Withanolides from Physalis angulata as Potent Antimelanoma Agents: Activation of the p53 Pathway In Vitro and In Vivo

Phytochemical investigation of the aerial parts of Physalis angulata led to the isolation of 15 undescribed withanolides, including an unprecedented 2,3-seco-1,3-cyclo-physalin (1) and a C27-nor-physalin (12), along with two known analogues (16 and 17). Their planar structures and absolute configurations were established by comprehensive spectroscopic analysis, together with single crystal X-ray diffraction, ECD spectroscopy, and DFT NMR or TDDFT ECD calculations. All isolates were evaluated for their antimelanoma activity. In vitro, compounds 6 and 14 markedly inhibited the proliferation of B16F10 and A375 cells by inducing cell-cycle arrest and apoptosis via activation of the p53 signaling pathway, which was further confirmed by Trp53 knockout in B16F10 cells. In vivo, compound 6 significantly suppressed the growth of B16F10 and A375 subcutaneous xenografts in mice and concomitantly activated intratumoral p53 signaling pathway. These findings indicated withanolides isolated from P. angulata exert antimelanoma effects by activating the p53 signaling pathway.