Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays

Abstract

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.

Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model

“…The model was first described in 2007 (Nicoli et al, 2007) and, since then, it has been used to further the knowledge of the mechanisms of tumour angiogenesis: identifying genes of interest, determining the cellular processes involved in tumour angiogenesis and elucidating the functions carried out by tumour blood vessels (Vlecken and Bagowski, 2009; Zhao et al, 2016, 2011b). The main strengths of this model are the ability to image tumour angiogenesis in vivo and the applicability for drug screening (Harfouche et al, 2009; Yang et al, 2014a,b; Muthukumarasamy et al, 2016; Zhao et al, 2011b, 2016). While this model has gained popularity, the exact mechanisms that underpin xenograft angiogenesis in zebrafish are still unclear.…”

Insect-Repellent and Mosquitocidal Effects of Noreremophilane- and Nardoaristolone-Based Compounds

“…30 Synthesis of compounds 12−17 were described in a recently published paper. 32 All the compounds were fully characterized by IR, 1 H NMR, 13 C NMR, and HRMS. Compounds 8, 19, 21, and 23 contain ∼10% diastereomer which was difficult to separate and they were screened as such; the remaining compounds were >95% pure as single diastereomers (judged from NMR).…”

“… − Similarly, synthesis of (±)-nardoaristolone B and its analogues with cyclopropyl ring fusion were prepared . Synthesis of compounds 12–17 were described in a recently published paper . All the compounds were fully characterized by IR, 1 H NMR, 13 C NMR, and HRMS.…”

Role of Small Molecule Targeted Compounds in Cancer: Progress, Opportunities, and Challenges

“…To date, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous angiogenesis peptide inhibitors, to small molecule drugs ( Figure 4 ). In the past few years, many emerging small molecule inhibitors have been synthesized, covering phosphatidylinositol 3-kinase, benzoxazines targeting receptor tyrosine kinase, 6-(pyrimidine-r-acyloxy)-naphthalene-1-carboxamides, and indoline-2-one group and noreremophilane-based inhibitors, respectively ( Al-Rawi et al, 2015 ; Muthukumarasamy et al, 2016 ). The mentioned emerging series of compounds showed potential for treating solid tumors in pre-clinical experiments.…”