title: Synthesis and testing of a focused phenothiazine library for binding to HIV-1 TAR RNA.
abstract: We have synthesized a series of phenothiazine derivatives, which were used to test the structure-activity relationship of binding to HIV-1 TAR RNA. Variations from our initial compound, 2-acetylphenothiazine, focused on two moieties: ring substitutions and n-alkyl substitutions. Binding characteristics were ascertained via NMR, principally by saturation transfer difference spectra of the ligand and imino proton resonance shifts of the RNA. Both ring and alkyl substitutions manifested NMR changes upon binding. In general, the active site, while somewhat flexible, has regions that can be capitalized for increased binding through van der Waals interactions and others that can be optimized for solubility in subsequent stages of development. However, binding can be nontrivially enhanced several-fold through optimization of van der Waals and hydrophilic sites of the scaffold.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.forename: Moriz
authors.initials: M
authors.lastname: Mayer
authors.forename: P Therese
authors.initials: PT
authors.lastname: Lang
authors.forename: Sabina
authors.initials: S
authors.lastname: Gerber
authors.forename: Peter B
authors.initials: PB
authors.lastname: Madrid
authors.forename: Irene Gómez
authors.initials: IG
authors.lastname: Pinto
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Thomas L
authors.initials: TL
authors.lastname: James
mesh_terms: D001665:Binding Sites; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D010640:Phenothiazines; D012367:RNA, Viral