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🏛️國立陽明交通大學機構典藏

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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.
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    Quimque, Mark Tristan J.
    ;
    Macabeo, Allan Patrick G.
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    Corpuz, Mary Jho-Anne T.
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    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.
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    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。
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    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 。
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    Statistical comparisons of the no-observed-effect concentration and the effective concentration at 10% inhibition (EC10) in algal toxicity tests
    (2001)
    Shieh, JN
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    Chao, MR
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    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.
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    Toxicity of nitriles and their derivatives on Raphidocelis subcapitata (Algae)
    (2005)
    Huang, Chun-Pin
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    Chen, Chung-Yuan
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    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.