Design, synthesis and evaluation of structurally diverse polycyclic harmaline scaffolds as anticancer agents

Here, we demonstrate that the first example of harmaline scaffolds serving as acceptor/acceptor-based N-C-C synthons triggered the ring opening and skeletal reconstruction of 3-vinyl benzofuranones for the construction of a library of skeletally diverse polycyclic harmaline scaffolds. These products...

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Published inNew journal of chemistry Vol. 48; no. 14; pp. 6322 - 6334
Main Authors Chen, Shuang, Wang, Xi-Rui, Wang, Wei-Na, Xu, Ke-Lan, Hu, Pan, Zhou, Ying, Pan, Bo-Wen, Wang, Qi-Lin, Liu, Xiong-Li
Format Journal Article
LanguageEnglish
Published CAMBRIDGE Royal Soc Chemistry 02.04.2024
Royal Society of Chemistry
Subjects
Anticancer properties
Apoptosis
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Ring opening
Scaffolds
Science & Technology
Toxicity
TETRAHYDRO-BETA-CARBOLINES
CYCLOADDITION
PYRROLIDINE
DRUG DISCOVERY
BENZOFURANONE
C-C
DOPAMINE/SEROTONIN RECEPTOR LIGANDS
CANCER
DERIVATIVES
SIMPLE INDOLE ALKALOIDS
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Summary:Here, we demonstrate that the first example of harmaline scaffolds serving as acceptor/acceptor-based N-C-C synthons triggered the ring opening and skeletal reconstruction of 3-vinyl benzofuranones for the construction of a library of skeletally diverse polycyclic harmaline scaffolds. These products were smoothly afforded in up to 77% yield, >20 : 1 dr under catalyst-free conditions, and expanded the chemical space of biologically significant harmaline derivative species. All synthetic compounds showed cytotoxic activity against tumor cells, especially compound 3at , which exhibited selective cytotoxicity against A549 cells and lower cytotoxicity against normal cells MRC-5 and HK-2. In further mechanism research, 3at inhibited A549 cell proliferation through the G1 phase arrest, induced A549 cell apoptosis through internal and external apoptosis pathways, and suppressed the migration and invasion abilities of A549 cells. These data indicated that compound 3at is the most effective compound in the series and can serve as a promising precursor for drug development. This is the first example of harmaline scaffolds as acceptor/acceptor-based N-C-C synthons and evaluation of 3at as an anticancer agent.
Bibliography:Electronic supplementary information (ESI) available. CCDC
2323856
(
https://doi.org/10.1039/d4nj00306c
For ESI and crystallographic data in CIF or other electronic format see DOI
3aj
ISSN:1144-0546
1369-9261
DOI:10.1039/d4nj00306c