Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays.

Noreremophilanes are a rare class of cis-hydrindanes produced by genus Ligularia herbaceous plants which are known to exhibit interesting biological activities. We synthesized cis-hydrindanes based on a naturally occurring noreremophilane scaffold using a Diels-Alder/aldol sequence and screened them for multiple biological activities using high-content zebrafish embryonic development assays. We discovered a noreremophilane that has strong anti-angiogenic effects on the developing zebrafish embryos as well as on tumor-induced angiogenesis in a zebrafish xenograft model. We synthesized several derivatives of this class of noreremophilanes and performed structure-activity relationship studies in zebrafish to identify more potent and less toxic analogs of the original structure.