A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

The semisynthesis of renieramycin-type derivatives was achieved under mild and facile conditions by attaching a 1,3-dioxole-bridged phenolic moiety onto ring A of the renieramycin structure and adding a 4′-pyridinecarbonyl ester substituent at its C-5 or C-22 position. These were accomplished through a light-induced intramolecular photoredox reaction using blue light (4 W) and Steglich esterification, respectively. Renieramycin M (4), a bis-tetrahydroisoquinolinequinone compound isolated from the Thai blue sponge (Xestospongia sp.), served as the starting material. The cytotoxicity of the 10 natural and semisynthesized renieramycins against non-small-cell lung cancer (NSCLC) cell lines was evaluated. The 5-O-(4′-pyridinecarbonyl) renieramycin T (11) compound exhibited high cytotoxicity with half-maximal inhibitory concentration (IC₅₀) values of 35.27 ± 1.09 and 34.77 ± 2.19 nM against H290 and H460 cells, respectively. Notably, the potency of compound 11 was 2-fold more than that of renieramycin T (7) and equal to those of 4 and doxorubicin. Interestingly, the renieramycin-type derivatives with a hydroxyl group at C-5 and C-22 exhibited weak cytotoxicity. In silico molecular docking and dynamics studies confirmed that the mitogen-activated proteins, kinase 1 and 3 (MAPK1 and MAPK3), are suitable targets for 11. Thus, the structure–cytotoxicity study of renieramycins was extended to facilitate the development of potential anticancer agents for NSCLC cells.