       Document 0325
 DOCN  M9610325
 TI    Synthesis and antiproliferative and antiviral activity of
       2'-deoxy-2'-fluoroarabinofuranosyl analogs of the nucleoside antibiotics
       toyocamycin and sangivamycin.
 DT    9601
 AU    Krawczyk SH; Nassiri MR; Kucera LS; Kern ER; Ptak RG; Wotring LL; Drach
       JC; Townsend LB; Department of Medicinal Chemistry, College of
       Pharmacy,; University of Michigan, Ann Arbor 48109-1065, USA.
 SO    J Med Chem. 1995 Sep 29;38(20):4106-14. Unique Identifier : AIDSLINE
       MED/96005110
 AB    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.
 DE    Antibiotics, Antineoplastic/*CHEMICAL SYNTHESIS  Antiviral
       Agents/*CHEMICAL SYNTHESIS  Arabinonucleosides/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Cytomegalovirus/DRUG EFFECTS  Herpesvirus 1,
       Human/DRUG EFFECTS  Human  HIV/DRUG EFFECTS  KB Cells  Pyrimidine
       Nucleosides/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Support, Non-U.S. Gov't
       Support, U.S. Gov't, P.H.S.  Toyocamycin/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

