Synthesis and activity of substituted 2-phenylquinolin-4-amines, antagonists of immunostimulatory CpG-oligodeoxynucleotides.
Fifty-seven 2-phenylquinolines substituted at the phenyl group and C4 of the quinoline were synthesized and analyzed for inhibition of the immunostimulatory effect of oligodeoxynucleotides with a CpG-motif. The Fujita-Ban variant of the classical Free-Wilson analysis gave a highly significant correlation for a series of 48 relatively small molecules demonstrating that (i) the partial contributions of substituents to biological activity (EC(50)) are additive and (ii) assuming similar bioavailability for all quinolines studied, the larger molecules cannot be accommodated within a still unknown biological receptor. The results suggest interaction of a basic antagonist molecule with weakly acidic groups in the antagonist-receptor complex. N-[2-(Dimethylamino)ethyl]-2-[4-(4-methylpiperazino)phenyl]quinolin-4-amine (50) is the most effective antagonist found in this study (EC(50) = 0.76 nM).
Strekowski
Lucjan
L
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA. Lucjan@gsu.edu
Say
Martial
M
Henary
Maged
M
Ruiz
Patricia
P
Manzel
Lori
L
Macfarlane
Donald E
DE
Bojarski
Andrzej J
AJ
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018899:CpG Islands; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009841:Oligonucleotides / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000634:Aminoquinolines; D007166:Immunosuppressive Agents; C473482:N-(2-(dimethylamino)ethyl)-2-(4-(4-methylpiperazino)phenyl)quinolin-4-amine; D009841:Oligonucleotides; D010879:Piperazines; D011804:Quinolines