Thymidine isosteres

These non-polar nucleotide isosteres were used as functional probes to elucidate the impact of hydrogen bonding on DNA polymerase selectivity. In preliminary experiments Kool et al. studied the insertion of dNTP opposite F, the non-polar isostere of thymidine (Figure 4.1.4), in the template strand [8], If purely hydrogenbonding drives selective nucleotide incorporation one would expect that incorporation opposite F is very inefficient and unselective. Interestingly, they observed the contrary when studying the Klenow fragment of E. coli DNA polymerase I. This... 

It has been shown that 2,3-difluorotoluene (36) serves as a nonpolar shape mimic of thymine (37) and difluorotoluene deoxyriboside (38) is, surprisingly, an excellent nonpolar nucleoside isostere of thymidine (39) (see Fig. 1.21) [126, 127], Thus, the nucleotide of 36 was incorporated into DNA by several high-fidelity DNA polymerases [126, 128],... 

Morales and KooP " have used a set of non-polar isosteres of natural DNA bases to probe the interactions at the active site of a number of different polymerases by replacing the deoxynucleoside analogues of difluorotoluene (F) for thymidine and 4-methylbenzimidazole (Z) or 9-methyl-l-if-imidazo[4,5-fe] pyridine (Q) (129) for adenosine. Their findings showed that each polymerase, Klenow (exo ) fragment, Taq, T7 and HIV-RT, were all able to efficiently generate the non-natural base-pairs A-F, F-A, F-Z and Z-F. Calf thymus DNA... 

There have been a number of reports on phosphonate analogues of nucleoside monophosphates, including a further paper on 2, 3 -dideoxy-3 -phosphonomethyl analogues (see Vol. 18, p.203) which reports the guanosine compound (176) for the first time.23i Phosphonoformate esters of anti-HIV nucleosides, such as (177), have been prepared,232 as has the 5 -0-phosphonomethyl compound (178), by alkylation of the unsaturated nucleoside, protection of the uracil NH being necessary.23 3 xhe isosteric phosphonates of type (179) have also been made, as outlined in Scheme 23, with the unsaturated thymidine member being a potent antiretroviral agent.234,235 x e phosphonomethyl derivative (180) of 3 -deoxy-3 -... 

Carbamate bridges were supposed to be superior to the isosteric carbonate analogs by having greater pH stability. The first S -O-S -N-caibamate-bridged dimer of thymidine was synthesized in 1974 by Gait et al., who obtained it in 38% yield by condensation of 3 -0-(2,2,2-trichloro-ethyl)carbonate of 5 -0-tritylthymidine with 5 -amino-5 -desoxy-thymidine (24) (Fig. 14). 

A number of intoesting papers have described the use of aminonucleosides to assemble neutral isosteric replacements for the intemucleosidic phosphodiester link (see Vols. 25 and 26 for earlio woik). The thymidine dimer 54 has been prepared, as has the related structure 55. The CH2CH2NH isostere has been assembled by reductive aminadon between a S -amino-S -deoxycompound and a unit branched at C-3, in a manner similar to that used for the NHCH2CH2 replacement (Scheme 7), where a unit extended at C-S was linked to a 3 -amino-3 -deoxy-compound. This latter approach could also be used when unit 56 was replaced by a building... 

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