螺旋?基異??類似物之合成與立體化學之研究

Synthesis and stereochemistry of spirobenzylisoquinoline analogues

黃孟婷(Huang Meng-ting)

指導教授 ： 陳繼明

臺北醫學大學/藥學院/藥學研究所/碩士(1998年)

摘要

螺旋?基異??類似物之合成與立 體化學之研究 JKL 1067 (2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquino line) (4)是一個合成的螺旋?基異??，具有增加心收縮力及減緩自發性心跳速率之抗 心律不整藥物。在本實驗室以往所合成出的十五種螺旋?基異??類似物中，發現三種類 似物之藥理活性與JKL 1067相當或更強，依據藥效較佳化合物之構造特徵，我們以化學合 成製備其類似物26。 化學合成方面，首先以?基異??類衍生物41進行Mannich縮合 反應合成原小蘗鹼型衍生物42，再與CH3I反應生成N-methiodide salt之後，經由Stevens 重排反應，在強鹼dimsyl sodium催化下合成類似物26。 由於合成之JKL 1067 (4) 結 構上具有一個不對稱中心，共存左右旋體，依前述之方法合成(*)-JKL 1067 (4)，再以S- (+)-binaphthyl-phosphoric acid (53a)和R-(-)-binaphthylphosphoric acid (53b)將( *)-JKL 1067 (4) 作光學切割，得到單一光學活性體 (-)-JKL 1067 (4a)及(+)-JKL 1067 (4b)，經旋光度測定法、對掌性管柱-高壓液相層析法及CD光譜確認無誤，然後將化合物 4, 4a, 4b及26作抗心律不整之活性測試，以期探討化學結構的特徵與藥理活性之關係。 而先前所合成結構上具有不對稱中心之化合物19, 20, 21, 22及25，也成功得以cellulos e-base chiral column分離，其分離係數a為1.3∼2.8。 最後我們將本實驗室所合成 過之十五種螺旋?基異??類似物的藥理評估結果，利用Catalyst這個軟體程式經電腦分 子模擬進行構形解析，產生皆由兩個氫鍵接受者及三個厭水性基團所組成之三度空間藥效 基團模型Hypo-R.V.及Hypo-L.A.，進而從NCI、MiniBioByte及Sample等資料庫（database ）中搜尋出具相同活性之化合物，作為未來設計抗心律不整藥物的重要參考標準。

關鍵字

螺旋?基異 ； 異 ； 立體化學

並列摘要

Synthesis and Stereochemistry of Spirobenzylisoquinoline Analogues JKL 1067 ( 2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquinoline ) (4), a synthetic antiarrhythmic drug can slow down the heart rate and enhance the cardiac contractility. In the previous study, three spirobenzylisoquinoline analogues, show the equal or somewhat even more potent effect compared with JKL 1067 (4) in cardiac tissues. In the present study, spirobenzylisoquinoline 26 were prepared based on the structure modification of these three analogues. Protoberberine42 was synthesized from the Mannich condensation of the benzyl- isoquinoline 41 with formalin and followed reaction with methiodide to yield the N-methyltetrahydroprotoberberinium iodide 43. Finally, Stevens rearrange- ment of 43 catalyzed by dimsyl sodium in DMSO gave the target compound 26. In order to study the enantioselectivity of JKL 1067 (4) on cardiac tissue, JKL 1067 (4) was prepared and then resoluted by S-(+)-binaphthylphosphoric acid (53a) and R-(-)-binaphthylphosphoric acid (53b) to gave two enantiomers, (-)-JKL 1067 (4a) and (+)-JKL 1067 (4b). Optical purity of the enatiomer was conformed by specific rotation, chiral HPLC, and CD spectra. Analog 4, 4a, 4b and 26 will be tested on the isolated cardiac tissue. Several spirobenzyliso- quinoline 19, 20, 21, 22 and 25 were also well-resolved in a cellulose-base chiral column by HPLC ( separation factor a = 1.3~2.8 ). A computer program of Catalyst, was utilized to perform conformational analysis of the fifteen analogues. Two three-dimensional pharmacophore models of hypo-R.V. and hypo-L.A. were generated. These composed of two hydrogen bond acceptors and three hydrophobic groups. Then we could use these models to search the biosteric compounds from the several databases such as NCI, Minibiobyte and Sample. The three-dimensional pharmacophore could be further utilized as one of the tools to design more active antiarrythemic drug.

並列關鍵字

Spirobenzylisoquinoline ； Isoquinoline ； Stereochemistry