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

Citation
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
Citations number
43
Categorie Soggetti
Biochemistry & Biophysics
Journal title
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
ISSN journal
15257770 → ACNP
Volume
20
Issue
1-2
Year of publication
2001
Pages
41 - 58
Database
ISI
SICI code
1525-7770(2001)20:1-2<41:SO1>2.0.ZU;2-0
Abstract
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.