Substitution at Phenyl Rings of Chalcone and Schiff Base Moieties Accounts for their Antiproliferative Activity.

BACKGROUND AND METHODS: In a continuous combat against cancer which is one of the leading causes of mortality now, chalcone and Schiff bases moieties have been incorporated and their antiproliferative activities and associated mechanisms against liver (HepG2) and breast (MCF-7) cell lines in addition to normal fibroblasts (WI-38) have been examined.

RESULTS: Derivatives 4 and 5 of Schiff bases only and chalcone derivatives of Schiff bases 1 and 2 were devoid of any antiproliferative activity. All three compounds (3, 6, and 7) with significant antiproliferative activity were selective and caused no growth inhibition in normal fibroblasts. Derivative 3 was a chalcone only with IC50 of ~20 μM and has a very interesting signature where it enhanced apoptosis in HepG2 by stimulating the expression of downstream execution caspase 3 without affecting neither p53 nor initiator caspase 9. In spite of the structural similarity between compounds 6 and 7, compound 6 discerned itself with a unique IC50 of ~ 10 μM. The antiproliferative activity of derivative 6 could be attributed to its unique capability of formation of free radicals such as phenoxide radicals which arrested the cell cycle through enhancing the expression of p53 and induced apoptosis by induction of both caspases 9 and 3. It was the only investigated derivative that inhibited the tyrosine kinase activity by 89%.

CONCLUSIONS: The antiproliferative activity of the compounds under investigation considerably depended on the nature of the substituent at position 4 in phenyl rings of both chalcone and Schiff base fragments. Derivative 6 with electron withdrawing chlorine substitution on phenyl ring of Schiff base fragment and an electron donating methoxy group on phenyl ring of chalcone fragment was the most active member.