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 again st HIV-1 at submicromolar concentrations. In an effort to improve and bette r understand this activity, we have conducted a structure-activity relation ship study to explore the tolerance of TCN to structural modifications at t he 6-position. A number of 6-N-acyltriciribine analogues were synthesized a nd evaluated for antiviral activity and cytotoxicity. The cytotoxicity of t hese 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 cytomegalov irus (HCMV). In contrast, most of the compounds exhibited moderate to high activity against human immunodeficiency virus type 1 (HIV-1), IC50's = 0.03 to 1 mu M. This structure-activity relationship study identified the N-hep tanoyl group as having the optimal carbon chain length. This compound was a s active against HIV-1 as TCN and TCN-P. Reverse phase HPLC of extracts fro m uninfected cells treated with 6-N-acyltriciribines detected sufficient TC N-P to account for anti-HIV activity thereby suggesting a prodrug effect. S tudies in an adenosine kinase deficient cell line showed that the 6-N-acyl derivative was not phosphorylated directly but first was metabolized to tri ciribine which then was converted to TCN-P.