SYNTHESIS AND ANTICANCER ACTIVITY OF VARIOUS 3'-DEOXY PYRIMIDINE NUCLEOSIDE ANALOGS AND CRYSTAL-STRUCTURE OF 1-(3-DEOXY-BETA-D-THREO-PENTOFURANOSYL)CYTOSINE
SYNTHESIS AND ANTICANCER ACTIVITY OF VARIOUS 3'-DEOXY PYRIMIDINE NUCLEOSIDE ANALOGS AND CRYSTAL-STRUCTURE OF 1-(3-DEOXY-BETA-D-THREO-PENTOFURANOSYL)CYTOSINE
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DOI：
10.1021/jm00106a034
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发表时间：
1991-02-01
影响因子：
7.3
通讯作者：
HSIUNG, GD
中科院分区：
文献类型：
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作者：
LIN, TS;YANG, JH;HSIUNG, GD
各种3'-脱氧嘧啶核苷类似物已被合成，作为潜在的抗癌和抗病毒药物进行评价。其中，1-（3-脱氧- β -d -三-戊呋喃基）胞嘧啶（10,3'-脱氧-ara- c）和3'-脱氧胞苷（22）对体外培养的CCRF-CEM、L1210、P388和S-180癌细胞具有显著的抗癌活性，3'-脱氧-ara- c（10）的ED50值分别为2、10、5和34 μ m；3'-脱氧胞苷的分子量分别为25、5、2.5和15 μ m（22）。因此，3'-deoxy-ara-C（10）对CCRF-CEM细胞的活性是3'-脱氧胞苷（22）的12.5倍。3'-脱氧-ara- c（10）的2'- o -乙酰基、5'- o -乙酰基和2',5'-二o -乙酰基衍生物，化合物34、31和30，对CCRF-CEM、L1210、P388和S-180细胞具有与3'-脱氧-ara- c（10）相同的抗癌活性。5′- o -乙酰基衍生物（31）对CCRF-CEM的ED50值为0.4，但该化合物对L1210、P388和S-180的ED50值也与3′-脱氧-ara- c相似，分别为3、3和13 μ m。3′-Deoxy-ara-C在体外对HSV-2、HCMV和GPCMV病毒也进行了评估，发现其IC50值分别为110、220和1000-mu-M，活性不高。用x射线晶体学测定了3′-脱氧-ara- c（10）的单晶结构。在不对称单元中有两个核苷分子和一个水分子。两种核苷分子的糖部分采用不同的构象。在分子A中，环状皱褶为C3'端，P = 18.7度，tau-m = 37.3度，CH2OH侧链为间扭式+。在分子B中，环状褶皱为C2'端，P = 156.8度，tau-m = 37.8度，侧链为反式。
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-mu-M, respectively, for 3'-deoxy-ara-C (10); and 25, 5, 2.5, and 15-mu-M, 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-mu-M, 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-mu-M. 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.