Antitubulin effects of aminobenzothiophene-substituted triethylated chromones
- Bioorg Med Chem Lett. 2017 Jun 15;27(12):2731-2735. doi: 10.1016/j.bmcl.2017.04.055.
- 1. School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
- 2. UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States. Electronic address: [email protected].
- 3. School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan; UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States. Electronic address: [email protected].
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 IC50 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.