Synthesis and anticancer and antiviral activities of various 2'- and 3'-methylidene-substituted nucleoside analogs and crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride

• Published in: Journal of medicinal chemistry Vol. 34; no. 8; pp. 2607 - 2615
• Main Authors: Lin, Tai Shun, Luo, Mei Zhen, Liu, Mao Chin, Clarke-Katzenburg, Regina H, Cheng, Yung Chi, Prusoff, William H, Mancini, William R, Birnbaum, George I, Gabe, Eric J, Giziewicz, Jerzy
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1991
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Carbohydrates. Nucleosides and nucleotides; Chemical Phenomena; Chemistry; Crystallization; Cytarabine - adverse effects; Cytarabine - therapeutic use; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemical synthesis; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Exact sciences and technology; Female; herpes simplex virus 1; herpes simplex virus 2; Humans; Leukemia L1210 - drug therapy; Leukemia P388 - drug therapy; Leukemia, Lymphoid - drug therapy; Mice; Molecular Structure; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Nucleosides - therapeutic use; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Sarcoma 180 - drug therapy; Simplexvirus - drug effects; Tumor Cells, Cultured; X-Ray Diffraction; Antineoplastic agent; Rodentia; Deoxyribonucleoside; Branched compound; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Mouse; Hydrochlorides; Animal; Antiviral; Pyrimidine nucleoside
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00112a040

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 microM, 0.6 and 0.4 microM, 1.5 and 1.5 microM, and 0.05 and 0.03 microM, 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 (greater than 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.