本研究在探討將核心胺基化合物與羧酸化合物以組合化學的方法在不分離純化的狀態於液相建立起醯胺化分子庫並進行細胞毒性分析。
在合成核心化合物的路徑上，先以一步驟的合成方法合成出4-azidobutan-1-amine做為供我們實驗室液相合成使用的連接體(Linker)，再將此連接體以醯胺化反應(amide formation)修飾原本就擁有抗癌潛力的化合物(Fenbufen以及Ethacrynic acid)，並且使連接體末端裸露出的Azido group(N3)還原成Amino group(NH2)藉此建立醯胺化分子庫以達到快速篩選的效果。
分子庫建立過程中使用肺癌A549細胞株以及乳癌MCF7細胞株還有人類直腸癌C26細胞株，以及老鼠胰臟癌Tramp細胞株來做為分子庫的毒殺試驗平台。使用多種細胞株的原因也是希望可以發現具有選擇性的毒殺化合物。
依據實驗結果發現了一些具有毒殺效果的化合物，其中包括了N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)butyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide、N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)
butyl)-2-ethylhexanamide以及4-(biphenyl-4-yl)-N-(4-(2-(2,3-
dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)butyl)-4-oxobutanamide。並且嘗試單獨製備純化並做進一步的生物分析。也代表了此一步驟合成連接體之方法可以用在修飾潛力藥物，並且用於我們實驗室所構築之醯胺化分子庫系統上。另外我們初步篩選到的潛力化合物針對不同的細胞具有不同的毒殺性，不過整體上來說此次分子庫建立以Fenbufen為主體修飾之核心化合物似乎毒殺效果上比Ethacrynic acid為主體之修飾物好些。

Aim of this research is to construct a library via amide formation under solution-phase condition.
To synthesize the core compound：a linker with amino and azido groups at the terminal end of butane, 4-azidobutan-1-amine), was prepared。After coupling with the activated acid derivatives of fenbufen and ethacrynic acid, the azido group was reduced to deliver the primary amines which could serve as a new core amine compound for construction of the library.
The cell lines used in our library included A549、MCF7、C26、and Tramp, which were derivated from lung cancer, breast cancer, colon cancer and pancreas cancer, respectively. Through the screening on the basis of the four different types of cancers, potential compound with selectivity may be easily discovered.
Indeed, after the first round of screening, three compound with improved cytotoxicity were found, e.g. N-(4-(4-(biphenyl-4-yl)-4-
oxobutanamido)butyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide、N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)
butyl)-2-ethylhexanamide and 4-(biphenyl-4-yl)-N-(4-(2-(2,3-
dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)butyl)-4-oxobutanamide. Further prepare of these compound and purification to determinate the IC50 value were performed. We can see that one-step synthesis linker to modify potential compound is succeed in our library system. In addition, we primary screening some potential anti-cancer compound seems that may have cytotoxic selectivity. Overall, we find that modified Fenbufen core amine is more cytotoxic than modified EA core amine.

(1) Cruz-Monteagudo, M. J. Comb. Chem 2008, 10(6), 897-913.
(2) Nature pubilsh group. Nature review drug discovery 2002, 418, 453-461.
(3) Thomas. G. Medicinal chemistry:an introduction, 2000.
(4) Inese Smukste a. Stockwell, B. R. Genomics Human 2005, 6, 261-286.
(5) Stockwell, B. R. Nature review genetics 2000, 1, 116-125.
(6) D. R. Spring, Chem. Soc. Rev 2005, 34, 472-482.
(7) Specht, K. M. a. Shokat, K. M., current opinion in cell biology 2002, 14, 155-159.
(8) Peterson JR, Proc Natl Acad Sci U S A. 2001, 98 (19), 10624-10629.
(9) B. Meunier, ACCOUNTS OF CHEMICAL RESEARCH 2008, 41, 69-77.
(10) Stockwell, B. R. Trends in Biotechnology 2000, 18, 449-455.
(11) Crews, C. M.; Splittgerber, U. Trends Biochem. Sci. 1999, 24, 317-320. "Chemical genetics: exploring and controlling cellular processes with chemical probes"
(12) Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchhausen, T.; Shair, M. D. Journal of the American Chemical Society 2001, 123, 6740-6741. "Use of Biomimetic Diversity-Oriented Synthesis toDiscover Galanthamine-Like Molecules with Biological Properties beyond Those of the Natural Product"
(13) Dolle, R. E. J. Comb. chem 2003, 5, 693-753.
(14) Boger, D. L., Desharnais, J. & Capps, K. Angew.chem 2003, 42, 4138-4176.
(15) Brik, A. Chemistry & Biology 2002, 9, 891-896.
(16) Wu, C.-Y. Angew. Chem 2003, 42, 4661-4664.
(17) Brik, A., Wong, C.-H. ChemBioChem 2003, 4, 1246-1248.
(18) Numa, M. M. D.; Lee, L. V.; Hsu, C.-C.; Bower, K. E.; Wong, C.-H. chembiochem 2005, 6, 1002-1006.
(19) Wu C.-Y., A. Birk., Wong C.-H. chembiochem 2005, 6, 2176-2180.
(20) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599.
(21) Sharpless, K. B. D.D.T. 2003, 8, 1128-1137.
(22) Cravatt, B. F. a. Anna, E. S. Chemistry & Biology 2004, 11(4), 535-546.
(23) Cravatt, B. F. a. Evans, M. J. Chem. Rev. 2006, 106, 3279-3301.
(24) Rankovic, Z. J. Med. Chem. 2005, 48, 6523–6543.
(25) Wang, C.-C., Wu, C.-Y., a. Wong C.-H. PNAS 2008, 105, 11661–11666.
(26) Mrksich, M. Chemistry & Biology, 2002, 9, 443–454.
(27) Aronson, J. K. J Clin Pharmacol, 2007, 64, 563-565.
(28) Thun, M. J., Henley, S. J., Patrono, C. J. Natl. Cancer Inst., 2002, 94, 252-266.
(29) Neidle, S., Thurston D.E. Nature Rev. Cancer 2005, 5, 285-296.
(30) Wang, R. L., C.; Song, D.; Zhao, G.; Zhao, L.; Jing, Y. Cancer Res 2007, 67(16), 7856-7864.
(31) Oakley, A. J. Biochemistry 1997, 36(3), 576-585.
(32) Shi, B. J. AM. CHEM. SOC 2006, 128, 8459-8467.
(33) Shi, B., Greaney, M. F. Chem. Commun 2005, 886-888.
(34) Michae, J. T. Journal of the National Cancer Institute 2002, 94(20), 1537-1545.
(35) McIlwain, C. C. Nature review 2006, 25, 1639-1648.
(36) Tew, K. D. Nature oncogene 2003, 22, 7369-7375.
(37) Nazar-Stewart,V. CANCER RESEARCH 1993, 53, 2313-2318.
(38) Mathieu, A. Cancer Res 2004, 101(5), 918-925.
(39) Shea, T. C. Cancer Res 1990, 50, 6848-6853.
(40) Ishii, T. Cancer Letters 2004, 216, 89-102.
(41) Alibin, N. Cancer Res 1993, 53, 3541-3546.
(42) Toussaint, C. Cancer Res 1993, 53, 4608-4612.
(43) Jari Peuralahti, L. J., Veli-Matti Mukkala, and Jari Hovinen Bioconjugate Chem 2006, 17, 855-859.
(44) Tornoe, C. W. Chem. Rev. 2008, 108, 2952-3015.
(45) Hang, H. C., Bertozzi, C.R. chem..Biol 2004, 11, 337-345.
(46) Katharine, A., Bertozzi, C.R. Chem. Biol 2002, 9, 113-129.
(47) Heo, D. S. Cancer Res 1990, 50, 3681-3690.
(48) Baird, M. C. Organometallics 2004, 23, 4486-4494.
(49) Alex A. Adjei. Clinical Cancer Research 1997, 3, 761-770.
(50) Del Bufalo D. European Journal of Cancer 2002, 38, 2455-2462.
(51) Yu, J. Cancer Chemother Pharmacol 2006, 58, 776-784.
(52) Stocks, P. A. Angew. Chem. Int. Ed 2007, 46, 6278 –6283.
(53) Kenneth, A. J. Chemistry & Biology 2005, 12, 237–247.
(54) Kalayda, G. V. J. Med. Chem. 2005, 48, 5191-5202.
(55) Gardner, R.A. J. Med. Chem. 2004, 47, 6055-6069.
(56) Stocks, P. A. Angew. Chem. Int. Ed. 2007, 46, 6278 –6283.
(57) Gao, Z.-G. Chemistry & Biology 2005, 12, 237-247.
(58) Masayasu Kuwahara1, Nucleic Acids Research, 2006, 34, 5383–5394.
(59) J. W. L. Tetrahedron Letters 2001, 42, 2709–2711.
(60) Gardner, R. A. J. Med. Chem. 2004, 47, 6055-6069.
(61) Gardner, R. A. J. Med. CHEM. 2007, 50, 308-318.
(62) Nyffeler, P. T., a.Wong C.-H. J. AM. CHEM. SOC. 2002, 124, 10773-10778.
(63) Ismail Celik, J Bıochem Mol Tox 2006, 20, 174–182.
(64) Janet Hernandez. Pesticide Bio and physiology 1998, 61, 87-94.