New structural analogues of tubulozole induce apoptosis, [Ca2+](i) modifications and cytoskeletal disorganization in glial (GL15) and neuronal-like (PC12) cell lines

The synthesis and the biological activity of (+/-)-cis- and (+/-)-trans-[4- [[2-[1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methy lthio]phenyl]carbamic acid ethyl esters (2a and 2b) are discussed. They wer e designed as structural analogues of Tubulozole. a synthetic tubulin polym erisation inhibitor with antimitotic properties. Biological tests were carr ied out on PC12, a neuronal-like cell line derived from rat pheochromocytom a, and on GL15, a cell line derived from human glioblastoma. The exposure ( from 5 to 20 h) of GL15 and PC12 cells to different concentrations (0.1-100 0 muM; IC50 similar to1 muM) of 2a or 2b resulted in a drastic decrease in the number of viable cells without an apparent effect on the cell distribut ion in the various phases of the cell cycle. Compound 2a or 2b (10 muM) ind uced cell death by activating apoptosis. This was correlated with the activ ation of an oscillating Ca2+-dependent mechanism which increased the intrac ellular calcium concentration ([Ca2+](i)) via Ca2+ release from internal st ores. Moreover, 2a (10 muM) also induced severe damage of cytoskeletal F-ac tin filaments after a 5 h incubation in GL15 cells. This was also observed but to a smaller extent, for 2b. Under the same experimental conditions, PC 12 cells showed similar actin deregulation.