본문 바로가기 주메뉴 바로가기
22대 대한민국 국회 국회정보길라잡이 국회의원검색
회원가입 로그인
HOME

정보검색

소장정보 검색

국회도서관 홈으로 정보검색 소장정보 검색
결과 내 검색 동의어 포함
결과 내 검색 동의어 포함

-

목차보기

표제지

목차

초록 20

1. Introduction 21

1. Anticancer Therapy 21

2. Molecular Hybridization 25

3. Conventional Drugs 27

3-1) Anticancer drugs 27

3-2) Other disease drugs 34

II. Research Objectives and Results 37

1. Drug Discovery 37

2. Design & Molecular Construction 39

2-1) Synthesis of hybrid compounds A-F derived from Omeprazole intermediate(이미지참조) 39

2-2) Synthesis of hybrid compounds G-L derived from Quinolone intermediate(이미지참조) 46

2-3) Synthesis of hybrid compounds M-R derived from Sorafenib intermediate(이미지참조) 54

2-4) Synthesis of hybrid compounds S-X derived from Dasatinib & Erlotinib intermediate(이미지참조) 61

2-5) Biological Assay 68

3. Diaryl Urea Derivatives 74

3-1) Diaryl urea inhibitor 74

3-2) Design and synthesis of compounds N & Q derivatives(이미지참조) 76

3-3) Biological Assay 83

4. Biological Evaluation of Compound N-3(이미지참조) 85

4-1) Apoptosis 87

4-2) Materials and methods 89

4-3) Biological evaluation 95

III. Experimental Section 109

1. Chemistry 109

2. General Procedures 115

2-1) General procedures for preparation of conventional drug intermediates 115

2-2) General procedures for preparation of hybrid compounds A-X(이미지참조) 141

IV. Conclusion 197

V. Reference 199

VI. Appendix 207

Abstract 287

표목차

[Table 1.] 화합물 A~F에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 68

[Table 2.] 화합물 G~L에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 69

[Table 3.] 화합물 M~R에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 70

[Table 4.] 화합물 S~X에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 71

[Table 5.] 화합물 N 유도체 합성 결과(이미지참조) 80

[Table 6.] 화합물 Q 유도체 합성 결과(이미지참조) 82

[Table 7.] 화합물 N 유도체에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 83

[Table 8.] 화합물 Q 유도체에 대한 SRB(sulforhodaime B) assay 측정결과(이미지참조) 83

[Table 9.] 실험에 사용한 사람 암 세포주 종류 89

그림목차

[Fig. 1.] Characteristic of cancer cells 21

[Fig. 2.] Classification of anti-cancer drugs 22

[Fig. 3.] History of therapy for anticancer drugs 23

[Fig. 4.] FDA-approved PKI drugs 24

[Fig. 5.] Proposal of chemical evolution by combination of different... 26

[Fig. 6.] Mechanism of action for Imatinib 27

[Fig. 7.] Mechanism of action for Sorafenib 28

[Fig. 8.] Mechanism of action for Nilotinib 29

[Fig. 9.] HER2-targeted therapies 30

[Fig. 10.] Mechanism of action for Dasatinib 31

[Fig. 11.] Mechanism of action for Erlotinib 32

[Fig. 12.] Mechanism of action for Decitabine 33

[Fig. 13.] A systemic diagram for developing of new drugs 37

[Fig. 14.] Mechanism of action for Omeprazole 39

[Fig. 15.] Molecular hybridization for synthesis of hybrid... 40

[Fig. 16.] Typical antibiotic drugs of fluoroquinolone 46

[Fig. 17.] Molecular hybridization for synthesis of hybrid... 48

[Fig. 18.] Ribbons diagram of B-RAF kinase domain in complex... 54

[Fig. 19.] Molecular hybridization for synthesis of hybrid... 56

[Fig. 20.] The generation mechanism of the Philadelphia chromosome 61

[Fig. 21.] Mechanism of action for Dasatinib 62

[Fig. 22.] Bcr-Abl binding with Imatinib, Dasatinib and Nilotinib 63

[Fig. 23.] Mechanism of action for Erlotinib 63

[Fig. 24.] Molecular hybridization for synthesis of hybrid... 64

[Fig. 25.] Hybrid compounds harboring diaryl urea scaffold (M, N, O, Q...(이미지참조) 72

[Fig. 26.] Hybrid compound W derived from Nilotinib and Dasatinib(이미지참조) 73

[Fig. 27.] Anticancer drugs harboring diaryl urea scaffold 75

[Fig. 28.] Crystal structure of Sorafenib bound to B-RAF kinase 76

[Fig. 29.] Structure of Sorafenib 77

[Fig. 30.] Design of compound N and compound Q(이미지참조) 77

[Fig. 31.] Synthetic plan of compound N derivatives(이미지참조) 79

[Fig. 32.] Synthetic plan of compound Q derivatives(이미지참조) 81

[Fig. 33.] Type of cell death 85

[Fig. 34.] Intrinsic/Extrinsic pathway of apoptosis 88

[Fig. 35.] Effect of compound N-3 on the viability of MCF-7,...(이미지참조) 96

[Fig. 36.] Effect of compound N-3 on apoptosis in MCF-7,...(이미지참조) 98

[Fig. 37.] Effect of compound N-3 on the levels of Bel-2 family...(이미지참조) 99

[Fig. 38.] Effect of compound N-3 on apoptosis in MCF-7,...(이미지참조) 100

[Fig. 39.] Effect of a caspase inhibitor (z-VAD-fmk) on cell death... 101

[Fig. 40.] Mechanism of action for apotosis 102

[Fig. 41.] Effect of compound N-3 on the PARP cleavage in...(이미지참조) 103

[Fig. 42.] Effect of compound N-3 on the levels of cell cycle...(이미지참조) 104

[Fig. 43.] ¹H-NMR spectrum of Imatinib intermediate 3(이미지참조) 208

[Fig. 44.] ¹H-NMR spectrum of Poziotinib intermediate 7(이미지참조) 208

[Fig. 45.] ¹H-NMR of spectrum Ticagrelor intermediate 11(이미지참조) 209

[Fig. 46.] ¹H-NMR spectrum of Omeprazole intermediate 15(이미지참조) 209

[Fig. 47.] ¹H-NMR spectrum of Venlafaxine intermediate 18(이미지참조) 210

[Fig. 48.] ¹H-NMR spectrum of Rebamipid intermediate 21(이미지참조) 210

[Fig. 49.] ¹H-NMR spectrum of Quinolone intermediate 26(이미지참조) 211

[Fig. 50.] ¹H-NMR spectrum of Nilotinib intermediate 28(이미지참조) 211

[Fig. 51.] ¹H-NMR spectrum of 2-Amino-9-(ethyl... 212

[Fig. 52.] DSC data of Famciclovir intermediate 34(이미지참조) 213

[Fig. 53.] ¹H-NMR spectrum of Famciclovir intermediate 34(이미지참조) 213

[Fig. 54.] ¹H-NMR spectrum of Dasatinib intermediate 37(이미지참조) 214

[Fig. 55.] ¹H-NMR spectrum of Erlotinib intermediate 40(이미지참조) 214

[Fig. 56.] ¹H-NMR spectrum of Sorafenib intermediate 43(이미지참조) 215

[Fig. 57.] DSC & TGA data of compound A(이미지참조) 216

[Fig. 58.] ¹H-NMR spectrum of compound A(이미지참조) 217

[Fig. 59.] ¹³C-NMR spectrum of compound A(이미지참조) 217

[Fig. 60.] DSC & TGA data of compound B(이미지참조) 218

[Fig. 61.] ¹H-NMR spectrum of compound B(이미지참조) 219

[Fig. 62.] ¹³C-NMR spectrum of compound B(이미지참조) 219

[Fig. 63.] DSC & TGA data of compound C(이미지참조) 220

[Fig. 64.] ¹H-NMR spectrum of compound C(이미지참조) 221

[Fig. 65.] ¹³C-NMR spectrum of compound C(이미지참조) 221

[Fig. 66.] DSC & TGA data of compound D(이미지참조) 222

[Fig. 67.] ¹H-NMR spectrum of compound D(이미지참조) 223

[Fig. 68.] ¹³C-NMR spectrum of compound D(이미지참조) 223

[Fig. 69.] DSC & TGA data of compound E 224

[Fig. 70.] ¹H-NMR spectrum of compound E(이미지참조) 225

[Fig. 71.] ¹³C-NMR spectrum of compound E(이미지참조) 225

[Fig. 72.] DSC & TGA data of compound F(이미지참조) 226

[Fig. 73.] ¹H-NMR spectrum of compound F(이미지참조) 227

[Fig. 74.] ¹³C-NMR spectrum of compound F(이미지참조) 227

[Fig. 75.] DSC & TGA data of compound G(이미지참조) 228

[Fig. 76.] ¹H-NMR spectrum of compound G(이미지참조) 229

[Fig. 77.] ¹³C-NMR spectrum of compound G(이미지참조) 229

[Fig. 78.] DSC & TGA data of compound H(이미지참조) 230

[Fig. 79.] ¹H-NMR spectrum of compound H(이미지참조) 231

[Fig. 80.] ¹³C-NMR spectrum of compound H(이미지참조) 231

[Fig. 81.] DSC & TGA data of compound I(이미지참조) 232

[Fig. 82.] ¹H-NMR spectrum of compound I(이미지참조) 233

[Fig. 83.] DSC & TGA data of compound J(이미지참) 234

[Fig. 84.] ¹H-NMR spectrum of compound J(이미지참조) 235

[Fig. 85.] ¹³C-NMR spectrum of compound J(이미지참조) 235

[Fig. 86.] DSC & TGA data of compound K(이미지참조) 236

[Fig. 87.] ¹H-NMR spectrum of compound K(이미지참조) 237

[Fig. 88.] ¹³C-NMR spectrum of compound K(이미지참조) 237

[Fig. 89.] DSC &TGA data of compound L(이미지참조) 238

[Fig. 90.] ¹H-NMR spectrum of compound L(이미지참조) 239

[Fig. 91.] ¹³C-NMR spectrum of compound L(이미지참조) 239

[Fig. 92.] DSC & TGA data of compound M(이미지참조) 240

[Fig. 93.] ¹H-NMR spectrum of compound M(이미지참조) 241

[Fig. 94.] ¹³C-NMR spectrum of compound M(이미지참조) 241

[Fig. 95.] DSC & TGA data of compound N(이미지참조) 242

[Fig. 96.] XRD data of compound N(이미지참조) 243

[Fig. 97.] ¹H-NMR spectrum of compound N(이미지참조) 244

[Fig. 98.] ¹³C-NMR spectrum of compound N(이미지참조) 244

[Fig. 99.] Mass spectrum of compound N(이미지참조) 245

[Fig. 100.] DSC data of compound N-2(이미지참조) 246

[Fig. 101.] ¹H-NMR spectrum of compound N-2(이미지참조) 246

[Fig. 102.] ¹³C-NMR spectrum of compound N-2(이미지참조) 247

[Fig. 103.] DSC data of compound N-3(이미지참조) 248

[Fig. 104.] ¹H-NMR spectrum of compound N-3(이미지참조) 248

[Fig. 105.] ¹³C-NMR spectrum of compound N-3(이미지참조) 249

[Fig. 106.] DSC data of compound N-4(이미지참조) 250

[Fig. 107.] ¹H-NMR spectrum of compound N-4(이미지참조) 250

[Fig. 108.] ¹³C-NMR spectrum of compound N-4(이미지참조) 251

[Fig. 109.] DSC data of compound N-5(이미지참조) 252

[Fig. 110.] ¹H-NMR spectrum of compound N-5(이미지참조) 252

[Fig. 111.] ¹³C-NMR spectrum of compound N-5(이미지참조) 253

[Fig. 112.] DSC & TGA data of compound O(이미지참조) 254

[Fig. 113.] ¹H-NMR spectrum of compound O(이미지참조) 255

[Fig. 114.] ¹³C-NMR spectrum of compound O(이미지참조) 255

[Fig. 115.] DSC & TGA data of compound P(이미지참조) 256

[Fig. 116.] ¹H-NMR spectrum of compound P(이미지참조) 257

[Fig. 117.] ¹³C-NMR spectrum of compound P(이미지참조) 257

[Fig. 118.] DSC & TGA data of compound Q(이미지참조) 258

[Fig. 119.] XRD data of compound Q(이미지참조) 259

[Fig. 120.] ¹H-NMR spectrum of compound Q(이미지참조) 260

[Fig. 121.] ¹³C-NMR spectrum of compound Q(이미지참조) 260

[Fig. 122.] Mass spectrum of compound Q(이미지참조) 261

[Fig. 123.] DSC data of compound Q-2(이미지참조) 262

[Fig. 124.] ¹H-NMR spectrum of compound Q-2(이미지참조) 262

[Fig. 125.] ¹³C-NMR spectrum of compound Q-2(이미지참조) 263

[Fig. 126.] DSC data of compound Q-3(이미지참조) 264

[Fig. 127.] ¹H-NMR spectrum of compound Q-3(이미지참조) 264

[Fig. 128.] ¹³C-NMR spectrum of compound Q-3(이미지참조) 265

[Fig. 129.] DSC data of compound Q-4(이미지참조) 266

[Fig. 130.] ¹H-NMR spectrum of compound Q-4(이미지참조) 266

[Fig. 131.] ¹³C-NMR spectrum of compound Q-4(이미지참조) 267

[Fig. 132.] DSC data of compound Q-5(이미지참조) 268

[Fig. 133.] ¹H-NMR spectrum of compound Q-5(이미지참조) 268

[Fig. 134.] ¹³C-NMR spectrum of compound Q-5(이미지참조) 269

[Fig. 135.] DSC data of compound R(이미지참조) 270

[Fig. 136.] ¹H-NMR spectrum of compound R(이미지참조) 271

[Fig. 137.] ¹³C-NMR spectrum of compound R(이미지참조) 271

[Fig. 138.] DSC & TGA data of compound S(이미지참조) 272

[Fig. 139.] ¹H-NMR spectrum of compound S(이미지참) 273

[Fig. 140.] ¹³C-NMR spectrum of compound S(이미지참조) 273

[Fig. 141.] DSC & TGA data of compound T(이미지참조) 274

[Fig. 142.] ¹H-NMR spectrum of compound T(이미지참조) 275

[Fig. 143.] ¹³C-NMR spectrum of compound T(이미지참조) 275

[Fig. 144.] DSC & TGA data of compound U(이미지참조) 276

[Fig. 145.] ¹H-NMR spectrum of compound U(이미지참조) 277

[Fig. 146.] ¹³C-NMR spectrum of compound U(이미지참조) 277

[Fig. 147.] DSC & TGA data of compound V(이미지참조) 278

[Fig. 148.] ¹H-NMR spectrum of compound V(이미지참조) 279

[Fig. 149.] ¹³C-NMR spectrum of compound V(이미지참조) 279

[Fig. 150.] DSC & TGA data of compound W(이미지참조) 280

[Fig. 151.] XRD data of compound W(이미지참조) 281

[Fig. 152.] ¹H-NMR spectrum of compound W(이미지참조) 282

[Fig. 153.] ¹³C-NMR spectrum of compound W(이미지참) 282

[Fig. 154.] Mass spectrum of compound W(이미지참조) 283

[Fig. 155.] DSC data of compound X(이미지참조) 284

[Fig. 156.] ¹H-NMR spectrum of compound X(이미지참조) 285

[Fig. 157.] ¹³C-NMR spectrum of compound X(이미지참조) 285

도식목차

[Scheme 1.] Synthesis of Imatinib intermediate 3(이미지참조) 42

[Scheme 2.] Synthesis of Poziotib intermediate 7(이미지참조) 43

[Scheme 3.] Synthesis of Ticagrelor intermediate 11(이미지참조) 44

[Scheme 4.] Synthesis of Omeprazole intermediate 15(이미지참조) 45

[Scheme 5.] Synthesis of Venlafaxine intermediate 18(이미지참조) 50

[Scheme 6.] Synthesis of Rebamipid intermediate 21(이미지참조) 51

[Scheme 7.] Synthesis of Quinolone intermediate 26(이미지참조) 52

[Scheme 8.] Synthesis of Nilotinib intermediate 28(이미지참조) 58

[Scheme 9.] Synthesis of Famciclovir intermediate 34(이미지참조) 59

[Scheme 10.] Synthesis of Dasatinib intermediate 37(이미지참조) 60

[Scheme 11.] Synthesis of Erlotinib intermediate 40(이미지참조) 66

[Scheme 12.] Synthesis of Sorafenib intermediate 43(이미지참조) 67

[Scheme 13.] Synthesis of compound N-3(이미지참조) 90

초록보기

티로신 키나아제(tyrosine kinase)는 세포 내 신호 전달과 세포 활동을 조절하여 정상 세포의 성장 등에 중요한 역할을 하지만 과도한 티로신키나아제 활성은 암 및 자가 면역 질환 등을 일으키는 원인으로 알려져 있다.

2001년 미국 FDA에서 Bcr-Abl 티로신 키나아제 억제제로서 Imatinib(글리벡)을 허가함에 따라 항암치료제 개발에 있어 표적항암제라는 선택적이고 특이적인 치료제 개발이 가능하게 되었다. 그러나, Imatinib의 내성이 알려지면서 티로신 키나아제의 structural biology에 관련한 지식을 바탕으로 한 rational drug design을 통한 2세대 약물이 개발되기 시작하였다.

본 연구에서는 새로운 항암제를 개발하고자 약리활성이 확인된 약물들의 key intermediate 성분의 조합에 기초하는 분자 결합(molecular hybridization) 개념을 이용하여 새로운 화합물을 합성하였고, 이에 대한 생물학적 평가를 진행하였다. 그 결과, 특히, 다이아릴 우레아(diaryl urea) 구조가 도입된 화합물의 경우 우수한 항암 활성을 나타내었다. 또한, 화합물 N-3의 암세포에 대한 증식 억제 효과가 세포자살(Apoptosis)에 의한 세포사멸 기전임을 밝혔다.

추천서가 (다양한 추천 자료를 만나보세요)

권호기사보기

권호기사 목록 테이블로 기사명, 저자명, 페이지, 원문, 기사목차 순으로 되어있습니다.
기사명 저자명 페이지 원문 기사목차