Potent small molecule Hedgehog agonists induce VEGF expression in vitro

Katrin Seifert; Anita Büttner; Stephan Rigol; Nicole Eilert; Elke Wandel; Athanassios Giannis

doi:10.1016/j.bmc.2012.08.026

Potent small molecule Hedgehog agonists induce VEGF expression in vitro

Bioorg Med Chem. 2012 Nov 1;20(21):6465-81. doi: 10.1016/j.bmc.2012.08.026. Epub 2012 Aug 28.

Authors

Katrin Seifert¹, Anita Büttner, Stephan Rigol, Nicole Eilert, Elke Wandel, Athanassios Giannis

Affiliation

¹ Universität Leipzig, Fakultät für Chemie und Mineralogie, Institut für Organische Chemie, Johannisallee 29, 04103 Leipzig, Germany.

PMID: 22985958
DOI: 10.1016/j.bmc.2012.08.026

Abstract

Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 μm.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Endothelial Cells / drug effects
Hedgehog Proteins / agonists*
Hedgehog Proteins / metabolism
Humans
Molecular Structure
Signal Transduction / drug effects
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor A / metabolism

Substances

Hedgehog Proteins
Small Molecule Libraries
Vascular Endothelial Growth Factor A