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; 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

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Title:	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;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
Authors:	周立琛;Li-Chen Chou
Contributors:	中國醫藥大學：藥物化學研究所博士班
Keywords:	YC-1;selenolopyrazole;furopyrazole;結構與活性關係;肺癌;腎癌;phosphate前藥;細胞凋亡;SAR;lung cancer;renal cancer;phosphate-prodrugs;apoptosis
Date:	2009-07-09
Issue Date:	2009-08-13 09:37:12 (UTC+8)
Abstract:	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.
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