Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of Plant Pathogenic Fungi

A series of tetrahydro-ß-carbolines substituted with an alkyl or acyl side chain was synthesized and screened for its antifungal activity against plant pathogenic fungi (Bipolaris oryzae, Curvularia lunata, Fusarium semitectum, and Fusarium fujikuroi). The structure activity relationship revealed that the substituent at the piperidine nitrogen plays an important role for increasing antifungal activities. In this series, 2-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3g) displayed potent antifungal activities with a minimum inhibitory concentration of 0.1 μg/mL, including good inhibitory activity to the radial growth of fungus at a concentration of 100 μg/mL compared to amphotericin B

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge <i>Xestospongia</i> sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

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