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.