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Title Page 2

Contents 2

Chapter Ⅰ. Synthesis and Evaluation of 6-Azauridine Analogs against RNA Viruses 5

Abstract 6

Contents 8

Abbreviations 12

Ⅰ. Introduction 14

Ⅱ. Results and discussion 21

2.1. Chemistry 21

2.1.1. Synthesis of 6-azauridine analogs 21

2.1.2. Synthesis of 6-azacytidine analogs 24

2.2. Biology 26

Ⅲ. Conclusion 29

Ⅳ. Experimental section 30

4.1. Chemistry 30

4.1.1. General experimental procedures 30

4.1.2. 1-O-Methyl-D-ribofuranose (5) 31

4.1.3. 1-O-Methyl-2,3,5-tri-O-benzoyl-D-ribofiiranose (6) 31

4.1.4. 1-O-Acetyl-2,3,4,-tri-O-benzoyl-β-D-ribofbranose (7) 32

4.1.5. 5-Bromo-6-azauracil (9a) 33

4.1.6. 5-Iodo-6-azauracil (9b) 33

4.1.7. (2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)tetrahydrofuran-3,4-diyl-dibenzoate (10a) 33

4.1.8. (2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(6-bromo-3,5-dioxo-4,5-di hydro-1,2,4-triazin-2(3H)-yl)tetrahydrofuran-3,4-diyl-dibenzoate (10b) 34

4.1.9. (2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(6-iodo-3,5-dioxo-4,5-di-hydro-1,2,4-triazin-2(3H)-yl)tetrahydrofuran-3,4-diyl-dibenzoate (10c) 35

4.1.10. 2((2R,3R,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofbran-2-y1)-1,2,4-triazine-3,5(2H,4H)-dione (11a) 35

4.1.11. 6-Bromo-2-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrah ydrofuran-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione (11b) 36

4.1.12. 2-(2R,3R,4R,5R))-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-iodo-l,2,4-triazine-3,5(2H,4H)-dione (11c) 36

4.1.13. (2R,3R,4R,5R)-2-(5-Amino-3-oxo-1,2,4-triazin-2(3H)-yl)-5-((benzo yloxy)methyl)tetrahydrofuran-3,4-diyl-dibenzoate (13) 36

4.1.14. 5-Amino-2-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrah ydrofuran-2-yl)-1,2,4-triazin-3(2H)-one (14) 37

4.1.15. (2R,3R,4R,5R)-2-((Benzoyloxy)methyl)-5-(5-(hydroxyamino)-3-oxo-1,2,4-triazin-2(3H)-yl)tetrahydrofuran-3,4-diyl-dibenzoate (15) 38

4.1.16. 2-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(hydroxyamino)-1,2,4-triazin-3(2H)-one (16) 38

4.2. Biology 39

References 42

Spectrum 46

국문초록 55

Chapter Ⅱ. Development of an Efficient Synthetic Method for Machilin A and Biological Activity Evaluation of Its Analogs Targeting Lactate Dehydrogenase A 57

Abstract 58

Contents 60

Abbreviations 64

Ⅰ. Introduction 65

Ⅱ. Results and discussion 70

2.1. Chemistry 70

2.1.1. Synthetic method of Machilin A 70

2.1.2. Synthesis of Machilin A analogs 73

2.2. Biology 75

2.2.1. Materials and methods 75

2.2.2. Biological activity of Machilin A analogs 75

Ⅲ. Conclusion 78

Ⅳ. Experimental section 79

4.1. Chemistry 79

4.1.1. General experimental procedures 79

4.1.2. l-(Benzo[d][l,3]dioxol-5-yl)propan-2-one (3) 79

4.1.3. l,4-Bis(benzo[d][l,3]dioxol-5-yl)-2,3-dimethylbutane-2,3-diol (4) 80

4.1.4. (E)-5,5'-(2,3-Dimethylbut-2-ene-l,4-diyl)bis(benzo[d][l,3]dioxole) (5a) 81

4,1.5. (Z)-5,5'-(2,3-Dimethylbut-2-ene-1,4-diyl)bis(benzo[d][1,3]dioxole) (5b) 82

4.1.6. (meso)-1,4-Bis(3,4-methylenedioxyphenyl)-2,3, dimethyl-butane (1) and (士)-l,4-bis(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane (6) 82

4,1.7. 3-(3,4-Dihydroxyphenyl)-2-methylpropanal (7) 83

4.1.8. 5-(2-Methylallyl)benzo[d][l,3]dioxole (8) 83

4,1.9. 4-(2-Methylprop-l-en-l-yl)benzene-l,2-diol (9) 84

Reference 86

Spectrum 88

국문초록 96

List of Tables 9

Chapter Ⅰ. Synthesis and Evaluation of 6-Azauridine Analogs against RNA Viruses 9

Table 1. Antiviral activity and cytotoxicity of 6-azauridine analogs in DENV-2 replicon BHK cells 27

Table 2. Antiviral activity and cytotoxicity of compound 10a 28

List of Figures 10

Chapter Ⅰ. Synthesis and Evaluation of 6-Azauridine Analogs against RNA Viruses 10

Figure 1. FDA Approved antiviral nucleos(t)ide analogs 14

Figure 2. Structure of nucleos(t)ide and nucleobase 15

Figure 3. Biological mechanism of nucleos(t)ide analogs 16

Figure 4. OMPDC-catalyzed synthesis of UMP from OMP 17

Figure 5. Metabolism and mechanism of 6-azauridine 18

Figure 6. Structure of 6-azauridine analogs for antiviral activity in vitro 19

Figure 7. Structure of 6-azauridine and targeting molecules 20

Figure 8. ¹H-NMR spectrum of compound 6 in CDCl₃ 47

Figure 9. ¹H-NMR spectrum of compound 7 in CDCl₃ 47

Figure 10. ¹H-NMR spectrum of compound 9a in DMSO-d₆ 48

Figure 11. ¹H-NMR spectrum of compound 9b in DMSO-d₆ 48

Figure 12. ¹H-NMR spectrum of compound 10a in CDCl₃ 49

Figure 13. ¹H-NMR spectrum of compound 10b in CDCl₃ 49

Figure 14. ¹H-NMR spectrum of compound 10c in CDCl₃ 50

Figure 15. ¹H-NMR spectrum of compound 11a in CD₃OD 50

Figure 16. ¹H-NMR spectrum of compound 11b in DMSO-d₆ 51

Figure 17. ¹H-NMR spectrum of compound 11c in CD₃OD 51

Figure 18. ¹³C-NMR spectrum of compound 11c in DMSO-d₆ 52

Figure 19. ¹H-NMR spectrum of compound 13 in CDCl₃ 52

Figure 20. ¹H-NMR spectrum of compound 14 in CD₃OD 53

Figure 21. ¹H-NMR spectrum of compound 15 in CDCl₃ 53

Figure 22. ¹H-NMR spectrum of compound 16 in CD₃OD 54

Chapter Ⅱ. Development of an Efficient Synthetic Method for Machilin A and Biological Activity Evaluation of Its Analogs Targeting Lactate Dehydrogenase A 62

Figure 1. The difference in energetic glycolysis between normal cells... 65

Figure 2. Subunits and isomeric enzymes of LDH 66

Figure 3. LDH conversion of pyruvate and lactate 67

Figure 4. Structure of potential small-molecule LDHA inhibitors 67

Figure 5. Structure of Machilin A and binding site in LDHA 68

Figure 6. Inhibitory effect of Machilin A analogs (6-9) on LDHA and LDHB 76

Figure 7. Dose-dependent of Machilin A and its analogs (6-9) 77

Figure 8. ¹H-NMR spectrum of compound 3 in CDCl₃ 89

Figure 9. ¹³C-NMR spectrum of compound 3 in CDCl₃ 89

Figure 10. ¹H-NMR spectrum of compound 4 in CDCl₃ 90

Figure 11. ¹³C-NMR spectrum of compound 4 in CDCl₃ 90

Figure 12. ¹H-NMR spectrum of compound 5a in CDCl₃ 91

Figure 13. ¹³C-NMR spectrum of compound 5a in CDCl₃ 91

Figure 14. ¹H-NMR spectrum of compound 5b in CDCl₃ 92

Figure 15. ¹H-NMR spectrum of compound 1 in CDCl₃ 92

Figure 16. ¹³C-NMR spectrum of compound 1 in CDCl₃ 93

Figure 17. ¹H-NMR spectrum of compound 7 in DMSO-d₆ 93

Figure 18. ¹³C-NMR spectrum of compound 7 in DMSO-d₆ 94

Figure 19. ¹H-NMR spectrum of compound 8 in CDCl₃ 94

Figure 20. ¹³C-NMR spectrum of compound 8 in CDCl₃ 95

Figure 21. ¹H-NMR spectrum of compound 9 in DMSO-d₆ 95

List of Schemes 9

Chapter Ⅰ. Synthesis and Evaluation of 6-Azauridine Analogs against RNA Viruses 9

Scheme 1. Synthesis of compound 7 21

Scheme 2. Synthesis of compound 9a-b 22

Scheme 3. Synthesis of compound lla-c 23

Scheme 4. Synthesis of compound 14 and 16 25

Chapter Ⅱ. Development of an Efficient Synthetic Method for Machilin A and Biological Activity Evaluation of Its Analogs Targeting Lactate Dehydrogenase A 61

Scheme 1. Synthesis of 5a and 5b 71

Scheme 2. Synthesis of Machilin A (1) and 6 71

Scheme 3. Synthesis of compound 7, 8, and 9 73

초록보기

 마칠린 A는 결장암, 유방암, 폐암, 간암 등 다양한 암 세포 유형에서 선택적인 LDHA 억제 활성을 나타내며, 호기성과 혐기성 조건 모두에서 암 성장을 억제하고 에너지 대사를 억제하는 효과가 있었습니다. 그 잠재력에도 불구하고, 천연 추출물인 마칠린 A는 높은 비용, 긴 추출 시간, 낮은 수율 등과 같은 단점으로 인해 생체 내 시험과 같은 생물학적 연구에 필요한 물질 공급에 한계가 있습니다. 따라서 우리는 마칠린 A(1)의 대규모 합성을 가능하게 하는 간단하고 경제적이며 효율적인 합성 방법을 개발하여, 4단계에 걸쳐 74%의 전체 수율을 달성했습니다. 우리의 마칠린 A(1) 합성법은 저렴하고 상업적으로 이용 가능한 1-피페로닐아세트산(2)을 출발 물질로 사용하며, Dakin-west 반응, McMurry 반응, 촉매 수소화 반응을 주요 단계로 포함합니다. 또한, 우리는 간단하게 구할 수 있는 출발 물질인 헤리오날(6)로부터 마칠린 A 유사체(7-9)를 합성하였고, 이들을 시험관 내에서 LDHA 및 LDHB 억제 활성을 평가했습니다. 그 중, 화합물 9는 시험관 내에서 마칠린 A(IC₅₀ 33.17 μM)보다 약 30배 향상된 효능(IC₅₀ 1.60 μM)을 가진 중간 정도의 LDHA 억제 활성을 나타냈습니다. 다른 마칠린 A 유사체들도 선택적인 LDHA 억제 효과를 보였으며, 시험관 내에서 LDHB 억제에는 큰 영향을 미치지 않았습니다. 따라서, 우리는 마칠린 A의 간결한 합성 경로를 제공하고 다양한 유사체의 개발과 생체 내 시험과 같은 생물학적 연구를 지원한다고 보고합니다.

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