Core-Scaffold-Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis

Document Type

Article

Publication Date

10-26-2015

Publication Title

Chemistry – A European Journal

DOI

10.1002/chem.201503063

ISSN

1521-3765

Abstract

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.

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