title: Synthesis of the diastereomers of 5-(2,2-dichlorocyclopropyl)- and 5-(2-chlorocyclopropyl)-2'-deoxyuridine, and the antiviral and cytotoxic activity of these and bromo analogues.
abstract: Syntheses of the two diastereomers (5a and 6a) of 5-(2,2-dichlorocyclopropyl)-, and of the four diastereomers (7a-10a) of 5-(2-chlorocyclopropyl)-2'-deoxyuridine are described. These, and corresponding diastereomers (5b and 6b; 7b-10b) of 5-(2,2-dibromocyclopropyl)- and 5-(2-bromocyclopropyl)-2'-deoxyuridine (prepared in an earlier investigation) were examined for antiviral and cytotoxic activity, in comparison with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 5-fluoro-2'-deoxyuridine (FDU). 5-[(1R,2R)-2-Chlorocyclopropyl]-2'-deoxyuridine (9a) was the most active antiviral agent (IC50 = 25 micrograms/ml) against herpes simplex virus type 1 (HSV-1) relative to BVDU (IC50 = 0.082 microgram/ml). Compounds having the R configuration at the C-1 and/or C-2 positions of the 5-[2,2-dichloro(or 2-chloro)cyclopropyl] substituent exhibited the most potent antiviral activity. The cytotoxic activities of the 5-(2,2-dihalocyclopropyl)- (5-6a and b) and 5-(2-halocyclopropyl)- diastereomers (7-10a and b) were dependent upon both the configuration of the C-1 and/or C-2 cyclopropyl carbons and the nature of the halogeno (Cl, Br) substituent. 5-[(1R)-2,2-Dichlorocyclopropyl]-2'-deoxyuridine (6a) was the most active cytotoxic compound in the CCRF-CEM (IC50 = 17 microM) and HL-60 (IC50 = 64 microM) screens relative to FDU, which exhibited IC50 values of 4.7 x 10(-3) and 77 microM in these respective screens.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Tandon
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: W P
authors.initials: WP
authors.lastname: Gati
authors.forename: M L
authors.initials: ML
authors.lastname: Tempest
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002850:Chromatography, Gel; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D018139:Simplexvirus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D003857:Deoxyuridine