Background:
Cancer being a complex disease, single targeting agents remain unsuccessful. This calls
for “multiple targeting”, wherein a single drug is so designed that it will modulate the activity of multiple protein
targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication,
Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the
present work, we have tried to develop dual inhibitors of Top2 and CK2.
Objective:
With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve
the anti-proliferative effects.
Methods:
Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures
were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and
Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the
Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for
Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis.
Results:
The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell
line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y
have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more
cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1
phase.
Conclusion:
We have successfully designed, synthesized, purified and structurally characterized 1-
acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase
enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.
Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres
