Novel indole-bearing combretastatin analogues as tubulin polymerization inhibitors.

Background: The combretastatins are a class of natural stilbenoids. These molecules generally share three common structural features: a trimethoxy "A"-ring, a "B"-ring containing substituent often at C3' and C4', and an ethene bridge between the two rings, which provides necessary structural rigidity. Members of the combretastatin family possess varying ability to cause vascular disruption in tumors. Combretastatin binds to the colchicine binding site of β-subunit of tubulin. Despite having a similar name, combretastatin is unrelated to statins, a family of cholesterol-lowering drugs.

Results: New combretastatin 2-(1-acetyl-1H-indole-3-yl)-3-(phenyl) propenoic analogues (2a to 2y), bearing indole moiety at the place of ring A of combretastatin (CA4), were synthesized and evaluated for anticancer activity against various cancer cell lines such as THP-1 (leukemia), A-549 (lung), IGROV-1 (ovary), HEP-2 (liver), MCF-7 (breast), and DU-145 (prostate). Compound 2d showed anti-cancer activity against THP-1 and MCF-7 with IC50 0.80 and 0.37 μM, respectively, and 2y showed against MCF-7 with IC50 3.60 μM comparable to paclitaxel.

Conclusions: The target compounds bind to the colchicine binding site which is situated at α and β interface of tubulin and prevent polymerization as it was confirmed by immunofluorescence technique. The molecular docking further confirmed the binding of the potent compound 2d to the colchicine binding site at α and β interface of tubulin.