Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor.
Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis-aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Kaitlin J
KJ
Basham
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Vasudev R
VR
Bhonde
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Collin
C
Kieffer
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
James B C
JB
Mack
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Matthew
M
Hess
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA.
Bryan E
BE
Welm
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: r.looper@utah.edu.
Ryan E
RE
Looper
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D018336:Receptors, Aryl Hydrocarbon
Aryl hydrocarbon receptor; Branching morphogenesis; Dioxin; Mammary gland; Oxadiazole