Naimi E, Duan W, Wiebe L I, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Nucleosides Nucleotides Nucleic Acids. 2001 Aug;20(8):1533-53. doi: 10.1081/NCN-100105246.
A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO2)2, I, CF3, CN, (E)-CH=CH-I, -C triple bond CH, -C triple bond C-I, -C triple bond C-Br, -C=C-Me], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. This class of compounds exhibited weak cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-5) M range) with the 4,7-dinitro derivative being the most cytotoxic, relative to thymidine (CC50 = 10(-3) to 10(-5) M range), against a variety of cancer cell lines. The 4,7-dinitro, 7-I and 7-C triple bond CH compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B), and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that these compounds are not substrates for HSV type-1 TK, and are therefore unlikely to be useful in gene therapy based on the HSV gene therapy paradigm.
设计合成了一组具有多种C-7取代基[H、4,7-(NO2)2、I、CF3、CN、(E)-CH=CH-I、-C≡CH、-C≡C-I、-C≡C-Br、-C=C-Me]的非天然1-(2-脱氧-β-D-核糖呋喃糖基)异喹啉酮，作为核苷类似物用于评估其作为抗癌和抗病毒药物的活性。相对于胸苷（CC50 = 10(-3)至10(-5) M范围），这类化合物在MTT试验中表现出较弱的细胞毒性（CC50 = 10(-3)至10(-5) M范围），其中4,7-二硝基衍生物对多种癌细胞系的细胞毒性最强。4,7-二硝基、7-I和7-C≡CH化合物对具有单纯疱疹病毒1型（HSV-1）胸苷激酶基因（TK+）的未转染（KBALB、143B）和HSV-1 TK+基因转染（KBALB-STK、143B-LTK）癌细胞系表现出相似的细胞毒性。这一观察结果表明这些化合物不是HSV-1 TK的底物，因此不太可能用于基于HSV基因治疗模式的基因治疗。
