What question did this study set out to answer?

The research aims to explore the anticancer effects of indole-based analogs of rutaecarpine through scaffold-hopping.

January 20, 20260 citations

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

MYMukul YadavNational Institute of Pharmaceutical Education and Research SBSantanu BasakNational Institute of Pharmaceutical Education and Research VGVaibhav GuptaNational Institute of Pharmaceutical Education and Research

Key Points

The research aims to explore the anticancer effects of indole-based analogs of rutaecarpine through scaffold-hopping.
Applied scaffold-hopping strategy to rutaecarpine
Prepared diverse 2-arylamino-3-indolylethyl compounds
Used Buchwald-Hartwig cross-coupling for synthesis
Evaluated antiproliferative effects on multiple cancer cell lines
Conducted western blot analysis to assess apoptosis markers.
Identified potent compound 11a with significant antiproliferative effects
Induced nuclear condensation, mitochondrial depolarization, and autophagosome formation
Reduced expression of Pro-caspase-3 and BCL-2 via western blot analysis
Showed activation of both apoptosis and autophagy pathways in cancer cells
SwissADME analysis confirmed favorable drug-likeness properties.

Abstract

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 indolo2',3':3,4pyrido2,1-bquinazolinone 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.

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