SYNTHESIS AND ANTICANCER AND ANTIVIRAL ACTIVITIES OF VARIOUS 2'-METHYLIDENE-SUBSTITUTED AND 3'-METHYLIDENE-SUBSTITUTED NUCLEOSIDE ANALOGS AND CRYSTAL-STRUCTURE OF 2'-DEOXY-2'-METHYLIDENECYTIDINE HYDROCHLORIDE

被引:43
作者
LIN, TS
LUO, MZ
LIU, MC
CLARKEKATZENBURG, RH
CHENG, YC
PRUSOFF, WH
MANCINI, WR
BIRNBAUM, GI
GABE, EJ
GIZIEWICZ, J
机构
[1] YALE UNIV,SCH MED,CTR COMPREHENS CANC,NEW HAVEN,CT 06510
[2] UNIV MICHIGAN,SCH MED,DEPT PHARMACOL,ANN ARBOR,MI 48109
[3] NATL RES COUNCIL CANADA,INST BIOL SCI,OTTAWA K1A 0R6,ONTARIO,CANADA
[4] NATL RES COUNCIL CANADA,INST ENVIRONM CHEM,OTTAWA K1A 0R6,ONTARIO,CANADA
[5] HLTH & WELF CANADA,BUR HUMAN PRESCRIPT DRUGS,OTTAWA K1A 1B8,ONTARIO,CANADA
关键词
D O I
10.1021/jm00112a040
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Various 2'- and 3'-methylidene-substituted nucleoside analogues have been synthesized and evaluated as potential anticancer and/or antiviral agents. Among these compounds, 2'-deoxy-2'-methylidene-5-fluorocytidine (22) and 2'-deoxy-2'-methylidenecytidine (23) not only demonstrated potent anticancer activity in culture against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF-CEM lymphoblastic leukemia, producing ED50 values of 1.2 and 0.3-mu-M, 0.6 and 0.4-mu-M, 1.5 and 1.5-mu-M, and 0.05 and 0.03-mu-M, respectively, but also were active in mice against murine L1210 leukemia. Of all the tested drug dosage levels (25, 50, and 75 mg/kg, respectively) compound 23 had no toxic deaths and compound 22 yielded only one toxic death at the highest dosage level. On the contrary, in the same study, 1-beta-D-arabinofuranosylcytosine (ara-C) resulted in 2/5, 5/5, and 5/5 toxic deaths, respectively. Both compounds 22 and 23 have shown better anticancer activity than ara-C, yielding higher T/C x 100 values and some long-term survivors (> 60 days). In addition, compounds 22 and 23 were found to have, respectively, approximately 130 and 40 times lower binding affinity for cytidine/deoxycytidine deaminase derived from human KB cells compared to ara-C, suggesting that the two 2'-methylidene-substituted analogues may be more resistant to deamination. Cytoplasmic deoxycytidine kinase (dCK) was required for compounds 22 and 23 action. Furthermore, compounds 14, 22, 23, and 24 also have antiherpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) activity in cell culture. In addition, the crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride (23-HCl) was determined by X-ray crystallography.
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页码:2607 / 2615
页数:9
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