Interaction of guanine phosphonomethoxyalkyl derivatives with GMP kinase isoenzymes.
Substrate activity and inhibitory potency of guanine phosphonomethoxyalkyl derivatives towards GMP kinase isoenzymes from L1210 cells were studied. 9-[2-(Phosphonomethoxy)ethyl]guanine (PMEG) and the (R)- and (S)-enantiomers of both 9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine (HPMPG) and 9-[2-(phosphonomethoxy)propyl]guanine (PMPG) were phosphorylated to the first step. Kinetic data showed that (R)-PMPG was a good substrate with a relative phosphorylation efficacy of 12% compared with the natural substrate GMP, whereas PMEG was a poor substrate with a relative phosphorylation efficacy of 1.1%. The structurally related 2,6-diaminopurine analogues 9-[2-(phosphonomethoxy)ethyl]-2, 6-diaminopurine (PMEDAP) and (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP) were not phosphorylated by any of the GMP kinase isoenzymes tested. The inhibitory activities of the individual compounds on GMP kinase isoenzymes decreased in the following order: (S)-HPMPG > (R)-PMPG > PMEG > (R)-HPMPG > (S)-PMPG > PMEDAP = (R)-PMPDAP = (S)-PMPDAP; each compound exerted a different type of inhibition.
Krejcová
R
R
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 6, Prague, Czech Republic.
Horská
K
K
Votruba
I
I
Holý
A
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives; D051528:Guanylate Kinases; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D013379:Substrate Specificity; D013552:Swine
C090125:9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine; D000970:Antineoplastic Agents; D007527:Isoenzymes; D009943:Organophosphorus Compounds; C058654:9-(3-hydroxy-2-phosphonomethoxypropyl)guanine; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D006147:Guanine; D006157:Guanosine Monophosphate; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D000225:Adenine