ABSTRACT
Synthetic neamine mimetics have been evaluated for binding to the HIV-1 Rev response element. Modified neamine derivatives, obtained from reductive amination of neamine, led to identification of new 6-amino modified neamine-type ligands with HIV-1 RRE binding affinity up to 20× that of neamine and up to 6× that of the more complex neomycin itself. This provides a noteworthy structure-activity increase and a useful lead to simplified, chemically accessible mimetics.
Subject(s)
Anti-HIV Agents/pharmacology , Framycetin/pharmacology , HIV-1/drug effects , Neomycin/pharmacology , RNA, Viral/drug effects , Response Elements/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , Framycetin/chemical synthesis , Framycetin/chemistry , Molecular Structure , Neomycin/analogs & derivatives , Neomycin/chemistry , Structure-Activity RelationshipABSTRACT
Glucosyl-novobiocin-based diazirine photoaffinity labelling reagents (PALs) were designed and synthesized to probe the Hsp90 C-terminal domain unknown binding pocket and the structure-activity relationship. Five PALs were successfully synthesized from novobiocin in six consecutive steps employing phase transfer catalytic glycosylation. Reactions were monitored and guided by analytical LC/MS which led to different strategies of adding either a PAL precursor or a sugar moiety first. The structures and bonding linkages of these compounds were characterised by various 2D-NMR spectroscopy and MS techniques. Synthetic techniques provide powerful probes for unknown protein binding pockets.
