Abstract
A series of 1,4-disubstituted-3,4-dihydroisoquinoline derivatives designed as tubulin polymerization inhibitors were synthesized. Their cytotoxic activities against the CEM leukemia cell line were evaluated. Most of them displayed moderate cytotoxic activities, and compounds 21 and 32 showed good activities with IC50 of 4.10 and 0.64 μM, respectively. The most potent compound 32 was further confirmed to be able to inhibit tubulin polymerization, and its hypothetical binding mode with tubulin was obtained by molecular docking.
Highlights
Microtubules, which are composed of the α/β heterodimeric tubulin proteins [1], have an important role in a variety of cellular process including mitosis and cell division [2,3]
Combretastatin A-4 (CA-4) like tubulin polymerization inhibitors were synthesized by our group previously, which showed moderate cytotoxic activities [7,8]
The general method used for the synthesis of the 3,4-dihydroisoquinoline derivatives was outlined in Scheme 1
Summary
Microtubules, which are composed of the α/β heterodimeric tubulin proteins [1], have an important role in a variety of cellular process including mitosis and cell division [2,3]. The compounds, which can regulate the polymerization dynamics of the tubulin, may prove useful in the development of anticancer drugs [4,5] They can be divided into the tubulin polymerization inhibitors such as colchicine, Combretastatin A-4 (CA-4) (Figure 1) and the vinca alkaloids, and microtubule stabilizing agents such as paclitaxel and epothilone [6]. 1-Phenyl-3,4-dihydroisoquinoline derivatives (e.g., compounds 1a and 1b) (Figure 2) designed as CA-4 like tubulin polymerization inhibitors were synthesized by our group previously, which showed moderate cytotoxic activities [7,8]. Their docking poses in the tubulin binding site were similar to colchicine. Molecular docking studies were performed to explain the SAR
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