Honda T, Kato M, Inoue M, Shimamoto T, Shima K, Nakanishi T, Yoshida T, Noguchi T
Suntory Institute for Biomedical Research, Osaka, Japan.
J Med Chem. 1988 Jul;31(7):1295-305. doi: 10.1021/jm00402a007.
A series of ellipticine glycosides [2-N-glycosyl quaternary pyridinium salts of three ellipticines: ellipticine (1), 9-methoxyellipticine (2), and 9-hydroxyellipticine (4)] were stereoselectively synthesized in good yields by an improved condensation reaction between ellipticines [1, 2, and 9-acetoxyellipticine (3)] and protected (peracylated and perbenzylated) glycosyl halides with cadmium carbonate, followed by deprotection. These glycosides were preliminarily evaluated for their antitumor activity in the L1210 leukemia system. Twenty-six (53%) of the 49 glycosides tested were curative, and five [9-hydroxyellipticine L-arabinopyranoside (41b), D-lyxofuranoside (43a), L-lyxopyranoside (44b), D-xylofuranoside (49a), and L-rhamnopyranoside (56)] were selected for extended evaluation on the basis of their high levels of activity. The structure-activity relationships are discussed. The selected glycosides showed remarkable activity in six different murine tumor systems with excellent therapeutic ratios; their efficacy surpassed that of doxorubicin against three of these systems. On the basis of these results and ease of formulation, the two glycosides 41b (SUN4599) and 49a (SUN5073) were selected for further preclinical evaluation and possible clinical development.
通过改进的椭圆玫瑰树碱[1、2和9-乙酰氧基椭圆玫瑰树碱(3)]与受保护的(全酰化和全苄基化)糖基卤化物在碳酸镉存在下的缩合反应，然后进行脱保护反应，以良好的产率立体选择性地合成了一系列椭圆玫瑰树碱糖苷[三种椭圆玫瑰树碱的2-N-糖基季吡啶盐：椭圆玫瑰树碱(1)、9-甲氧基椭圆玫瑰树碱(2)和9-羟基椭圆玫瑰树碱(4)]。对这些糖苷在L1210白血病系统中的抗肿瘤活性进行了初步评估。在所测试的49种糖苷中，有26种(53%)具有治愈效果，基于其高活性水平，选择了5种[9-羟基椭圆玫瑰树碱-L-阿拉伯吡喃糖苷(41b)、D-来苏呋喃糖苷(43a)、L-来苏吡喃糖苷(44b)、D-木糖呋喃糖苷(49a)和L-鼠李吡喃糖苷(56)]进行进一步评估。讨论了构效关系。所选糖苷在六种不同的小鼠肿瘤系统中显示出显著活性，治疗比优异；它们对其中三种系统的疗效超过了阿霉素。基于这些结果和制剂的简便性，选择了两种糖苷41b(SUN4599)和49a(SUN5073)进行进一步的临床前评估和可能的临床开发。
