ANTIPROLIFERATIVE, DIFFERENTIATING AND APOPTOTIC EFFECTS ELICITED BY IMIDAZO[1,2-A]PYRAZINE DERIVATIVES

1. The activity of two series of imidazo[1,2-a]pyrazine derivatives on cell proliferation and differentiation and on apoptosis was examined in relation to their effects on phosphodiesterase (PDE) activity and o n purinoceptors. 2. In the first series SC-18 and SC-51 inhibited mito gen-induced H-3-thymidine incorporation in human lymphocytes. 3. The c ompounds of the new series PAB13, PAB23 and SCA40 inhibited the prolif eration of the HEL cell line. 4. Nine imidazo[1,2-a]pyrazine derivativ es of the new series have been studied on the Dami cell proliferation. SCA41 and SCA44 inhibited cell growth, SCA40 and PAB40 were moderatel y effective, whereas PAB12 and PAB30 were devoid of effect. The antipr oliferative effects of these six non-cytotoxic compounds could not be related to their action on PDE or on purinoceptors, but rather to thei r lipophilicity. Conversely, for PAB13, PAB15, and PAB23, the decrease in cell number was related to their cytotoxic and apoptotic effects t hrough their cAMP-increasing and PDE-inhibitory potency, but unrelated to an effect on purinoceptors, 5. Imidazo[1,2-a]pyrazine derivatives decreased the expression of Glycoprotein (GP)IL, in Dami cells while s ome of them enhanced that of GPIIb/IIIa. These effects appeared to inv olve inhibition of both cAMP- and cGMP-PDE. 6, These studies demonstra te the potential interest of imidazo[1,2 a]pyrazine derivatives in the query of novel anticancer drugs. (C) 1998 Elsevier Science Inc.