Premium
Core‐Scaffold‐Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis
Author(s) -
Leng HaiJun,
Peng Fu,
Zingales Sarah,
Huang Wei,
Wang Biao,
Zhao Qian,
Zhou Rui,
He Gu,
Peng Cheng,
Han Bo
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201503063
Subject(s) - apoptosis , scaffold , cell growth , cancer research , chemistry , core (optical fiber) , microbiology and biotechnology , biology , medicine , materials science , biochemistry , biomedical engineering , composite material
The highly enantioselective preparation of pharmacologically interesting hexahydropyridazine derivatives based on a multicomponent cascade reaction is described. This one‐pot approach utilizes an organocatalytic Michael reaction followed by intermolecular α‐amination and intramolecular hemiaminalization to yield a chiral pyridazine backbone with contiguous stereogenic centers and multiple functional groups in good yield and with high stereoselectivity. Compounds synthesized by this method potently inhibited proliferation of MCF‐7 breast cancer cells. Mechanistic studies suggest that compound 5 c exerts these anticancer effects by inducing apoptosis through extracellular signal related kinase (ERK)‐ and poly(adenosine diphosphate ribose) polymerase (PARP)‐regulated pathways, as well as mitochondrial pathways.