organic and metallic toxicants. Toxicity testing was conducted by transferring adequate amounts of algal suspension, dilution water (with culture growth medium), and toxicants into 300-mL BOD bottles. The BOD bottles were completely filled up with no head-space left. The initial cell density and the exposure time were 15,000 cells/mL and 48 h, respectively. The performance of the above test method was evaluated using three heavy metals and six organic toxicants based on three different test endpoints, i.e., dissolved oxygen production, algal growth rate, and cell density. The proposed test revealed excellent test sensitivity and reproducibility. Currently, none of the existing algal toxicity test protocols is adequate for assessing the toxicity of organic chemicals. The closed-system algal toxicity tests developed by previous researchers also may not be ideal because the enlarged headspace and/or enriched bicarbonate buffer may result in either underestimations of the exposure concentrations or insensitive responses to both heavy metals and organic toxicants. Compared to the aforementioned algal toxicity test methods, the proposed technique in the present study has a more general applicability under conditions such as effluent samples containing both metals and organic toxicants or samples with unknown compositions. (c) 2005 Elsevier Ltd. All rights reserved.
Toxicity assessment of pesticides to Pseudokirchneriella subcapitata under air-tight test environment
(2006-04-17)
Yeh, HJ
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
This paper presents the toxicity data of seven pesticides including atrazine, parathion, dichlorvos, malathion, fenthion, 2-methyl-4-chiorophenoxyacetic acid, and pentachlorophenol on Pseudokirchneriella subcapitata based on a new algal toxicity testing technique conducted under air-tight environment. The dissolved oxygen production and the cell density were adopted as the response endpoints. Median effective concentrations (EC50) range from 0.0035 to 3.40 mg/L (DO production) and from 0.0067 to 3.12 mg/L (cell density). No-observed-effect concentration (NOEC) was determined using the Dunnett's test. NOEC values are with in the range of 0.001-1.20 mg/L. In general, the two test endpoints revealed similar sensitivities. From comparisons of literature data also based on Pseudokirchneriella subcapitata, it is clear that conventional batch tests tend to underestimate the toxicity of pesticides due to their open test environment. Closed-system tests, i.e., microplate test, respirometer test, and our BOD-bottle test, generally provide better assessment to the effects of pesticides. Data based on our test method reveals much higher toxicity (3-100 times) than that from the conventional batch tests. Furthermore, for organophosphorus insecticides, results from the present study show that Pseudokirchneriella subcapitata is less sensitive than Daphnia magna and rainbow trout, but is more susceptible than fathead minnow. The closed-system test applied in this study provides more adequate assessment for the toxicity of pesticides than the conventional batch tests. (c) 2005 Elsevier B.V. All rights reserved.
The combined toxic effects of nonpolar narcotic chemicals to Pseudokirchneriella subcapitata
(2006-06-01)
Hsieh, SH
;
Tsai, KP
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
This paper presents the toxicity data of 10 nonpolar narcotic chemicals on Pseudokirchneriella subcapitata (green algae) assessed by a new algal toxicity testing technique conducted under air-tight environment. Based on DO production, median effective concentration (EC50) varies from 1.73mg/L (1-octanol) to8040 mg/L (2-propanol). The endpoint of algal growth rate reveals similar sensitivity as that from DO production. Compared to literature data, Pseudokirchneriella subcapitata and Nitrosomonas are apparently more sensitive to nonpolar narcotics than other organisms such as minnow, daphnia, and Tetrahymena pyriformis. Furthermore, good correlations between toxic effects observed from Pseudokirchneriella subcapitata and other aquatic organisms were found. Hence, algal toxicity test can be considered as a surrogate test for estimating the toxicity of nonpolar chemicals to fathead minnow, Microtox, activated sludge, Daphina magna, and Tetrohymena pyriformis. The combined effects of 13 binary mixtures of nonpolar chemicals were investigated using both additive-index method and isobologram analysis. overall speaking, the joint actions between these chemicals are strictly additive. Model analyses indicate that these compounds act on identical reaction sites or receptors, which verify that these chemicals are of the same toxicity mechanism (narcosis). (c) 2006 Elsevier Ltd. All rights reserved.

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