Lin T S, Yang J H, Liu M C, Shen Z Y, Cheng Y C, Prusoff W H, Birnbaum G I, Giziewicz J, Ghazzouli I, Brankovan V
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
J Med Chem. 1991 Feb;34(2):693-701. doi: 10.1021/jm00106a034.
Various 3'-deoxy pyrimidine nucleoside analogues have been synthesized for evaluation as potential anticancer and antiviral agents. Among these compounds, 1-(3-deoxy-beta-D-threo-pentofuranosyl)cytosine (10, 3'-deoxy-ara-C) and 3'-deoxycytidine (22) had significant anticancer activity against CCRF-CEM, L1210, P388, and S-180 cancer cell lines in vitro, producing ED50 values of 2, 10, 5, and 34 microM, respectively, for 3'-deoxy-ara-C (10); and 25, 5, 2.5, and 15 microM, respectively, for 3'-deoxycytidine (22). Thus, 3'-deoxy-ara-C (10) was 12.5 times more active against CCRF-CEM cells than 3'-deoxycytidine (22). The 2'-O-acetyl, 5'-O-acetyl, and 2',5'-di-O-acetyl derivatives of 3'-deoxy-ara-C (10), compounds 34, 31, and 30, demonstrated anticancer activity in the same range as 3'-deoxy-ara-C (10) against CCRF-CEM, L1210, P388, and S-180 cells. The 5'-O-acetyl derivative (31) had significantly greater activity against CCRF-CEM with an ED50 value of 0.4, but this compound also showed similar activity, as did 3'-deoxy-ara-C, against L1210, P388, and S-180 with ED50 values of 3, 3, and 13 microM, respectively. 3'-Deoxy-ara-C was also evaluated in vitro against HSV-2, HCMV, and GPCMV viruses and was found to be not very active with respective IC50 values of 110, 220, and 1000 microM. The single-crystal structure of 3'-deoxy-ara-C (10) was determined by X-ray crystallography. There are two molecules of the nucleoside and one molecule of water in the asymmetric unit. The sugar moieties of the two nucleoside molecules adopt different conformations. In molecule A, the ring pucker is C3'-endo with P = 18.7 degrees and tau m = 37.3 degrees, while the CH2OH side chain is gauche+. In molecule B, the ring pucker is C2'-endo with P = 156.8 degrees and tau m = 37.8 degrees and the side chain is trans.
已合成了多种3'-脱氧嘧啶核苷类似物，作为潜在的抗癌和抗病毒药物进行评估。在这些化合物中，1-(3-脱氧-β-D-苏式-戊呋喃糖基)胞嘧啶（10，3'-脱氧阿糖胞苷）和3'-脱氧胞苷（22）在体外对CCRF-CEM、L1210、P388和S-180癌细胞系具有显著的抗癌活性，3'-脱氧阿糖胞苷（10）对CCRF-CEM、L1210、P388和S-180癌细胞系的ED50值分别为2、10、5和34μM；3'-脱氧胞苷（22）的ED50值分别为25、5、2.5和15μM。因此，3'-脱氧阿糖胞苷（10）对CCRF-CEM细胞的活性是3'-脱氧胞苷（22）的12.5倍。3'-脱氧阿糖胞苷（10）的2'-O-乙酰基、5'-O-乙酰基和2'，5'-二-O-乙酰基衍生物，即化合物34、31和30，对CCRF-CEM、L1210、P388和S-180细胞显示出与3'-脱氧阿糖胞苷（10）相同范围的抗癌活性。5'-O-乙酰基衍生物（31）对CCRF-CEM具有显著更高的活性，ED50值为0.4，但该化合物对L1210、P388和S-180细胞也显示出与3'-脱氧阿糖胞苷类似的活性，其ED50值分别为3、3和13μM。还在体外评估了3'-脱氧阿糖胞苷对单纯疱疹病毒2型（HSV-2）、人巨细胞病毒（HCMV）和豚鼠巨细胞病毒（GPCMV）的活性，发现其活性不强，IC50值分别为110、220和1000μM。通过X射线晶体学确定了3'-脱氧阿糖胞苷（10）的单晶结构。不对称单元中有两个核苷分子和一个水分子。两个核苷分子的糖部分采用不同的构象。在分子A中，环皱为C3'-内型，P = 18.7°，τm = 37.3°，而CH2OH侧链为邻位交叉式。在分子B中，环皱为C2'-内型，P = 156.8°，τm = 37.8°，侧链为反式。
