title: Synthesis and antiproliferative and antiviral activity of 2'-deoxy-2'-fluoroarabinofuranosyl analogs of the nucleoside antibiotics toyocamycin and sangivamycin.
abstract: The glycosylation of 3,4-dicyano-2-[(ethoxymethylene)amino]pyrrole (7) with 2-deoxy-2-fluoro-alpha-D-erythro-pentofuranosyl bromide (2) furnished an anomeric mixture of nucleosides (8a,b). This mixture was separated, and the individual anomers were treated with methanolic ammonia to effect a concomitant deblocking and ring closure. This furnished both anomers of 2'-deoxy-2'-fluoro-ara-toyocamycin (9a,b). The cyano moiety of 9b was converted to the carboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-sangivamycin (10) and to the thiocarboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-thiosangivamycin (11). The target compounds 10 and 11 showed similar antiproliferative activity against L1210 cells in vitro, with IC50's of 3 and 5 microM. Antiviral evaluation revealed a somewhat different pattern of activity. All analogs, both alpha and beta anomers, were active against human cytomegalovirus (HCMV), albeit the beta anomers were most active. The beta anomers also were active against herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus (HIV). Compound 10 was most active in the series, ca. 10-fold more potent than 11; IC50's for 10 ranged from 4 to 25 nM for HCMV, HIV, and varicella zoster virus (VZV) and from 30 to 500 nM for HSV-1. Even though compound 10 was cytotoxic, which will probably preclude its use as an antiviral drug (IC50's = 0.2-5.5 microM), the difference between cytotoxicity and activity against HCMV, HIV, and VZV was sufficient to indicate specific activity against a viral target.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Krawczyk
authors.forename: M R
authors.initials: MR
authors.lastname: Nassiri
authors.forename: L S
authors.initials: LS
authors.lastname: Kucera
authors.forename: E R
authors.initials: ER
authors.lastname: Kern
authors.forename: R G
authors.initials: RG
authors.lastname: Ptak
authors.forename: L L
authors.initials: LL
authors.lastname: Wotring
authors.forename: J C
authors.initials: JC
authors.lastname: Drach
authors.forename: L B
authors.initials: LB
authors.lastname: Townsend
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001087:Arabinonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D006678:HIV / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007624:KB Cells; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D014127:Toyocamycin / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D000998:Antiviral Agents; D001087:Arabinonucleosides; D011741:Pyrimidine Nucleosides; C005699:sangivamycin; D014127:Toyocamycin