Deoxy sugar analogues of triciribine: correlation of antiviral and antiproliferative activity with intracellular phosphorylation.
Triciribine (TCN) and triciribine monophosphate (TCN-P) have antiviral and antineoplastic activity at low micromolar or submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore requirements for the number of hydroxyl groups on the ribosyl moiety for biological activity. 2'-Deoxytriciribine (2'-dTCN), 3'-deoxytriciribine (3'-dTCN), 2', 3'-epoxytriciribine (2',3'-epoxyTCN), 2',3'-dideoxy-2', 3'-didehydrotriciribine (2',3'-d4TCN), and 2',3'-dideoxytriciribine (2',3'-ddTCN) were synthesized and evaluated for activity against human immunodeficiency virus (HIV-1), herpes simplex virus type 1 (HSV-1), and human cytomegalovirus (HCMV). Antiproliferative activity of the compounds also was tested in murine L1210 cells and three human tumor cell lines. All compounds were either less active than TCN and TCN-P or inactive at the highest concentration tested (100 microM) in both antiviral and antiproliferative assays. Reverse-phase HPLC of extracts from uninfected cells treated with the deoxytriciribine analogues only detected the conversion of 3'-dTCN and 2',3'-ddTCN to their respective monophosphates. Therefore, either the deoxytriciribine analogues were not transported across the cell membrane or, more likely, they were not substrates for a nucleoside kinase or phosphotransferase. We have concluded that the hydroxyl groups on the ribosyl ring system of TCN and TCN-P must be intact in order to obtain significant antiviral and antineoplastic activity.
Porcari
A R
AR
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Ptak
R G
RG
Borysko
K Z
KZ
Breitenbach
J M
JM
Vittori
S
S
Wotring
L L
LL
Drach
J C
JC
Townsend
L B
LB
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010766:Phosphorylation; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D010948:Viral Plaque Assay
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D012263:Ribonucleosides; C023764:triciribine