Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds.
Cyclin-dependent kinases (cdk) have recently raised considerable interest in view of their essential role in the regulation of the cell division cycle. The structure-activity relationships of cdk inhibition showed that the 1, 3; and 7 positions of the purine ring must remain free, probably for a direct interaction, in which it behaves as a hydrogen bond acceptor. Olomoucine (6-(benzylamino)-2-[(2-hydroxyethyl)amino]-9-methylpurine, OC), roscovitine (6-(benzylamino)-2(R)-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpur ine), and other N6,2,9-trisubstituted adenines were found to exert a strong inhibitory effect on the p34cdc2/cyclin B kinase. Removal or change of the side chain at position 2 or the hydrophobic group at position 9 dramatically decreased the inhibitory activity of olomoucine or roscovitine. Inhibition of cdk with OC and related compounds clearly arrests cell proliferation of many tumor cell lines at G1/S and G2/M transitions and also triggers apoptosis in the target tumor cells in vitro and in vivo. Thus, from a pharmacological point of view, OC may represent a model compound for a new class of antimitotic and antitumor drugs.
Havlícek
L
L
Central Radioisotope Laboratory, Medical Faculty 1, Charles University, Prague, Czech Republic.
Hanus
J
J
Veselý
J
J
Leclerc
S
S
Meijer
L
L
Shaw
G
G
Strnad
M
M
D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D017489:CDC28 Protein Kinase, S cerevisiae / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007701:Kinetin; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D013215:Starfish; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004791:Enzyme Inhibitors; D011687:Purines; D000077546:Roscovitine; C090046:olomoucine; D016203:CDC2 Protein Kinase; D017489:CDC28 Protein Kinase, S cerevisiae; D007701:Kinetin