TY - JOUR
T1 - Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway
AU - Break, Mohammed Khaled Bin
AU - Hossan, Md Shahadat
AU - Khoo, Yivonn
AU - Qazzaz, Mohannad Emad
AU - Al-Hayali, Mohammed Z.K.
AU - Chow, Sek Chuen
AU - Wiart, Christophe
AU - Bradshaw, Tracey D.
AU - Collins, Hilary
AU - Khoo, Teng Jin
PY - 2018/3
Y1 - 2018/3
N2 - Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2 μM and 0.7 μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.
AB - Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2 μM and 0.7 μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.
KW - Cardamonin
KW - Caspase
KW - Cell-cycle arrest
KW - Cytotoxicity
KW - mTOR
KW - Semi-synthesis
UR - http://www.scopus.com/inward/record.url?scp=85041410490&partnerID=8YFLogxK
U2 - 10.1016/j.fitote.2018.01.006
DO - 10.1016/j.fitote.2018.01.006
M3 - Article
C2 - 29355749
AN - SCOPUS:85041410490
SN - 0367-326X
VL - 125
SP - 161
EP - 173
JO - Fitoterapia
JF - Fitoterapia
ER -