Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring.

ABSTRACT: A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6'-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with α-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both α- and β-tubulin.

SUBMITTER: Nakagawa-Goto K 

PROVIDER: S-EPMC4394749 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature