Background: Recently, it is reported that heterocycles containing pyrimidoquinoline
moiety show a broad spectrum of medicinal and pharmacological properties including anticancer,
anti-microbial, anti-inflammatory activities, analgesic and antiviral. In additions, spirocyclicoxindole
containing compounds represent an important class of compounds that exhibit wide range
of biological properties. The asymmetric chiral spiro carbon is considered to be the main criteria of
the bioactivities. Spirooxindole structures represent the main skeleton for various alkaloids and
pharmaceutically important compounds. Among them, the naturally occurring pyrrolidinylespirooxindole
alkaloid, horsifiline that exhibits anticancer activity against human brain cancer cell lines.
Objective: The objective of this study is the synthesis of novel bis spiro-cyclic 2-oxindole of
pyrimido[4,5-b]quinoline derivatives 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 breast cancer.
Method: An efficient one pot synthesis of bis spiro-cyclic 2-oxindole derivatives of pyrimido[4,5-
b]quinoline-4,6-dione using 6-aminouracil, bis-isatin and dimedone has been developed. The cytotoxic
effect against different human cell lines MCF7, HCT116 and A549 cell lines was evaluated.
The derivative 6a, was found the most encouraging compound in this series and it was selected for
molecular studies against MCF7.
Results: Our data indicated that compound 6a is an attractive target for breast cancer, as it inhibits
proliferation, cell cycle progression and induces apoptosis of tumor cells. This inhibition is mediated
by fragmentation of genomic DNA, up-regulation of [caspase-3, tumor suppressor gene p53, and
pro-apoptotic gene BAX], and down-regulation of anti-apoptotic BCL2 gene. In additions it caused
cell cycle arrest in S phase. This work provides an evidence of the potent effect of the new compound
6a and assists in the progress of new healing agents for cancer.
Conclusion: We have developed an efficient method for the synthesis of novel bioactive bis spirocyclic
2-oxindole derivatives incorporating pyrimido[4,5-b]quinoline derivatives. Most of our new
derivatives give potent cytotoxic effect more than the standard drug Fluorouracil (5-FU) especially,
compound 6a which was the most active and promising one in this series against MCF7, HCT116,
and A549 cell lines.