Secrist J A, Tiwari K N, Shortnacy-Fowler A T, Messini L, Riordan J M, Montgomery J A, Meyers S C, Ealick S E
Section of Biochemistry, Molecular and Cell Biology, Biotechnology Building, Cornell University, Ithaca, New York 14855, USA.
J Med Chem. 1998 Sep 24;41(20):3865-71. doi: 10.1021/jm980195+.
A series of 4'-thio-D-arabinofuranosylpurine nucleosides was prepared and evaluated as potential anticancer agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained through an X-ray crystal structure of 9alpha as well as through NOE experiments on 9beta and 9alpha. All six target compounds were evaluated in a series of human cancer cell lines in culture. Two target compounds, beta anomers with diaminopurine (12) and guanine (16) as the bases, had significant cytotoxicity. One of these compounds (12) was selected for animal studies but was found to have no selectivity at the maximum tolerated dose in the murine colon 36 tumor model.
制备了一系列4'-硫代-D-阿拉伯呋喃糖基嘌呤核苷，并将其作为潜在的抗癌剂进行评估。本文介绍了碳水化合物前体1-O-乙酰基-2,3,5-三-O-苄基-4-硫代-D-阿拉伯呋喃糖（6）简便且高产率的合成细节。通过9α的X射线晶体结构以及对9β和9α的NOE实验，确定了核苷所有手性中心的结构和构型。在一系列培养的人类癌细胞系中对所有六种目标化合物进行了评估。两种目标化合物，即碱基为二氨基嘌呤（12）和鸟嘌呤（16）的β异头物，具有显著的细胞毒性。其中一种化合物（12）被选用于动物研究，但发现在小鼠结肠36肿瘤模型中，在最大耐受剂量下没有选择性。
