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

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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)

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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

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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