Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes: "Thymine replacement" analogs of thymidine for evaluation as anticancer and antiviral agents
Zx. Wang et al., Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes: "Thymine replacement" analogs of thymidine for evaluation as anticancer and antiviral agents, NUCLEOS NUC, 20(1-2), 2001, pp. 41-58
A group of unnatural 1-(2-deoxy-beta -D-ribofuranosyl)-2,4-difluorbenzenes
having a variety of C-5 two-carbon substituents II-CC-X, X = I, Br; -Cr=CH;
(E)- CH=CH-X, X = I, Br; - CH=CH2; - CH2CI1; -CH(N-3) CH2Br], designed as
nucleoside mimics, were synthesized for evaluation as anticancer and antivi
ral agents. The 5-substituted (E)-CH=CH-I and -CH2CH3 compounds exhibited n
egligible cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-4)M range), rel
ative to thymidine (CC50 10-3 to 10(-5) M range), against a variety of canc
er cell lines. In contrast, the C-5 substituted -C=C-I and -CH(N-3)CH2Br co
mpounds were more cytotoxic (CC50 = 10(-5) to 10(-6) M range). The -C=C-I a
nd -CH2CH3 compounds exhibited similar cytotoxicity against non-transfected
(KBALB, 143B) and HSV-1 TK+ gene transfected (KBALB STK, 143B-LTK) cancer
cell lines expressing the herpes simplex virus type 1 (HSV-1) thymidine kin
ase gene (TK+). This observation indicates that expression of the viral TK
enzyme did not provide a gene therapeutic effect. The parent group of 5-sub
stituted compounds, that were evaluated using a wide variety of antiviral a
ssay systems [HSV-1, HSV-2, varicella-zoster virus (VZV), vaccinia virus, v
esicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency (HIV
-1, HIV-2) viruses], showed that this class of unnatural C-aryl nucleoside
mimics are inactive and/or weakly active antiviral agents.