Synthesis and biological evaluation of 5-substituted derivatives of the potent antiherpes agent (north)-methanocarbathymine.
The conformationally locked nucleoside, (north)-methanocarbathymine (1a), is a potent and selective anti-herpes agent effective against herpes simplex type 1 (HSV1) and type 2 (HSV2) viruses. Hereby, we report on the synthesis and biological evaluation of a small set of 5-substituted pyrimidine nucleosides belonging to the same class of bicyclo[3.1.0]hexane nucleosides. Both the 5-bromovinyl (4) and the 5-bromo analogue (3) appeared to be exclusive substrates of HSV1 thymidine kinase (TK), contrasting with the 5-iodo analogue (2), which was significantly phosphorylated by the human cytosolic TK. The binding affinity constant and catalytic turnover for HSV1 TK were measured to assess the influence of the substitution on these parameters. In the plaque reduction and cytotoxicity assays, the 5-bromo analogue (3) showed good activity against HSV1 and HSV2 with less general toxicity than 1a. Against varicella-zoster virus (VZV), the north-locked 5-bromovinyl analogue (4) proved to be as potent as its conformationally unlocked 2'-deoxyriboside equivalent BVDU. The three compounds were also tested in vitro as prodrugs used in a gene therapy context on three osteosarcoma cell lines, either deficient in TK (TK(-)), nontransduced, or stably transduced with HSV1 TK. The 5-iodo compound (2, CC(50) 25 +/- 7 microM) was more efficient than ganciclovir (GCV, CC(50) 75 +/- 35 microM) in inhibiting growth of HSV1-TK transfected cells and less inhibitory than GCV toward TK(-) cells, whereas compound 3 inhibited transfected and nontransfected cell lines in a relatively similar dose-dependent manner.
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles St., Frederick, Maryland 21702, USA.
Pamela
P
Russ
Pierre
P
Schelling
Leonardo
L
Scapozza
Gerd
G
Folkers
Erik De
ED
Clercq
Victor E
VE
Marquez
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D006564:Herpesviridae / Q000187:drug effects* / Q000254:growth & development; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000254:growth & development; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D011212:Poxviridae / Q000187:drug effects / Q000254:growth & development; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000737:chemistry; D013941:Thymine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014616:Vaccinia virus / Q000187:drug effects / Q000254:growth & development; D010948:Viral Plaque Assay
C479688:(north)-methanocarbathymine; D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013941:Thymine