Synthesis and anticancer activity of various 3'-deoxy pyrimidine nucleoside analogues and crystal structure of 1-(3-deoxy-beta-D-threo-pentofuranosyl)cytosine.

Abstract

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.

• Authors: T S Lin, J H Yang, M C Liu, Z Y Shen, Y C Cheng, W H Prusoff, G I Birnbaum, J Giziewicz, I Ghazzouli, V Brankovan
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 34 Issue 2 Pg. 693-701 (Feb 1991) ISSN: 0022-2623 [Print] United States
• PMID: 1995894 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Pyrimidine Nucleosides
• Cytarabine
• 1-(3-deoxypentofuranosyl)cytosine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, therapeutic use)
• Cell Line
• Chemical Phenomena
• Chemistry
• Cytarabine (analogs & derivatives, chemical synthesis, therapeutic use)
• Leukemia L1210 (drug therapy)
• Leukemia P388 (drug therapy)
• Mice
• Pyrimidine Nucleosides (chemical synthesis, therapeutic use)
• Sarcoma 180 (drug therapy)
• Structure-Activity Relationship
• X-Ray Diffraction