Cyclopropyl Dafachronic Acid Stereoisomers as Conformationally Constrained DAF-12 Ligands

The development and lifespan of Caenorhabditis elegans are regulated by the action of the nuclear hormone receptor DAF-12 (‘DAuer larva Formation-12’).[1] As with its mammalian homologues vitamin D and liver X receptors, DAF-12 function is modulated by steroid-like ligands namely dafachronic acids (DAs), C3-keto steroidal acids formed from the catabolism of cholesterol. Upon the binding to DAF-12, DAs modulate DAF-12 target genes, trigger reproductive development and prevent the entry of C. elegans into the dauer recovery, a reversible state of dormancy.[2] Upon unfavourable conditions and difficult environmental plights, the absence of ligands induces the dauer stage in which the nematode exhibits developmental arrest, more stress resistance, extended larval survival and increased lifespan. Remarkably, recent studies suggest that DA/DAF-12 pathway is similar in parasitic nematodes and that administration of DAs is effective in the reduction of the infection progression.[3] These important findings reveal a new therapeutic option to treat a wide range of parasitosis, which affect more than 1 billion people worldwide, as well as pathogenic infestations of livestock and plants. In this communication, with the aim to better explore the molecular mechanism governing DAF-12 action as well as to further define structure-activity relationships of DA derivatives,[4] we report the synthesis and characterization of all four stereoisomers of C24,25-cyclopropyl DAs. The synthesized compounds were evaluated for their ability to activate DAF-12 and the data were revised in the light of computational studies. The results obtained have provided new insights into the molecular features of the DAF-12 activation and may be useful in designing and identifying novel DA-based modulators.