靛玉紅衍生物之合成研究及其抗癌作用

1. 靛玉紅衍生物之合成研究及其抗癌作用 • 中文摘要 • indirubin藥理作用具有抑制cyclin-dependent kinase(CDKs)、glycogen synthesis kinase(GSK-3)也是aryl hydrocarbon receptor (AhR)致效劑。因indirubin抑制CDK便會造成細胞週期停止在G1 and G2/M phase，進而抑制細胞增生或是細胞毒殺。Indirubin曾在慢性骨髓白血病(CML)臨床試驗發現副作用很少，不會影響造血功能、肝及腎功能。為改善indirubin溶解度不佳，並增加活性，經化學構造修飾並探討indirubin之化學構造與藥效關係。本論文擬合成indirubin衍生物並探討結構與藥效的關係，提供藥物設計者的重要參考。 • 合成indirubins最簡便的方法就是在無氧的情況下結合indoxyl acetate和isatins(63~73)便得到化合物3、30~39 (產率：70~90%)。利用3,4位不同取代的aniline加入chloral hydrate和NH2OH HCl反應得到isonitrosoacetanilides (57~62)，以濃硫酸或是BF3當催化劑加熱會產生isatins (63~68)。Indirubins(3、30~39)用pyridine溶解再加入NH2OH HCl即能得到indirubins -3’-oximes(20、40~49)，產率為70~80%。 • 藉由MTT assay可發現對於MCF-7抗乳癌活性最好的是化合物49和48，IC50為9.67、16.9μM；對於U937抗白血病活性最好的是化合物44和42 ，IC50為3.95、4.67μM，化合物40、41、43、48、49仍比化合物20有效，化合物45、46、47對兩種細胞均無抑制作用。

2. Synthesis of indirubin analogues as antitumor agents • 英文摘要 • Indirubins were found to inhibit the cell cycle regulating cyclin-dependent kinases(CDKs),glycogen synthesis kinase(GSK-3) and aryl hydrocarbon receptor (AhR) agonist. Indirubins inhibit the proliferation of cells through arresting the cells in the G1 and G2/M phase of the cell cycle by inhibition of CDKs. Indirubins exhibited good antitumor activity and minor toxicity in chronic myelocytic leukemia clinical trials. Indirubin didn’t affect the production of haematopoietic stem cells nor the function of liver and kidney. To improve the indirubin’s defect of poor solubility and absorption, we design a series of indirubin analogues by chemical modification for its structure. In this paper, we synthesis several indirubin analogues and provide the SAR study for further drug designer. • For synthesis of indiruins(3、30~39), the most convenient method is that dimerization of indoxyl acetate and isatins(63~73).The desired isatins were prepared through using the corresponding 3,4-mono or bisubstituted anilines as starting materials. The appropriate anilines were reacted with chloral hydrate and hydroxylamine hydrochloride to give the corresponding isonitrosoacetanilides (57~62), and were heated with c-H2SO4 or BF3 to give desired isatins(63~68)。The indirubins - 3’ – oximes (20、40~49) were synthesized from the indirubins(3、30~39) with hydroxylamine hydrochloride in pyridine under reflux.(yield：70~80%) • For anti-proliferation of MCF-7(human breast cancer epithelial cell line), the most potent compound of 49 and 48 showed a IC50 of 9.67 and 16.9μM ；For anti-proliferation of U937(human monocytic leukemia cells), the most potent compound of 44 and 42 showed a IC50 of 3.95 and 4.67μM. Compound 40、41、43、48、49 were still more potent than compound 20 but compound 45、46、47 were inactive in both MCF-7 and U937 cells.