Inhibition of Tubulin Polymerization by 5,6-Dihydroindolo[2,1-a]isoquinoline Derivatives

Abstract

6-Alkyl-12-formyl-5,6-dihydroindolo[2,1-alpha]isoquinolines have been shown to inhibit the growth of human mammary carcinoma cells by an unknown mode of action. One of the possible molecular targets is the tubulin system which is involved in cell division. A number of 5,6-dihydroindolo[2,1-alpha]isoquinolines with methoxy or hydroxy groups in positions 3, 9, and/or 10 and various functional groups such as formyl, acetyl, cyano, alkylimino, and alkylamino in position 12 were synthesized and evaluated for both inhibition of tubulin polymerization and cytostatic activity in MDA-MB 231 and MCF-7 human breast cancer cells. In the tubulin polymerization assay, only hydroxy derivatives were active, whereas both the hydroxy derivatives and some of the methoxy compounds inhibited cell growth. In order to establish a correlation between the inhibition of tubulin polymerization and cytostatic activity in the hydroxy series, two of the most active racemates were separated into the enantiomers. In both assays, the relative potencies of the hydroxy derivatives were in a similar order. Highest activity was found for the (+)-isomers of 6-propyl- (6b) and 6-butyl-12-formyl-5,6-hydro-3,9-dihydroxyindolo[2,1-alpha]isoquino line (6c) with IC50 values of 11 +/- 0.4 and 3.1 +/- 0.4 microM, respectively, for the polymerization of tubulin at 37 degrees C (colchicine: 2.1 +/- 0.1 microM). The active hydroxy derivatives displaced 40-70% of [3H]colchicine from its binding site in the tubulin at concentrations 10-fold higher than that of colchicine. The data suggest that hydroxy-substituted indolo[2,1-alpha]isoquinolines bind to the colchicine-binding site and inhibit the polymerization of tubulin. This action can be assumed to be responsible for the cytostatic activity of the hydroxy derivatives and might also contribute to the antitumor effect of the corresponding methyl ethers.

Indole, a core nucleus for potent inhibitors of tubulin polymerization

“…This series of compounds showed a cytostatic effect related to their tubulin polymerization inhibition (Table II). 34 The 2-phenylindoles were obtained by reacting ring-substituted anilines with bromoacetophenones in N,N-dimethylaniline (DMA) at 170 C following the Bischler method. Formylation at position 3 of indole was achieved by the Vilsmeier reaction by reacting 2-phenylindoles with DMF and POCl 3 .…”

Synthesis of Pyrido[1,2-a]indole Malonates and Amines through Aryne Annulation

“…1 A series of indolo[2,1- a ]isoquinoline compounds have been shown to possess a wide range of biological activities, including cytostatic, 2,3 antiviral, 4 immunosuppressive 5 and tubulin polymerization inhibiting activities. 6 Another series of compounds known as metosenes have shown significant antitumor activity. 7 However, the fully aromatic pyridoindole core has been mentioned in the literature only briefly, mainly due to the challenges in the preparation of this system.…”

Synthesis of Dihydroindoloisoquinolines through Copper‐Catalyzed Cross‐Dehydrogenative Coupling of Tetrahydroisoquinolines and Nitroalkanes

“…In this regard, studies on the biological activity of 5,6‐dihydroindolo[2,1‐ a ]isoquinolines have revealed promising results to advance in the treatment of manifold diseases. For instance, compounds 1 a and 1 b strongly inhibit tubulin polymerization and the growth of human breast cancer cells in vitro,, whereas compound 1 c is a melatonin agonist (Figure ) . Modern synthetic methods towards the 5,6‐dihydroindolo[2,1‐ a ]isoquinoline skeleton rely on the intramolecular cyclization of N ‐aryl‐1,2,3,4‐tetrahydroisoquinolines .…”