ANTIPROLIFERATIVE EFFECTS OF IMIDAZO[1,2-A]PYRAZINE DERIVATIVES ON THE DAMI CELL-LINE

Since cyclic 3',5'-adenosine monophosphate (cAMP) is involved in cell proliferation and as previous data showed that imidazo[1,2-alpha]pyraz ine derivatives (PAB12, PAB30, PAB40, SCA40, SCA41, and SCA44) inhibit ed cAMP breakdown by a phosphodiesterase (PDE)-inhibitory effect, the aim of the present study was to investigate the effects of these deriv atives on proliferation of the Dami cell line in relation with their a ctions on cAMP content and on PDE isoenzymes isolated from Dami cells. SCA41 and SCA44 inhibited cell growth in a dose dependent manner, whi le SCA40 and PAB40 induced a weak inhibition; Growth inhibitions were 40%, 91%, and 60% for SCA41, SCA44 (at 100 mu M), and IBMX (at 1000 mu M), respectively, and could not be related to their effects on cAMP l evels. In addition, although all compounds potentiated cAMP formation by prostaglandin E1 (PGE1), no potentiations were observed when the an tiproliferative effects of SCA41 and SCA44 were considered. Investigat ion of derivatives on PDE isoenzymes III, IV, and V indicated non-sele ctive PDE inhibitory effects for SCA41 and SCA44, while SCA40 elicited preferences for type III, and PAB30 and PAB40 preferences for type IV isoenzymes. These effects could not totally explain the antiprolifera tive activity of the derivatives. The activation of P2 purinoceptors b y imidazo[1,2-alpha]pyrazine did not lead to their antiproliferative e ffects. Thus, the mechanism of the antiproliferative effects of the co mpounds remains to be determined. It does, however, depend on the chem ical substitutions of the imidazo[1,2-alpha]pyrazine skeleton and in p articular on the 2-carbonitrile presence and the length of the 8-amino aliphatic group. (C) 1997 Elsevier Science Inc.