Stereochemical promiscuity in artificial transcriptional activators.
Small molecule replacements of transcriptional activation domains are highly desirable targets due to their utility as mechanistic tools and their long-term therapeutic potential for a variety of human diseases. Here, we examine the ability of amphipathic isoxazolidines differing only in the placement of constituent side chains to function as transcriptional activation domains. The results reveal that precise positioning of functional groups within a conformationally constrained small molecule scaffold is not required for transcription function; rather, the balance of polarity and hydrophobicity within the scaffold is the more important determinant of transcription function. This suggests that a number of different organic molecule scaffolds should function as transcriptional activator domains when appropriately functionalized, a hypothesis currently under investigation.
Buhrlage
Sara J
SJ
Department of Chemistry and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Brennan
Brian B
BB
Minter
Aaron R
AR
Mapp
Anna K
AK
D004247:DNA / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism; D015534:Trans-Activators / Q000737:chemistry*; D015533:Transcriptional Activation
D015534:Trans-Activators; D004247:DNA