Nonpolar thymidine analogs
View Patent ↗Nonpolar thymidine analogs are provided comprising a dihalogenated or trihalogenated base of the structure: where R 1 is a sugar moiety; R 2 is H or CH 3 ; an imaging moiety or a cytotoxic moiety and X 1 and X 2 are independently selected from I, Cl, Br, and F, with the proviso that not more than one F will be present at these positions.
1. A nucleoside analog comprising a halogenated base of the structure:
where R 1 is a sugar moiety;
R 2 is H, CH 3 , an imaging moiety selected from 11 CH 3 , 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 128 I, 111 In, 67 Ga and 99m Tc or a cytotoxic moiety selected from 123 I, 125 I, 131 I, 90 Y, 211 At, 67 Cu, 186 Re, 188 Re, 212 Pb, and 212 Bi; and
X 1 and X 2 are a combination selected from 2,4-dichloro; 2,4-dibromo; 2-chloro,4-bromo; 2-bromo,4-chloro; 2-bromo,4-fluoro; and 2-fluoro,4-bromo.
2. A nucleotide comprising the nucleoside analog of claim 1 .
3. The nucleoside analog of claim 1 , wherein the halogenated base is 2-chloro-4-bromo-toluene or 2,4-dichlorotoluene.
4. The nucleoside analog of claim 1 , wherein R 1 is selected from a ribose, deoxyribose or dideoxyribose sugar modified at one or more of the 2′, 3′, 4′ and 5′ positions, which modification terminates polymerization.
5. A polynucleotide comprising at least one nucleoside analog according to claim 1 .
6. The polynucleotide according to claim 5 , wherein said analog is at one or both terminal positions.
7. The polynucleotide according to claim 5 , wherein said analog is at other than a terminal position.
8. A nucleoside analog comprising a halogenated base of the structure:
where R 1 is a sugar moiety;
R 2 is an imaging moiety selected from 11 CH 3 , 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 128 I, 111 In, 67 Ga and 99m Tc; and
X 1 and X 2 are independently selected from I, Cl, Br, and F, with the proviso that not more than one F will be present at these positions.
9. The nucleoside analog of claim 8 , wherein R 2 is selected from 11 CH 3 , 18 F, 123 I, 124 I, 125 I and 128 I.
10. A nucleoside analog comprising a halogenated base of the structure:
where R 1 is a sugar moiety;
R 2 is a cytotoxic moiety selected from 123 I, 125 I, 131 I, 90 Y, 211 At, 67 Cu, 186 Re, 188 Re, 212 Pb, and 212 Bi; and
X 1 and X 2 are independently selected from I, Cl, Br, and F, with the proviso that not more than one F will be present at these positions.
11. A nucleoside analog comprising the structure
where R 1 is a sugar moiety;
R 2 is H or CH 3 ; and
X 1 and X 2 are independently selected from I, Cl, Br, and F, and wherein at least one of X 1 and X 2 is 123 I, 125 I, 131 I.
12. A pharmaceutical formulation comprising a nucleoside analog according to claim 1 or polynucleotide according to claim 5 , and a pharmaceutically acceptable excipient.
13. A method of polynucleotide polymerization, the method comprising:
polymerizing a polynucleotide utilizing as a substrate a nucleotide analog comprising a halogenated base of the structure:
where R 1 is a sugar moiety;
R 2 is H, CH 3 , an imaging moiety selected from 11 CH 3 , 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 128 I, 111 In, 67 Ga and 99m Tc or a cytotoxic moiety selected from 123 I, 125 I, 131 I, 90 Y, 211 At, 67 Cu, 186 Re, 188 Re, 212 Pb, and 212 Bi; and
X 1 and X 2 are are a combination selected from 2,4-dichloro; 2,4-dibromo; 2-chloro,4-bromo; 2-bromo,4-chloro; 2-bromo,4-fluoro; and 2-fiuoro,4-bromo.
14. The method according to claim 13 , the method comprising:
polymerizing a polynucleotide utilizing as a substrate a nucleotide analog comprising a halogenated base selected from 2-chloro-4-bromo-toluene or 2,4-dichlorotoluene.
15. The method according to claim 13 , wherein said reaction in performed in vivo.
16. The method according to claim 13 , wherein said reaction is performed in vitro.
17. The method according to claim 13 , wherein said polymerization reaction is catalyzed by one of DNA dependent DNA polymerase, DNA dependent RNA polymerase, RNA dependent DNA polymerase, and RNA dependent RNA polymerase.
18. The method of claim 13 , wherein said reaction is an isothermal amplification reaction.
19. A method of inhibiting polynucleotide polymerization, the method comprising;
polymerizing a polynucleotide utilizing as a substrate a nucleotide analog comprising a halogenated base of the structure:
where R 1 is a ribose, deoxyribose or dideoxyribose sugar modified at one or more of the 2′, 3′, 4′ and 5′ positions with a modification that inhibits polymerization;
R 2 is H, CH 3 , an imaging moiety selected from 11 CH 3 , 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 128 I, 111 In, 67 Ga and 99m Tc or a cytotoxic moiety selected from 123 I, 125 I, 131 I, 90 Y, 211 At, 67 Cu, 186 Re, 188 Re, 212 Pb, and 212 Bi; and
X 1 and X 2 are a combination selected from 2,4-dichloro; 2,4-dibromo; 2-chloro,4-bromo; 2-bromo,4-chloro; 2-bromo,4-fluoro; and 2-fiuoro,4-bromo,
wherein polymerization is inhibited by said nucleotide analog.