3-(3,4,5-Trimethoxyphenylselenyl)-1H-indoles and their selenoxides as combretastatin A-4 analogs: Microwave-assisted synthesis and biological evaluation

•3-(3,4,5-Trimethoxyphenylselenyl)-1H-indoles were designed as novel analogs of CA-4.•A microwave-assisted progress for the synthesis of 3-arylselenylindoles was developed.•Most of the analogs showed potent antitumor activity; some showed nanomolar IC50s.•Compound 13a inhibited tubulin polymerization and disrupted microtubule dynamics.•Compound 13a exhibited a binding mode similar to that of CA-4.

A series of 3-(3,4,5-trimethoxyphenylselenyl)-1H-indoles and their selenoxides were designed as a new class of combretastatin A-4 (CA-4) analogs. The B ring and the cis double bond of CA-4 were replaced by an indole moiety and selenium atom, respectively. A facile and efficient microwave-assisted synthesis of 3-arylselenylindoles was developed to prepare the target compounds, which were then evaluated for antiproliferative activity against three human cancer cell lines using an MTT assay. Most of these compounds exhibited significant antiproliferative activity, with some showing nanomolar IC50 values. Tubulin polymerization and immunostaining experiments revealed that 13a potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a similar manner to CA-4. Docking studies demonstrated that 13a adopts an orientation similar to that of CA-4 at the colchicine binding site on tubulin.

Graphical abstractA microwave-assisted procedure for the effective synthesis of a series of 3-(3,4,5-trimethoxyphenylselenyl)-1H-indoles is reported. The target compounds showed potent in vitro activity against cancer cell proliferation and tubulin polymerization.Figure optionsDownload full-size imageDownload as PowerPoint slide