Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives

Abstract

Newly developed acyclic nucleoside phosphonates, derivatives of adenine and 2,6-diaminopurine bearing the 2-hydroxy-3-(phosphonomethoxy)propyl (HPMP) moiety at the N 9-side chain (i.e., HPMPA and HPMPDAP, respectively) were screened for in vitro immunobiological activity, using mouse resident peritoneal macrophages and splenocytes. Both HPMPA and HPMPDAP augmented the interferon-γ-triggered production of NO as well as expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages. HPMPDAP activated secretion of tumor necrosis factor-α (TNF-α), chemokines “regulated-upon-activation, normal T cell expressed and secreted” (RANTES) and macrophage inflammatory protein-1α (MIP-1α), and marginally also secretion of interleukin-10 (IL-10) in both macrophages and splenocytes. The HPMPA, less prominently than HPMPDAP, elevated only secretion of RANTES and TNF-α. The compounds also activated secretion of TNF-α (HPMPDAP > HPMPA) in human peripheral blood mononuclear cells (PBMC). Distinct N 6-substituted derivatives, i.e., N 6-dimethyl-, N 6-cyclopropyl-, N 6-piperidin-1-yl-, N 6-(2-methoxyethyl)-, N 6-(2-hydroxyethyl)-, N 6-allyl- and N 6-2-(dimethylamino)ethyl-HPMPA/HPMPDAP as well as 6-thio and 6-hydroxy derivatives usually showed loss of the activity compared to the parent compounds. The immunomodulatory effects were found to be at least in part dependent on P 1 purinoreceptors, and mediated by transcriptional factor nuclear factor-κB.