Development of Tubulin-Polymerization Inhibitors Based on the Thalidomide Skeleton

Abstract

We synthesized a series of compounds based on the potent tubulin-polymerization inhibitor 5-hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione [5HPP-33 (3)], which is structurally derived from thalidomide (1), and investigated their inhibitory effects on tubulin polymerization. Direct interaction between 5HPP-33 (3) and a a,b b-tubulin heterodimer protein was demonstrated by means of a surface plasmon resonance study.Key words thalidomide; phthalimide skeleton; tubulin polymerization inhibitor; surface plasmon resonance Chem. Pharm. Bull. 55(6) 944-949 (2007) Notes

Thalidomide as a Multi‐Template for Development of Biologically Active Compounds

“…Our findings suggest that 5HPP-33 5 binds only to free a,b-tubulin heterodimer protein to inhibit tubulin polymerization, but not to polymerized tubulin. In fact, studies using surface plasmon resonance (SPR) measurement techniques suggested that 5HPP-33 5 binds directly to a,b-tubulin heterodimer protein with the calculated association constant of 4.5610 6 M -1 under our experimental conditions [32]. The calculated value is in good agreement with the IC 50 value of 5HPP-33 5 for inhibition (6.9 lM) of tubulin polymerization.…”

“…Investigations using porcine tubulin fraction revealed that 5-OH-thalidomide 9 and N-OH-thalidomide 10 possess moderate tubulin polymerizationinhibiting activity (Fig. 5A) [30,32].…”

Identification of Binding Proteins of Fusarielin A as Actin and Tubulin

“…Briefly, nucleophilic attack of ethylenediamine in methanol toward FSA (1) occurred selectively at the 11-position to give DAFSA (9), which was used as a substrate for coupling with Affi-Gel 10 (Chart 2). As expected, DAFSA (9) showed only very weak anti-proliferative activity toward HL-60 cells (IC 50 value of Ͼ100 mM; growth was inhibited by only 24% at 100 mM concentration) and moderate anti-angiogenic activity measured by assay of HUVEC tube formation-inhibitory activity (Table 1), indicating the suitability of DAFSA-Gel as a negative control gel.…”

Design and synthesis of silicon-containing tubulin polymerization inhibitors: Replacement of the ethylene moiety of combretastatin A-4 with a silicon linker

“…All of the prepared compounds were initially screened at 30 lM concentration by means of TPI assay, 31 used in identifying tubulin polymerization inhibitors. Secondly, the tumor cell growth-inhibitory activity of the synthesized compounds towards human breast cancer cell line (MCF-7) was evaluated.…”

“…31 Briefly, microtubule protein was prepared from porcine brain by several cycles of assembly-disassembly, as described. 32 Tubulin solution was prepared at a concentration of 1.8-2.0 mg/ml.…”