Liriodenine類似物之化學合成研究

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題名:	Liriodenine類似物之化學合成研究 Synthesis of Liriodenine Analogs
作者:	蘇春綿 Chun-Mien Su
貢獻者:	藥學研究所
關鍵詞:	Liriodenine Liriodenine
日期:	2003
上傳時間:	2009-09-11 16:56:55 (UTC+8)
摘要:	中文摘要 Liriodenine類似物之化學合成研究 Liriodenine(1) 是從Liriodendron tulipifera L 之heartwood中分離出的7-oxoaporphine的生物鹼。最近的報告證實liriodenine為一種很強topoisomeraseⅡ抑制劑，利用其平面的分子結構，如同DNA的崁入劑般發揮抗癌作用。此外有一些體內的藥理研究報告證明lirodenine也有抗心律不整的作用。Liriodenine經藥理活性篩選發現其對於carbachol誘發天竺鼠支氣管平滑肌之收縮具有鬆弛作用，但對心臟強心作用之活性僅為平滑肌鬆弛作用之十分之一而已。這些藥理作用證實liriodenine也是屬於一選擇性的M3 receptor抑制劑，且其結構與其他的選擇性的M3 receptor抑制劑( 如, 4-DAMP)有很大的不同。因此，本實驗室的研究重點將著重於發展並找出新又簡易之合成liriodenine的方法，並嘗試去合成更多與liriodenine結構類似的衍生物，以利於將來的新藥的研發。本實驗室之採用兩種方法進行liriodenine的合成。方法一、二，皆是先利用piperonal及aminoacetaldehyde dimethyl acetal 進行縮合反應後再運用Pomeranz-Fritsch reaction進行isoquinoline環化反應來製備6,7-methylenedioxyisoquinoline (23)，然後再將23與benzoyl chloride 及trimethylsilyl cyanide 去製備 isoquinoline reissert 化合物24 。接下來，方法一則是將24與2-bromobenzaldehyde反應形成 benzylisoquinoline ester 27，經水解得到16，與tributyltin hydride 進行自由基分子內的環化反應即可得到liriodenine (產率35%) 及一副產物32 (產率55%)。第二種方法是將24與2-bromobenzyl chloride反應形成1-bromobenzyl-6,7-methylene- dioxyisoquinoline (34) 後再運用Bu3SnH/AIBN進行環化反應，所得之中間體沒有分離出來使直接經由空氣中自行氧化得到liriodenine (產率15%)，從研究結果發現所採用的方法較文獻所述簡單，但liriodenine的總產率並無提高，又本化合物由方法ㄧ總產率較方法二微高。本研究也合成兩種liriodenine衍生物38及39，係由化合物1分別與hydroxylamine hydrochloride及hydrazine hydrate反應而得 (產率約80%)。 Abstract Synthesis of Liriodenine Analogs Liriodenine (1) ， an 7-oxoaporphine alkaloid was isolated from the heartwood of Liriodendron tulipifera L。 Recently，it was found that the nature product exhibited inhibitory activity against TopoⅡ because of its planar molecule having DNA intercalation capability。 The in vivo biological studies also know that liriodenine possessed a prominent antiarrhythmic activity ， antimicrobial action，antibacterial，antifungal activity，mutagenicity andantiplatelet actions。Tracheal contraction of guinea-pig induced by carbachol was inhibited by liriodenine。 The cardiotonic effect of this agent was just only one tenth potency compared with smooth muscle relaxation effect。It demonstrated that liriodenine is a selective muscarinic M3 subtype receptor antagonist。 Since the natural product is structurally different from the known M3 antagonist (e.g. 4-DAMP)。 It is of great interest to develop a new and facile synthesis route for liriodenine, and its analogs as selective M3 antagonists。 Two methods were applied for the synthesis of liriodenine。The natural product 1 was prepared by starting from the reaction of piperonal and aminoacetaldehyde dimethyl acetal to form 6,7-methylenedioxyisoquinoline 23 via Promeranz-Fritsch reaction in 4 steps。Compound 23 was then treated with benzoyl chloride，followed with trimethylsilyl cyanide to yield isoquinoline Reissert compound 24 in good yield。In Method 1: Compound 24 was reacted with 2-bromobenzaldehyde to form benzylisoquinoline ester 27，which was then hydrolyzed to afford 16。Treatment of compound 16 with tributyltin hydride followed with air autooxidation to give the desired product 1 together with by-product 32，Alternatively (method 2): compound 24 was reacted with 2-bromobenzyl chloride to give 1-bromobenzyl-6,7-methyleedioxyisoquinoline (34)，which was further treated with Bu3SnH/AIBN and air autooxidation in one-pot reaction to afford liriodenine (1) in low yield 。 The present results showed that the overall yield of liriodenine by Method 1 was slightly higher than that by Method 2。Two new analogues of liriodenine，compounds 38 and 39，were also prepared in high yield (80%) by the reaction of compound 1 with hydroxylamine hydrochloride and hydrazine hydrate，respectively。
資料類型:	thesis
顯示於類別:	[藥學系] 博碩士論文

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