Background:
Cancer is a complex genetic disease which is characterized by an abnormal cell growth,
invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage
and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects
such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer
cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been
paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR)
modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also
1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila.
Objective:
The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages
and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in
an attempt to know the mechanism of action of this compound against lung cancer.
Method:
An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been
developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated.
Results:
All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With
respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds
7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one
was compound 7, while compound 8 recorded the least activity.
Conclusion:
we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives
incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so
that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all
compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed
the results of cell cycle assay which showed good binding energy between the compounds and the active site of
enzyme indicating the inhibition of the enzyme.
Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299