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研究生:周立琛
研究生(外文):Li-Chen Chou
論文名稱:1,3,5-取代硒吩[3,2-c]吡唑類緣化合物之合成及其抗癌活性、2-苯基-4-喹啉酮類衍生物磷酸鹽前驅藥之合成及其抗癌活性
論文名稱(外文):Synthesis and anticancer activity of 1,3,5-substituted selenolo[3,2-c]pyrazole analogues、Synthesis and anticancer activity of hydrophilic phosphate prodrugs of 2-phenyl-4-quinolone derivatives
指導教授:郭盛助郭盛助引用關係
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:藥物化學研究所博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:375
中文關鍵詞:YC-1selenolopyrazolefuropyrazole結構與活性關係肺癌腎癌phosphate前藥細胞凋亡
外文關鍵詞:YC-1selenolopyrazolefuropyrazoleSARlung cancerrenal cancerphosphate-prodrugsapoptosis
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本研究之目的在開發具有潛能之抗癌活性的化合物做為準新藥。此論文分成二部份,其中第一部份,著者為拓展YC-1的物質專利版圖和尋找到抗癌活性較YC-1更為優越之新藥候補物質(new candidate),合成了四種不同骨架YC-1的furopyrazole衍生物 (11−22, 28−36)、thienopyrazole衍生物 (42−45, 50−53)、 selenolopyrazole衍生物 (67−72, 75−77) 及indazole衍生物 (99−118, 123−128),並將合成之化合物針對NCI-H226肺癌細胞及A498腎癌細胞建立SAR的關係。繼而從SAR的結果中挑選出四種不同骨架中活性最優越的化合物13 (CLC107), 44 (CLC015), 69 (CLC005)及127 (CLC802a)送往美國NCI進行60種human cancer cell line抗癌活性評估及COMPARE program比對,結果預測這四個化合物具有新穎的作用機轉與現有抗癌藥物不同,極具開發價值。最後也經動物實驗證實化合物127 (CLC802a)的抗癌活性與YC-1相當,可以說尋找到一個YC-1在新藥開發的候選物質。
第二部份,著者解決了2-phenyl-4-quinolone類緣化合物在藥物動力學上所遇到的問題,試著在2-phenyl-4-quinolone的4位ketone上接phosphoric acid做成phosphate prodrugs來改善其水溶性的困擾,順利合成出2-phenyl-4-quinolone類緣化合物的單鈉磷酸鹽的親水性前驅藥 (35-40),期望可以適合用於臨床上口服(PO)及靜脈注射(IV)的給藥方式。
我們以2-phenyl-4-quinolone類緣化合物中抗腫瘤活性最優越的化合物8 (CHM-1)為研究重點。經藥物動力學測試結果,確定化合物35 (CHM-1-P-Na)在生物體內會轉變為化合物8 (CHM-1)。並且我們由酵素活性分析(enzyme activity assay)及受體結合實驗分析(receptor binding assay)來評估化合物8 (CHM-1)及化合物35 (CHM-1-P-Na) 的安全性藥理(safety pharmacology),推測在臨床試驗中不會有太多的副作用,可謂是非常安全及有效的藥物。此外,我們在SKOV-3 Xenograft SCID mice model及CT-26 colon adenocarcinoma Balb/c mice orthotopic model中具有優異的抗腫瘤活性,證實化合物35 (CHM-1-P-Na)為具有發展為抗癌臨床試驗的候選藥物,希望這系列化合物可以成功地發展為臨床用藥來造福人群。
The purpose of this study is to develop compounds with potential anticancer activity as new drug candidate. This thesis consists of two parts. In the first part, four different skeletons of YC-1 derivatives [furopyrazole derivatives (11-22, 28-36), thienopyrazole derivatives (42-45, 50-53), selenopyrazole derivatives (67-72, 75-77), and indazole derivatives (99−118, 123−128)] were synthesized in order to expand the substance patent’s inclusion of YC-1 and find new candidate with better anticancer activity than YC-1, and constructed their SAR in NCI-H226 and A498 cells. Compound 13 (CLC107), 44 (CLC015), 69 (CLC005), and 127 (CLC802a) were chosen for evaluation against 60 human cancer cell lines (the NCI-60) and COMPARE program analysis, and indicated that four compounds were with great development value since they possessed novel mechanism of action different from existing anticancer drugs. Finally compound 127 was proved to demonstrate anticancer activity similar to YC-1 in animal model, it is thus a new candidate of YC-1 in drug development.
In the second part, the problem of 2-phenyl-4-quinolone derivatives in pharmacokinetics is resolved. In order to improve solubility problem, a phosphoric acid was attempted to be attached to 4-ketone of 2-phenyl-4-quinolone, and thus phosphate monosodium salts of 2-phenyl-4-quinolone derivatives were successfully created, which were expected to be applied by po and iv routes in clinics.
Among 2-phenyl-4-quinolone derivatives, we focus on compound 8 which demonstrated the most significant antitumor activity. According to the data of Pharmacokinetics, compound 35 was proved to be transformed in vivo to compound 8 (CHM-1). After the assessment of safety pharmacology of compound 35 in enzyme activity assay and receptor binding assay, we predict it is very effective and safe drug while there should not be too many side effects in clinical trials. Besides, it showed excellent antitumor activity in SKOV-3 Xenograft SCID mice model and CT-26 colon adenocarcinoma Balb/c mice orthotopic model. It is confirmed that compound 35 (CHM-1-P-Na) is a drug candidate for further development as a potential anticancer agent in the clinic. We hope this series of compounds can successfully become clinical therapeutic agents which are beneficial to human beings.
I. 1,3,5-取代硒吩[3,2-c]吡唑類緣化合物之合成及其抗癌活性
目錄 ………. I
圖目錄 ………. V
表目錄 ………. VI
縮寫表 ………. VII
標的化合物代號與結構對照表 ………. VIII
化合物之光譜圖(MS, IR, NMR圖譜)目錄 ………. XI
第一章 緒論 ………. 1
第一節 癌症流行病學 ………. 1
第二節 YC-1之研究概況 ………. 5
I. cGMP依存性的藥理作用(cGMP-dependent pharmacological action) ………. 5
II. 優越的抗癌活性 ………. 6
II-1. 體外試驗(in vitro test) ………. 6
II-1-1. 抗血管新生活性(anti-angiogenesis) ………. 6
II-1-2. 促進癌細胞凋亡(apoptosis) ………. 7
II-1-3. 選擇的細胞致毒活性 ………. 8
II-1-4. 抑制 Matrix Metalloproteinases(MMPs)活性 ………. 8
II-2. 活體試驗(in vivo test) ………. 8
第三節 五員雜環(five membered heterocycles)的基本性質 ………. 10
I. Furan, thiophene及selenophene的鍵長(bond length)與鍵角(bond angle) ………. 10
II. Furan, thiophene及 selenophene的物理性質 ………. 12
III. Furan, thiophene及selenophene 的芳香性質(aromaticity) ………. 13
III-1. 從共振混成體(resonance hybrids)來討論五員雜環的芳香性 ………. 13
III-2. 從共振能(resonance energy)的大小來討論五員雜環的芳香性 ………. 14
III-3. 利用五員雜環C(2)-C(3)與C(3)-C(4)鍵長的比值來評估其的芳香性 ………. 14
III-4. 利用環狀電流(ring current)的比較來評估五員雜環的芳香性 ………. 14
第二章 研究動機與目的 ………. 15
I. 拓展YC-1的物質專利版圖 ………. 15
I-1. 標的化合物之設定 ………. 15
I-1-1. 1,3,5-Substituted furo[3,2-c]pyrazole derivatives ( I ) ………. 15
I-1-2. 1,3,5-Substituted thieno[3,2-c]pyrazole derivatives ( II ) ………. 16
I-1-3. 1,3,5-Substituted selenolo[3, 2-c]pyrazole derivatives ( III ) ………. 16
I-1-4. 1,3,5,6-Substituted indazole derivatives ( IV ) ………. 17
II. 建立YC-1 analogues在抗癌活性上的SAR ………. 18
第三章 研究經過 ………. 20
第一節 化學合成 ………. 20
I. 1,3,5-Substituted furo[3, 2-c]pyrazole derivatives ( I )之合成概論 ………. 20
I-1. 1-Substituted-3-(5-substituted-2-furyl)-5-methyl- furo[3,2-c]pyrazole (11–16)之合成 (Scheme 1) ………. 20
I-2. 1-Benzyl-3-(5-substituted-2-furyl)-5-methyl- furo[3,2-c]pyrazole (18, 19, 22 )衍生物之合成 (Scheme 2) ………. 27
I-3. 1-Substituted-3-(4-substituted-phenyl)-5-methyl- furo[3,2-c]pyrazole (28–36)衍生物之合成 (Scheme 3) ………. 32
II. 1,3,5-Substituted thieno[3,2-c]pyrazole derivatives ( II )之合成概論 ………. 36
II-1. 1-Substituted-3-(5-substituted-2-furyl)-5-methyl- thieno[3,2-c]pyrazole (42–45)之合成(Scheme 4) ………. 36
II-2. 1-Substituted-3-(4-substituted phenyl)-5-methyl- thieno[3,2-c]pyrazole (50–53)衍生物之合成 (Scheme 5) ………. 40
III. 1,3,5-Substituted selenolo[3,2-c]pyrazole derivatives ( III )之合成概論 ………. 41
III-1. 1-Benzyl-3-(5-substituted-2-furyl)-5-substituted selenolo[3,2-c]pyrazole (67–72)之合成 (Scheme 6) ………. 41
III-2. 1-Benzyl-3-(4-substituted-phenyl)- selenolo[3,2-c]pyrazole (75–77)衍生物之合成(Scheme 7) ………. 47
IV. 1,3,5,6-Substituted indazole derivatives ( IV )之合成概論 ………. 48
IV-1. 1-Benzyl-3-(5-substituted-2-furyl)-5,6- substituted indazole (99–118)之合成(Scheme 8) ………. 48
IV-2. 1-Substituted-3-(5-substituted-2-furyl)indazole (120–128)之合成(Scheme 9) ………. 50
第二節 藥理活性試驗結果 ………. 53
I. 細胞致毒活性 ………. 53
I-1. Furo[3,2-c]pyrazole衍生物的癌細胞致毒活性 ………. 53
I-2. Thieno[3,2-c]pyrazole衍生物的癌細胞致毒活性 ………. 55
I-3. Selenolo[3,2-c]pyrazole衍生物的癌細胞致毒活性 ………. 56
I-4. YC-1的indazole衍生物的癌細胞致毒活性 ………. 57
II. 利用NCI 60種人類腫瘤細胞株(human cancer cell line panel)評估抗癌活性 ………. 60
II-1. One Dose Mean Graph (10 ?嵱)篩選結果 ………. 61
II-2. Mean Graphs (Finger print) ………. 66
II-3. COMPARE program ………. 76
III. 動物試驗評估 ………. 78
第四章 結論 ………. 80
第五章 實驗部份 ………. 83
第一節 試藥與溶媒 ………. 83
第二節 重要儀器與實驗材料 ………. 85
第三節 化合物之製備 ………. 87
第四節 藥理活性試驗方法 ………. 155
I. 細胞致毒活性 ………. 155
II. 利用NCI 60種人類腫瘤細胞株(human cancer cell line panel)評估抗癌活性 ………. 156
III. 動物試驗評估 ………. 156
參考文獻 ………. 157
化合物之光譜圖(MS, IR, NMR圖譜) ………. 163
II. 2-苯基-4-喹啉酮類衍生物磷酸鹽前驅藥之合成及其抗癌活性
目錄 ………. XIX
圖目錄 ………. XXI
表目錄 ………. XXIV
縮寫表 ………. XXV
標的化合物代號與結構對照表 ………. XXVI
第一章 緒論 ………. 305
第一節 2-Phenyl-4-quinolone類緣化合物之研究概況 ………. 305
I. CHM-1之體外試驗 (in vitro test) ………. 306
I-1. 微小管抑制活性(Microtubule Inhibition) ………. 306
I-2. 促進癌細胞凋亡(Apoptosis Induction) ………. 306
I-3. 抑制癌細胞轉移(Anti-metastasis) ………. 306
I-4. COMPARE correlation ………. 306
II. CHM-1之抗癌動物試驗(in vivo test) ………. 307
II-1. HA-22T hepatoma xenograft SCID mice model ………. 307
II-2. OVCAR-3 xenograft mice model ………. 309
第二節 細胞週期(Cell cycle)調控機制 ………. 310
第三節 細胞凋亡(Apoptosis) ………. 313
第四節 2-phenyl-4-quinolone衍生物之合成 ………. 316
第二章 研究動機與目的 ………. 319
第三章 研究經過 ………. 321
第一節 化學合成 ………. 321
I. 中間體 (8-10, 19-21)的合成 ………. 321
II. Monosodium phosphate salt of 2-phenyl-4-quinolone類緣化合物 (35-40) 之合成 (Scheme 7) ………. 322
第二節 藥物動力學評估 ………. 329
I. 2-(2-Fluorophenyl)-6,7-methylenedioxy-quinolon ( 8 ) (CHM-1)之藥物動力學 ………. 329
I-1. 腹腔注射單一劑量投藥評估 ………. 329
II. Sodium 2-(2-fluorophenyl)-6,7- methylenedioxyquinolin-4-yl hydrogen phosphate (35)(CHM-1-P-Na)之藥物動力學 ………. 330
II-1. 靜脈注射單一劑量投藥評估 ………. 330
II-2. 口服單一劑量投藥 ………. 332
第三節 安全性藥理評估 ………. 335
I. 2-(2-Fluorophenyl)-6,7-methylenedioxy-quinolon (8) (CHM-1)之安全性藥理 ………. 336
II. Sodium 2-(2-fluorophenyl)-6,7- methylenedioxyquinolin-4-yl hydrogen phosphate (35)(CHM-1-P-Na)之安全性藥理 ………. 337
第四節 動物試驗評估 ………. 338
I-1. SKOV-3 Xenograft SCID mice model (PO給藥) ………. 338
II-2. SKOV-3 Xenograft SCID mice model (IV 給藥) ………. 339
II-3. CT-26 colon adenocarcinoma Balb/c mice orthotopic model (PO 給藥) ………. 341
第五節 作用機轉 ………. 344
I. 化合物8 (CHM-1)對CT-26細胞之細胞週期影響 ………. 344
II. 化合物8 (CHM-1)對CT-26細胞之細胞週期G2/M期相關蛋白質影響 ………. 345
III. 化合物8 (CHM-1)誘導CT-26細胞凋亡 ………. 346
IV. 化合物8(CHM-1)對細胞凋亡Bcl-2家族蛋白的影響 ………. 348
第四章 結論 ………. 350
第五章 實驗部份 ………. 352
第一節 試藥與溶媒 ………. 352
第二節 重要儀器與實驗材料 ………. 354
第三節 化合物之製備 ………. 356
第四節 藥物動力學評估方法 ………. 367
第五節 安全性藥理評估方法 ………. 368
第六節 動物試驗評估方法 ………. 368
第七節 藥理實驗(作用機轉)評估方法 ………. 369
參考文獻 ………. 371
I. 1,3,5-取代硒吩[3,2-c]吡唑類緣化合物之合成及其抗癌活性
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