6-N-Acyltriciribine analogues: structure-activity relationship between acyl carbon chain length and activity against HIV-1.
Triciribine (TCN) and triciribine-5'-monophosphate (TCN-P) are active against HIV-1 at submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore the tolerance of TCN to structural modifications at the 6-position. A number of 6-N-acyltriciribine analogues were synthesized and evaluated for antiviral activity and cytotoxicity. The cytotoxicity of these compounds was minimal in three human cell lines (KB, CEM-SS cells, and human foreskin fibroblasts (HFF)). The compounds were marginally active or inactive against herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). In contrast, most of the compounds exhibited moderate to high activity against human immunodeficiency virus type 1 (HIV-1), IC(50)'s = 0.03 to 1 microM. This structure-activity relationship study identified the N-heptanoyl group as having the optimal carbon chain length. This compound was as active against HIV-1 as TCN and TCN-P. Reverse phase HPLC of extracts from uninfected cells treated with 6-N-acyltriciribines detected sufficient TCN-P to account for anti-HIV activity thereby suggesting a prodrug effect. Studies in an adenosine kinase deficient cell line showed that the 6-N-acyl derivative was not phosphorylated directly but first was metabolized to triciribine which then was converted to TCN-P.
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
Drach
J C
JC
Townsend
L B
LB
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D012263:Ribonucleosides; C023764:triciribine