Synthesis and Biology of Isomalyngamide A  Analogs Containing Ribose as Anti-Migration and  Anti-Tube Formation Inhibitors

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：11

、訪客IP：3.140.242.165

姓名

石晴瑩(Ching-Ying Shih) 查詢紙本館藏

畢業系所

化學學系

論文名稱

(Synthesis and Biology of Isomalyngamide A Analogs Containing Ribose as Anti-Migration and Anti-Tube Formation Inhibitors)

相關論文

★ 含胺基之二苯乙烯衍生物的分子內光誘導電子轉移之C-N斷鍵反應及激態錯合體之研究	★ 新型含1,2,3-三氮唑之雙光子吸收材料的合成及其光學性質探討
★ 紫質衍生物研究：間位苯卟啉分子的鋅離子感測及大環紫質的構型	★ Squamocin 之合成研究
★ 發展4,4’-亞甲基對苯胺或聯苯胺為骨架的四氯衍生物作為人類麩胺基硫轉移酶抑制劑的合成及構效關係的探討	★ 含有香豆素的石膽酸類似物作為唾液酸轉移酶抑制劑的合成與初步活性測試
★ 石膽酸C4含氟唾液酸轉移酶抑制劑和苯並惡嗪酮相關的螢光探針之合成及生物研究	★ 合成和優化2-(1-乙基-3,5-二甲基-1H-吡唑-4-基)乙-1-胺衍生物和其抗三陰性乳腺癌細胞的體外活性研究
★ 以蛋白質體學探討在大腸桿菌中甲醇利用代謝途徑	★ LCA-Fentanyl Hybrid Molecules: Anaesthetic Implications of Antimetastasis Chemotherapy
★ Data-independent acquisition mass spectrometry analysis for identification of cerebrospinal fluid biomarker of reversible cerebral vasoconstriction syndrome	★ 從手性N-亞磺醯胺進行非對映選擇性磷酯基化反應建構高度選擇性的α-胺基磷酸酯
★ DNA型式碳水化合物抗原之生物偵測器的開發及應用	★ 設計合成新型的唾液酸轉移酶抑制劑
★ 合成具有分子腳架之多並苯化合物且用於自組裝分子薄膜之研究	★ 1,3-偶極環化加成反應在藥物合成與醣晶片上的應用

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

[檢視]

[下載]

本電子論文使用權限為同意立即開放。
已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

摘要(中)

三陰性乳癌是一種類型的乳癌，其具有高復發性、高死亡率、高轉移性，轉移是造成病患主要的死亡原因，因為其轉移不同於其他癌症，三陰性乳癌的腫瘤還沒長到一定大小就具有轉移性，且對於腦及肺的轉移率比其他類型的乳癌都還要高。由於缺少了其他乳癌細胞常見的受體，所以目前也沒有針對三陰性乳癌的標靶藥物，以往治療三陰性乳癌的方式僅限於手術及化療，現在，搭配抗轉移、抗血管增生藥物來延長病患的存活時間已經是一種治療趨勢。
幾年前，我們實驗室發現藍綠藻分離出的天然物 isomalyngamide A、A-1 對三陰性乳癌的細胞株 MDA-MB-231 具有很強的抗轉移效果，但是這種天然物的合成很困難，因此，我們實驗室設計了一些骨架簡單、易於合成的類似物，並且利用醣基化來增加它的抗轉移能力。在這篇論文中，我們將會以核糖、不同的長度的 linkers 合成一系列化合
物，探討結構改變對生物活性的影響，希望能藉此讓化合物的抗轉移能力提升。
在這系列醣基化的 isomalyngamide A 衍生物中，化合物 CY01 具有最好的MDA-MB-231 細胞抗轉移活性，其 IC50 值為 7.56μM；除此之外，我們實驗室也發現 CY01對 HUVEC (人類臍帶靜脈內皮細胞) 的 tube formation 有不錯的抑制效果，而 Western blot 測試揭露CY01 是透過抑制 pVEGFR2/pAKT 的信號路徑來達到抗轉移與抗 tube
formation 的效果。

摘要(英)

Triple-negative breast cancer is a subtype of breast cancer that demonstrates unique properties of high recurrence, mortality, and metastasis. Metastases to a person’s lung and brain are the two leading causes of death by triple-negative breast cancer. Since triple-negative breast cancer tumors lack common receptors that other types of breast cancer have, there is no specific target drugs against triple-negative breast cancer in clinic. Traditional treatments for triple-negative breast cancer patients are surgery and chemotherapy; yet in nowadays, treatments combined with anti-migration and anti-angiogenesis drugs are the latest trend of therapy.
Previously our laboratory identified and isolated isomalyngamide A and A-1 from marine cyanobacteria. We discovered that these two substances had profound anti-migration effects against triple-negative breast cancer cell line MDA-MB-231. However, routine preparation/production of isomalyngamides required tedious separations of intermediates and lengthy total synthesis. Hence, our laboratory designed a series of analogs of isomalyngamide A with the aid of simple and optimized synthetic procedures. Accordingly we uncovered that compounds derived from glycosylation of isomalyngamide A analogs have better anti-metastatic properties than nonglycosylated ones. Based on these results, we investigated the structure-activity relationship of those synthetic glycosylated isomalyngamide A analogs where the ribose and different lengths of linkers were incorporated in this study.
Among this series of glycosylated isomalyngamide A analogs (CY01-CY12), CY01 is the best compound showing the potential against MDA-MB-231 under nontoxic concentration level. Furthermore, we uncovered that CY01 suppressed tube formation of HUVEC (human umbilical vein endothelial cells) efficiently. Western blot assay revealed that CY01 inhibited metastasis and tube formation by inhibiting the pVEGFR2/pAKT signaling pathway.

關鍵字(中)

★ Isomalyngamide A
★ Anti-tube formation
★ Anti-migration

關鍵字(英)

★ Isomalyngamide A
★ Anti-tube formation
★ Anti-migration

論文目次

摘要 ............................................................................................................................................. I

Abstract .................................................................................................................................... II

Acknowledgments ................................................................................................................... III

Table of Contents .................................................................................................................... IV

List of Figures ....................................................................................................................... VII

List of Tables ........................................................................................................................... IX

List of Schemes ........................................................................................................................ X

List of Abbreviations .............................................................................................................. XI

一、 Introduction .................................................................................................................. 1

1.1 Study Background .................................................................................................... 1

1.2 Introduction of Triple-Negative Breast Cancer (TNBC) ...................................... 1

1.2.1 Introduction of Breast Cancer .................................................................................... 1

1.2.2 Treatment for TNBC .................................................................................................. 2

1.3 Introduction of Isomalyngamides and Malyngamides .......................................... 6

1.3.1 Structure of Isomalyngamides .................................................................................... 6

1.3.2 Bioactivity of malyngamides ..................................................................................... 7

二、 Result and Discussion ................................................................................................... 11

2.1 Research Motive ..................................................................................................... 11

2.2 Retrosynthetic Analysis of Glycosylated Isomalyngamide A Analogs .............. 12

2.3 Synthesis of Intermediates ..................................................................................... 13

2.3.1 Synthetic route of compound 11 .......................................................................... 13

V

2.3.2 Synthetic route of compound 15, 19 .................................................................... 13

2.4 Synthesis of Glycisylated Isomalyngamide A Analogs ........................................ 15

2.4.1 Synthetic route of CY01 and CY02 ......................................................................... 15

2.4.2 Synthetic route of CY03 and CY04 .................................................................... 16

2.4.3 Synthetic route of CY05 and CY06 .................................................................... 17

2.4.4 Synthetic route of CY07and CY08 .......................................................................... 18

2.4.5 Synthetic route of CY09 and CY10 ......................................................................... 19

2.4.6 Synthetic route of CY11 and CY12 ......................................................................... 20
2.5 In vitro studies of CY01CY08 (由本實驗室張梓庭助理操作) .......................... 22

2.5.1 Cytotoxicity for compounds CY01-CY08 on MDA-MB-231 cell proliferation ..... 22
2.5.2 Inhibitory effects of CY01CY08 on MDA-MB-231 cell migration ...................... 23
2.5.3 Effect of compounds CY01-CY08 on HUVEC proliferation .................................. 24

2.5.4 Inhibitory effects of target compounds on HUVEC tube formation ........................ 25

2.5.5 Mechanism study of CY01-mediated anti-angiogenesis effect................................ 26

三、 Conclusion ................................................................................................................... 27

.................................................................................................................................................. 27

四、 Methodology .................................................................................................................. 28

4.1 General information ............................................................................................... 28

4.2 Experimental Method ............................................................................................ 28

4.2.1 Synthesis of coupling reagent DMTMMBF4 ........................................................... 28

4.2.2 Synthesis of compound 11 ....................................................................................... 28

4.2.3 Synthesis of compound 15 ....................................................................................... 29

VI

4.2.4 Synthesis of compound 19 ....................................................................................... 31

4.2.5 Synthesis of compound CY01.................................................................................. 32

4.2.6 Synthesis of compound CY02.................................................................................. 34

4.2.7 Synthesis of compound CY03.................................................................................. 35

4.2.8 Synthesis of compound CY04.................................................................................. 37

4.2.9 Synthesis of compound CY05.................................................................................. 39

4.2.10 Synthesis of compound CY06................................................................................ 41

4.2.11 Synthesis of compound CY07................................................................................ 42

4.2.12 Synthesis of compound CY08................................................................................ 45

4.2.13 Synthesis of compound CY09................................................................................ 47

4.2.14 Synthesis of compound CY10................................................................................ 49

4.2.15 Synthesis of compound CY11................................................................................ 50

4.2.16 Synthesis of compound CY12................................................................................ 52

五、 References ..................................................................................................................... 55

六、 Spectral Appendix ........................................................................................................ 58

參考文獻

(1) Lips, E. H.; Mulder, L.; DeRonde, J. J.; Mandjes, I. A. M.; Koolen, B. B.; Wessels, L.
F. A.; Rodenhuis, S.; Wesseling, J.Breast Cancer Res. Treat. 2013, 140 (1), 63–71.
(2) Schnitt, S. J.Mod. Pathol. 2010, 23 (S2), S60–S64.
(3) Sandhu, R.; Parker, J. S.; Jones, W. D.; Livasy, C. A.; Coleman, W. B.Lab. Med. 2010,
41 (6), 364–372.
(4) Pareja, F.; Geyer, F. C.; Marchiò, C.; Burke, K. A.; Weigelt, B.; Reis-Filho, J. S.npj
Breast Cancer 2016, 2 (June), 16036.
(5) Volkova, M.; Russell, R.Curr. Cardiol. Rev. 2012, 7 (4), 214–220.
(6) Murphy, M. L.1966.
(7) Minotti, G.Pharmacol. Rev. 2004, 56 (2), 185–229.
(8) Thorn, Caroline; Oshiro, Connie; Marsh, Sharon; Hernandez-Boussard, Tina; McLeod,
Howard; Klein, Teri; Altman, R.Pharmacogenet Genomics 2012, 21 (7), 440–446.
(9) Schiff, P. B.; Fant, J.; Horwitz, S. B.Nature. 1979, pp 665–667.
(10) Orr, G. A.; Verdier-Pinard, P.; McDaid, H.; Horwitz, S. B.Oncogene 2003, 22 (47),
7280–7295.
(11) ROSENBERG, B.; VANCAMP, L.; KRIGAS, T.Nature 1965, 205 (4972), 698–699.
(12) Alderden, R. A.; Hall, M. D.; Hambley, T. W.J. Chem. Educ. 2006, 83 (5), 728.
(13) Kelland, L.Nat. Rev. Cancer 2007, 7 (8), 573–584.
(14) Johnstone, T. C.; Park, G. Y.; Lippard, S. J.Anticancer Res. 2014, 34 (1), 471–476.
(15) Stordal, B.; Davey, M.IUBMB Life 2007, 59 (11), 696–699.
(16) Folkman, J.Semin. Oncol. 2002, 29 (6Q), asonc02906q0015.
(17) Kondo, Y.; Arii, S.; Mori, A.; Furutani, M.; Chiba, T.; Imamura, M.Clin. Cancer Res. 56, 2000, 6 (2), 622–630.
(18) Manuscript, A.; Paradigms, E.2012, 147 (2), 275–292.
(19) Orjala, J.; Nagle, D.; Gerwick, W. H.J. Nat. Prod. 1995, 58 (5), 764–768.
(20) Yoshikai, N.; Iida, R.; Nakamura, E.2008, 63 (Scheme 1), 1063–1072.
(21) Chang, T. T.; More, S.V.; Lu, I. H.; Hsu, J. C.; Chen, T. J.; Jen, Y. C.; Lu, C. K.; Li, W.
S.Eur. J. Med. Chem. 2011, 46 (9), 3810–3819.
(22) Malloy, K. L.; Villa, F. A.; Engene, N.; Matainaho, T.; Gerwick, L.; Gerwick, W. H.J.
Nat. Prod. 2011, 74 (1), 95–98.
(23) Nangia-makker, P.; Baccarini, S.; Raz, A.2000, 51–57.
(24) Kannagi, R.; Izawa, M.; Koike, T.; Miyazaki, K.; Kimura, N.Cancer Sci. 2004, 95 (5),
377–384.
(25) Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M.Vasc. Health Risk Manag.
2006, 2 (3), 213–219.
(26) Johnstone, K. D.; Karoli, T.; Liu, L.; Dredge, K.; Copeman, E.; Li, C. P.; Davis, K.;
Hammond, E.; Bytheway, I.; Kostewicz, E.; Chiu, F. C. K.; Shackleford, D. M.;
Charman, S. A.; Charman, W. N.; Harenberg, J.; Gonda, T. J.; Ferro, V.J. Med. Chem.
2010, 53 (4), 1686–1699.
(27) Karoli, T.; Liu, L.; Fairweather, J. K.; Hammond, E.; Li, C. P.; Cochran, S.; Bergefall,
K.; Trybala, E.; Addison, R. S.; Ferro, V.J. Med. Chem. 2005, 48 (26), 8229–8236.
(28) Pinho, S. S.; Reis, C. A.Nat. Rev. Cancer 2015, 15 (9), 540–555.
(29) Narayanaperumal, S.; DaSilva, R. C.; Monteiro, J. L.; Corrêa, A. G.; Paixão, M. W.J.
Braz. Chem. Soc. 2012, 23 (11), 1982–1988.
(30) Demchenko, A.V.Handb. Chem. Glycosylation Adv. Stereoselectivity Ther. Relev. 2008, 1–27.
(31) Wang, J.; Luis, J.; Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.2013. 57
(32) Holmes, K.; Roberts, O. L.; Thomas, A. M.; Cross, M. J.Cell. Signal. 2007, 19 (10), 2003–2012.

指導教授

李文山、侯敦仁(Wen-Shan Li Duen-Ren Hou)

審核日期

2017-7-24

推文