I. Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4. II. Construction of a synthetic library of macrolides

I. Ataxia telangiectasia mutated (ATM)- and Rad3-related protein (ATR) is a phosphatidylinositol kinase (PIK)-related kinase that has been implicated in the response of human cells to multiple forms of DNA damage and may play a role in the DNA replication checkpoint. The purification of an ATR complex allowed identification of chromodomain-helicase-DNA-binding protein 4 (CHD4) as an ATR associated protein by tandem mass spectrometric sequencing. CHD4 (also called Mi-2β) is a component of a histone deacetylase 2 (HDAC2)-containing complex, the nucleosome remodeling and deacetylating (NRD) complex. Endogenous ATR, CHD4, and HDAC2 are shown to co-immunoprecipitate, and ATR and HDAC2 co-elute through two biochemical purification steps. Other members of the NRD complex, HDAC1, MTA1 and MTA2 are also detectable in ATR immunoprecipitates. ATR's association with CHD4 and HDAC2 suggests that there may be a link between ATR's role in mediating checkpoints induced by DNA damage and chromatin modulation via remodeling and deacetylation.; II. Many simple macrolides have interesting biological activity and diverse modes of action. Thus, they represent an important target class for diversity-oriented synthesis. Parallel solution synthesis was used to construct regio- and stereochemically diverse protected hydroxyacids efficiently. These hydroxyacids were used to synthesize a library of 13- and 14-membered macrolides on the solid phase. An acid on polystyrene resin was coupled to an alcohol added in solution. The termini of this linear molecule were deprotected and cyclization was performed. Twenty two macrolides were synthesized with yields of the cyclization product ranging between 13 and 75%.