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. We predict that, when a compound/ligand, such as 8, forms H-bonds to both α- and β-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules.

Design, synthesis and structure–activity relationships of (±)-isochaihulactone derivatives

“…15 Paclitaxel was used as the positive reference. In previous studies, 6 compound 2 exhibited potent activity in vitro and in vivo against A549 and LNCaP cells.…”

“…Because compound 20a was highly potent against A549, KB and KB-VIN cell lines, a flow cytometry analysis 15 was performed to evaluate its effect on cell cycle progression and probe its mode of action. DMSO and combretastatin A-4 (CA-4), a tubulin polymerization inhibitor inducing cell cycle arrest in G 2 /M, were used as controls in this experiment.…”

“…Antiproliferative activity of compounds were determined by sulforhodamine B (SRB) assay as previously described. 15 In brief, freshly trypsinized cell suspensions were seeded in 96-well microtiter plates at densities of 4,000–7,500 cells per well (bases on the doubling time of the cell line) with compounds. After 72 h in culture with test compounds, cells were fixed in 10% trichloroacetic acid and then stained with 0.04% SRB.…”

“…15 Briefly, freshly trypsinized A549 cells were seeded in 12-well plates at densities of 75,00 cells per well 24 h prior to treatment with compounds. After a 24 h treatment, supernatants and trypsinized cells were collected together, followed by centrifugation for 10 min at 1,000 rpm.…”

A Novel Clerodane Diterpene from <i>Vitex cofassus</i>

“…28) Briefly, all cell lines were grown in T-75 flasks at 37°C with 5% CO 2 in air. Freshly trypsinized cell suspensions were seeded on 96-well microtiter plates at the density of 4000-12000 cells per well and treated with the compounds.…”