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]pyrazine derivatives (PAB12, PAB30, PAB40, SCA40, SCA41, and SCA44) inhibited cAMP breakdown by a phosphodiesterase (PDE)-inhibitory effect, the aim of the present study was to investigate the effects of these derivatives on proliferation of the Dami cell line in relation with their actions on cAMP content and on PDE isoenzymes isolated from Dami cells. SCA41 and SCA44 inhibited cell growth in a dose-dependent manner, while SCA40 and PAB40 induced a weak inhibition. Growth inhibitions were 40%, 91%, and 60% for SCA41, SCA44 (at 100 microM), and IBMX (at 100 microM), respectively, and could not be related to their effects on cAMP levels. In addition, although all compounds potentiated cAMP formation by prostaglandin E1 (PGE1), no potentiations were observed when the antiproliferative effects of SCA41 and SCA44 were considered. Investigation of derivatives on PDE isoenzymes III, IV, and V indicated non-selective 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 antiproliferative activity of the derivatives. The activation of P2 purinoceptors by imidazo[1,2-a]pyrazine did not lead to their antiproliferative effects. Thus, the mechanism of the antiproliferative effects of the compounds remains to be determined. It does, however, depend on the chemical substitutions of the imidazo[1,2-a]pyrazine skeleton and in particular on the 2-carbonitrile presence and the length of the 8-aminoaliphatic group.
Zurbonsen
K
K
INSERM U.300, Faculté de Pharmacie, Montpellier, France.
Michel
A
A
Vittet
D
D
Bonnet
P A
PA
Chevillard
C
C
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D007093:Imidazoles; D011719:Pyrazines; D011724:Pyridazines; D018048:Receptors, Purinergic P2; C107725:SCA 44; C080660:6-bromo-8-methylaminoimidazo(1,2-a)pyrazine-2-carbonitrile; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000527:Alprostadil; D015056:1-Methyl-3-isobutylxanthine