Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon
Language English Country Netherlands Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
8649338
Knihovny.cz E-resources
- MeSH
- DNA Polymerase II antagonists & inhibitors MeSH
- DNA Polymerase III MeSH
- DNA metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Nucleic Acid Synthesis Inhibitors * MeSH
- Kinetics MeSH
- Rats MeSH
- Nucleotides pharmacology MeSH
- Rats, Sprague-Dawley MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Polymerase II MeSH
- DNA Polymerase III MeSH
- DNA MeSH
- Enzyme Inhibitors MeSH
- Nucleic Acid Synthesis Inhibitors * MeSH
- Nucleotides MeSH
Based on the powerful virostatic potency and cytostatic activity of adenine, 2,6-diaminopurine, and guanine derivatives of acyclic phosphonate nucleotide analog (S)-1-(3-hydroxy-2-phosphonomethoxypropyl) and 9-(2-phosphonomethoxyethyl) series, we examined the inhibitory potencies of their diphosphates [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine diphosphate (HPMPApp), 9-(2-phosphonomethoxyethyl)adenine diphosphate, 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine diphosphate (PMEDAPpp), and 9-(2-phosphonomethoxyethyl)guanine diphosphate, analogs of nucleoside 5'-triphosphates] toward cellular DNA polymerases alpha, delta, and epsilon (isolated from tumors of T cell spontaneous acute lymphoblastic leukemia in Sprague-Dawley inbred rats). Kinetic measurements (K(m), K(i), and V(max)) of synthetic homopolymeric template primers have shown that HPMPApp is a selective and potent inhibitor of polymerase epsilon, whereas PMEDAPpp strongly inhibits polymerase delta. These two compounds may be useful for elucidating the roles of polymerases delta and epsilon. Of the nucleotide analogs tested, 9-(2-phosphonomethoxyethyl) guanine diphosphate is the most efficient inhibitor of polymerases alpha and epsilon, whereas the diphosphate of 9-(2-phosphonomethoxyethyl) adenine, the therapeutically important agent adefovir, inhibits polymerases alpha and epsilon relatively poorly and exerts only moderate inhibition of polymerase delta. These data are quite consistent with previously reported cytostatic activity of these nucleotide analogs. All of the enzymes studied catalyze the incorporation of 9-(2-phosphonomethoxyethyl)adenine, 9-(2-phosphonomethoxyethyl)-2, 6-diaminopurine, and (S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine into DNA chain. 9-(2-Phosphonomethoxyethyl)adenine diphosphate and PMEDAPpp were confirmed to be DNA chain terminators. On the other hand, HPMPApp formed poly(dT)/oligo(dA(18)-[(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)a denine]2-4 structures.
Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects
