Objective:
Several anti-tubulin agents were introduced for the cancer treatment so far.
Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral
neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral
neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining
in a preclinical stage.
Methods:
Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer
activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin
V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay.
Results:
One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells
(IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100 μM). All of the tested compounds
showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In
the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell
cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an
increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with
the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction
by more potent compounds was due to activation of caspase 3.
Conclusion:
Newly synthesized compounds exerted acceptable anticancer activity and further investigation
of current scaffold would be beneficial.
A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy
