Scaffold‐Hopping of Natural Alkaloid Rutaecarpine: Synthesis and Anticancer‐Apoptosis and Autophagy Effects of Indole‐Based Analogs

Natural products have been recognized as important molecular skeletons in drug discovery due to their structural diversity and promising bioactivity. In this study, a scaffold-hopping strategy was applied to Rutaecarpine, an indolo[2',3':3,4]pyrido[2,1-b]quinazolinone alkaloid with antiproliferative activity. A novel series of 2-arylamino-3-indolylethyl-amines/alcohols was prepared by an explored synthetic approach with a Buchwald-Hartwig cross-coupling key step to introduce diverse aryl/heteroaryl amines. The compounds showed notable antiproliferative properties against MCF-7, T-47D, A-549, AGS, SNU-1, HL-60, and MOLT-4 cell lines. The most potent compound, 11a, induced nuclear condensation, mitochondrial membrane depolarization, and autophagosome formation. Western blot analysis confirmed a significant reduction in expression of Pro-caspase-3 and BCL-2. The in vitro results collectively implicate the investigated molecule's significant effect on anticancer properties with simultaneous activation of intrinsic apoptosis and autophagy in cancer cells. SwissADME analysis indicated favorable drug-likeness properties. This work demonstrates the value of a natural product-inspired scaffold-hopping strategy in identifying promising new anticancer molecules with important pharmacological properties.