Antitubulin effects of aminobenzothiophene-substituted triethylated chromones.

Authors :: Kobayashi Y
Saito Y
Goto M
Nakagawa-Goto K
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Jun 15; Vol. 27 (12), pp. 2731-2735. Date of Electronic Publication: 2017 Apr 19.
Publication Year :: 2017
Abstract: In the course of our continuing studies on the 2-(benzo[b]thiophene-3'-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5'- and 6'-amino derivatives, 6 and 7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC <subscript>50</subscript> values of 0.50-1.01µM were 3-6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.<br /> (Copyright © 2017. Published by Elsevier Ltd.)