Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK inhibitor

The synthesis of compounds based on fragments derived from natural products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, the indole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffold was based on the structural characteristics of four natural products, namely tryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent components of the pentacycle, containing the indole, quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-tumor activity efficacy against A549 cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.