Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer

Inspired by the natural product evodiamine,
a novel antitumor indolopyrazinoquinazolinone
scaffold was designed by scaffold hopping. Structure–activity
relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116
cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin
and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium
salt of compound 15j (compound 15js) exhibited
excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft
model with low toxicity. Indolopyrazinoquinazolinone derivatives represent
promising multitargeting antitumor leads for the development of novel
antitumor agents.