Analogues of Pyrimidines

Since one of the catalytic actions of reverse transcriptase is DNA synthesis, analogues of pyrimidine and purine nucleotides inhibit this process. A drug, zidovudine, azi-... 

It is fluorinated analogue of pyrimidine, act by binding the enzyme thymidylate synthetase and preventing the production of basic component of DNA-th5miine. It... 

A number of 1,2,4-triazines are of interest owing to their biological activity. 1,2,4-Triazine-3,5-diones (6) represent aza analogues of pyrimidine nucleic acid bases, a number of natural antibiotics are derivatives of pyrimido[5,4-e][l,2,4]triazine (7), and 4-amino-6-r-butyl-3-methylthio-l,2,4-triazin-5-one (8) and 4-amino-3-methyl-6-phenyl-l,2,4-triazin-5-one (9) are used as herbicides. 

A number of currently prescribed NRTIs are shown in Figure A.44. Compounds A.155 through A.158 are all analogues of pyrimidine nucleosides. Compounds A.159 and A.160 are both purine nucleoside analogues. Abacavir (Ziagen, A.160) is inactive until it is metabolized to carbovir (A.161) in vivo. The seven drugs in Figure A.44 were approved in the United States over a span of more than 25 years. Zidovudine reached the market first in 1987, and emtricitabine was the last to be approved in 2003. The steady release... 

Possible modes of chemosterilant action include aldehyde formation and antimetabolic effects as analogues of pyrimidine and folate... 

Unsaturattd nucleosides, cyclic and acyclic, have also become a focus of much attention as antiviral and antitumor agents. Thus, analogues of pyrimidine 2 -deoxyribo-... 

AZIDO, 3 -AMINO, 2, 3 -UNSATURATED, 2, 3 -DIDEOXY, AND 5-SUBSTITUTED ANALOGUES OF PYRIMIDINE NUCLEOSIDES... 

Figure L Structures of various azido, amino, 2 ,3 -unstaturated, and 3 -deoxy analogues of pyrimidine 2 -deoxynucleosides.

Compounds 1-9, as well as other 3 -azido analogues of pyrimidine deoxyribo-nucleosides (compounds 25-37), which were also synthesized in our laboratory, were evaluated against HIV-1 in vitro, and the antiviral activity was expressed by the concentration ( jM) that inhibits 50% of viral replication. The results are shown in Table 2. ... 

Among the 3 -azido analogues of pyrimidine deoxyribonucleosides, 3 -azido-3 -deoxy-thymidine (2, AZT) was the most active against HIV-1 in vitro with an EC50 value of 0.002 jaM. Conversely, 3 -azido-3 -deoxy-6-azathymidine (37) was practically inactive (EC50 >100 aM). The 3 -azido derivatives of 3 -deoxy-3-(3-oxo-l-propenyl)thymidine (36), 2 -deoxyuridine (1), 5-bromo-2 -deoxyuridine (5), 2 -deoxy-5-fluorocytidine (8), 2 -deoxy-5-iodouridine (6), 2 -deoxycytidine (7), 2 -deoxy-5-fluorouridine (4), 2 -deoxy-5-thio-... 

Table 2. Antiviral activity of various 3 -azido analogues of pyrimidine deoxyribonucleo-sides on the replication of human immunodeficiency virus (HIV-1) in human peripheral blood mononuclear cells.

Figure 4. Structures of various 3 -azido and 3 -azido-2,5 -anhydro analogues of pyrimidine 2 -deoxyyiibo-nucleosides.

Table 8. Comparison of the ECso values of several 3 -amino analogues of pyrimidine deoxyribonucleosides and their corresponding nitrosourea derivatives on the replication of L1210 cells in vitro.

K. E.B. Parkes, N.A. Roberts, G.J. Thomas, S.A. Galpin, and D. Kinchington, Synthesis and antiviral activity of monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1), 7. Med. Chem. 33 2137 (199.0). 

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