β-Azatyrosinamides 之合成及抗癌活性研究   全文下載

Preparation and Antitumor Activities of β-Azatyrosinamides

攝護腺腫瘤為男性腫瘤死亡原因之第二位。大部分攝護腺腫瘤屬緩慢增生型，目前臨床使用之抗腫瘤細胞毒藥物（cytotoxic agents）多具有效果不彰而毒性太大的缺點。由於腫瘤的增生與細胞訊息傳導有關，研究報導由Streptomyces chibanensis 所產生之azatyrosine 對若干ras-基因變異之細胞例如NIH3T3 及攝護腺腫瘤PC3 等的生長具有選擇性抑制作用，而對非ras-基因變異之細胞則不具抑制作用。唯azatyrosine的藥理活性不夠大，本研究以azatyrosine 作為先導藥物，合成一系列β-azatyrosine 衍生物4-15 。該系列化合物對ras-基因變異之NIH3T3 細胞株的抑制活性（IC50）在0.13 ± 0.01 mM至3.16 ± 1.45 mM 之間，為azatyrosine的2-57倍，然而對ras-基因變異NIH3T3細胞株與野生型NIH3T3 細胞株之抑制活性（IC50）的比值為0.7-11.9 ，顯示抑制腫瘤的選擇性不夠理想。該系列化合物對PC-3 人類攝護腺腫瘤細胞株的抑制活性（IC50）在0.15 ± 0.02 mM 至13.05 ± 9.41 mM之間，為azatyrosine的0.4-33.3倍。

A large number of human prostate cancer cases has been proven to be genetically associated with ras-mutation. A series of α-azatyrosinamides prepared in this laboratory demonstrated selective cytotoxicity against ras-mutated NIH3T3 cells while with little toxicity on wild type NIH3T3 cells. The compounds also proved to be active in inhibiting human prostate cancer cell lines. Using α-azatyrosinamides as the leads, we prepared another series of novel β-azatyrosinamides for the purpose of treating human prostate cancer. Preparation of the β-azatyrosinamides starts from 5-benzyloxypyridin- 2-ylaldehyde (1), which upon reaction with malonic acid and ammonium acetate afforded 5-benzyloxy-β-azatyrosine (2). This intermediate was allowed to react with benzyloxycarbonic anhydride followed by coupling with a variety of amines to form the desired β-azatyrosinamides 4- 15. The compounds exhibited an inhibitory effect on the growth of ras-mutated NIH3T3 cells with IC50 ranged between 0.13 ± 0.01 mM and 3.16 ± 1.45 mM, which were with activities 2-57 fold higher than that of azatyrosine, but were much less active than their α-amino acid analogues. The selective toxicity, in terms of the ratio of IC50 against wild type NIH3T3 to that against ras-transformed NIH3T3 cell lines, is at the range of 0.7-11.9. The IC50’s of β-azatyrosinamides 4-15 on PC-3 human prostate cancer cell line ranged between 0.15 ± 0.02 mM and 13.05 ± 9.41 mM, which were 0.4-33 fold lower than that of azatyrosine. 攝護腺腫瘤為男性腫瘤死亡原因之第二位。大部分攝護腺腫瘤屬緩慢增生型，目前臨床使用之抗腫瘤細胞毒藥物（cytotoxic agents）多具有效果不彰而毒性太大的缺點。由於腫瘤的增生與細胞訊息傳導有關，研究報導由Streptomyces chibanensis 所產生之azatyrosine 對若干ras-基因變異之細胞例如NIH3T3 及攝護腺腫瘤PC3 等的生長具有選擇性抑制作用，而對非ras-基因變異之細胞則不具抑制作用。唯azatyrosine的藥理活性不夠大，本研究以azatyrosine 作為先導藥物，合成一系列β-azatyrosine 衍生物4-15 。該系列化合物對ras-基因變異之NIH3T3 細胞株的抑制活性（IC50）在0.13 ± 0.01 mM至3.16 ± 1.45 mM 之間，為azatyrosine的2-57倍，然而對ras-基因變異NIH3T3細胞株與野生型NIH3T3 細胞株之抑制活性（IC50）的比值為0.7-11.9 ，顯示抑制腫瘤的選擇性不夠理想。該系列化合物對PC-3 人類攝護腺腫瘤細胞株的抑制活性（IC50）在0.15 ± 0.02 mM 至13.05 ± 9.41 mM之間，為azatyrosine的0.4-33.3倍。