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

Phytochemical investigation of the aerial parts of <i>Physalis angulata</i> led to the isolation of 15 undescribed withanolides, including an unprecedented 2,3-<i>seco</i>-1,3-<i>cyclo</i>-physalin (<b>1</b>) and a C27-nor-physalin (<b>12</b>), along with two known analogues (<b>16</b> and <b>17</b>). 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 <b>6</b> and <b>14</b> 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 <b>6</b> 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 <i>P. angulata</i> exert antimelanoma effects by activating the p53 signaling pathway.