Apoptotic effects of imidazo[1,2-a]pyrazine derivatives in the human Dami cell line.
cAMP-elevating agents like phosphodiesterase inhibitors and purines have been shown to induce apoptosis. In the present work we have studied the effects of imidazo[1,2-a]pyrazine derivatives with a purine-like structure: PAB13 (6-bromo-8-(methylamino)imidazo[1,2-a] pyrazine), PAB15 (6-bromo-8-(ethylamino)imidazo[1,2-a]pyrazine), PAB23 (3-bromo-8-(methylamino)imidazo[1,2-a]pyrazine) on the growth of the Dami cell line in comparison to that of adenosine. The growth effect of PAB13, PAB15 and PAB23 was investigated in relation to their phosphodiesterase-inhibitory action and their activity on purinoceptors. Inhibition in cell growth was up to 71.0%, 76.3% and 89.7% for PAB23, PAB13 and PAB15, respectively and 100% for adenosine. Cell viability was affected in a concentration-dependent manner by PAB13, PAB15 and adenosine, with a correlation between growth inhibition and cytotoxicity. These effects of imidazo[1,2-a]pyrazine derivatives were found to be unrelated to an action on purinoceptors, but rather appear quantitatively linked to their ability in inducing apoptosis through their cAMP-increasing and phosphodiesterase-inhibitory potency.
Zurbonsen
K
K
INSERM U300, Faculté de Pharmacie, Montpellier, France.
Michel
A
A
Bonnet
P A
PA
Gannoun-Zaki
L
L
Mathieu
M N
MN
Chevillard
C
C
D000241:Adenosine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D004247:DNA; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000241:Adenosine