Design, synthesis and anticancer properties of novel oxa/azaspiro[4,5]trienones as potent apoptosis inducers through mitochondrial disruption

A series of twenty seven oxa/azaspiro[4,5]trienone derivatives were synthesized and their Anticancer properties have been explored. GI50 values of all these compounds were evaluated against four types of human Cancer cell lines, i.e. MCF-7 (breast), DU-145 (prostate), A549 (lung) and HepG2 (liver). Five compounds of the series exhibited good Anticancer potential against MCF-7 with GI50 values less than 2 μM. Detailed biological studies of the two representative compounds 9b and 9e revealed that they arrest cell cycle in G0/G1 phase and induce mitochondria mediated Apoptosis, that was further confirmed by measurement of mitochondrial membrane potential (ΔΨm), intracellular ROS generation, Caspase 9 activity and Annexin V-FITC assay. Furthermore, western blot analysis suggested that these compounds up-regulate the levels of p53, p21, p27 and Bax, and down-regulate the level of Bcl-2 confirming the Apoptosis inducing properties.

Anticancer activity; Apoptosis; Azaspiro[4,5]trienone; Cell cycle analysis; Ipsocyclization; Mitochondrial membrane potential (ΔΨm); Oxaspiro[4,5]trienone; Western blot analysis.