Nucleic acid prodrugs
The invention relates to deoxynucleotide prodrugs and pharmaceutical preparations thereof. The deoxynucleotide prodrugs include, but are not limited to, The invention further relates to methods of treatment of a mitochondrial DNA (mtDNA) depletion syndrome (MDS) by administering a therapeutically-effective amount of a deoxynucleotide prodrug of the present invention.
1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is aryl or;
R 2 and R 2 ′, each independently, are hydrogen, alkyl, or aralkyl;
R 3 is alkyl or aralkyl;
R 4 is hydrogen or alkyl;
NT is a nucleobase.
2. The compound of claim 1 , wherein the nucleobase is selected from:
and further wherein R 5 is alkyl or aralkyl.
3. The compound of claim 2 , wherein R 5 is methyl, ethyl, isopropyl, or benzyl.
4. The compound of claim 1 , wherein R 1 is phenyl, naphthyl, or 4-fluorophenyl.
5. The compound of claim 1 , wherein R 2 is alkyl.
6. The compound of claim 1 , wherein R 2 ′ is H.
7. The compound of claim 1 , wherein R 3 is methyl, benzyl, neopentyl or isopropyl.
8. The compound of formula (I) in claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is aryl;
R 2 is hydrogen, or alkyl or aralkyl;
R 3 is alkyl or aralkyl;
R 4 is hydrogen or alkyl; and
NT is 9-adeninyl, 9-guaninyl, 1-cytosinyl, or 1-thyminyl.
10. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.