Nucleic Acids in Chemistry and Biology

The Sonogashira substitution has also been widely employed by Seela in the syntheses of C7-modified
7-deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides43,44(Figure 3.30). These analogues have attracted
widespread interest since they represent 7-substituted purine nucleosides that can maintain Watson–Crick
base pairing while retaining the normal anti-conformation about the glycosylic bond (Section 2.1.4). The
5 -triphosphates of 7-deaza-2-deoxyadenosine, 7-deaza-2-deoxyguanosine and their 7-substituted
analogues are generally excellent substrates for many DNA polymerases and have been widely used in
developing DNA sequencing methodology.^67 In addition, 7-deazapurine forms the basis of a number of
naturally occurring antibiotics such as tubercidin, toyocamycin, sangivamycinand cadeguomycin
(Figure 3.30), while several 7-substituted 7-deazaguanosines such as nucleoside Qare found in some
tRNAs. Furthermore, many 7-substituted 7-deazapurine nucleoside analogues have been shown to stabi-
lize DNA duplexes.^70
Many nucleosides have been modified at the 4-position of pyrimidine or 6-position of purine, starting from
uridine or guanosine respectively. The modification of pyrimidine nucleosides at C-4 can be achieved through
nucleophilic substitution of 4-triazolo-pyrimidine nucleoside derivatives, which are stable, isolable compounds
that can be transformed into a variety of analogues (Figure 3.31).^71 O^4 - Methylthymidine is an important ana-
logue formed during DNA damage by alkylating agents, while the highly mutagenic analogues N^4 -amino- and
N^4 -hydroxy-2-deoxycytidine are formed by the action of hydrazine and hydroxylamine on DNA (Section 8.4).
The reaction of triazolo derivatives with ammonia is particularly useful for converting uracil into cytosine-con-
taining nucleosides, especially for analogues containing modified sugars.^72 Activation at O-4 for subsequent
nucleophilic displacement may also be achieved by use of nitrophenoxy-, dinitrophenylthio- and sulfonate
esters, although these are often generated and used in situbecause of their high reactivity.
Nucleosides containing bases with 6-keto functions, such as guanine and hypoxanthine, can also be
transformed in a similar way into 6-substituted purine nucleosides. O^6 -Sulfonate estersof purines can be
displaced by a variety of nucleophiles, although hard nucleophiles such as alkoxide react at sulfur, and so
6-alkoxypurines are made via the highly reactive trimethylammonium salt (Figure 3.32).
Thus, syntheses of compounds such as 2-aminopurinenucleosides (a fluorescent base analogue),^73
2-amino-6-vinylpurine-2-deoxyriboside^74 (allows covalent cross-linking within DNA) and O^6 -methyl-
2 -deoxyguanosine^75 (an important analogue resulting from DNA alkylation damage) are possible,
while a variation on this theme leads to 6-thio-2-deoxyguanosine^76 and other analogues (Figure 3.33).

96 Chapter 3

HO O

HO

N

N N

X

I

Y

HO O

HO

N

N N

X

R

Y

HO O

HO OH

N

N NH

O

NH 2

HO 2 C

HO O

HO

N

N N

NH 2

X

(i)

X=NH2,Y=H:

R=TMS,t-Bu, C 10 H 21 ,C 4 H 9 ,

Me, CH 2 NHCOCF 3 ,cholesteryl-,

CH 2 CH 2 OTHP, CH 2 TMS

X=OH, Y=NH 2 :

R=Me,CH 2 NHCOCF 3

(CH 2 )3or10NHCOCF 3

X = H, tubercidin

X = CN, toyocamycin

X=CONH 2 ,sangivamycin

cadeguomycin

Figure 3.30 Syntheses of 7-substituted 7-deaza-2-deoxyadenosine and 7-deaza-2-deoxyguanosine nucleosides
(upper). Reagents: (i) terminal alkyne, Pd(PPh 3 ) 4 , CuI, Et 3 N, DMF. Some naturally occuring antibiotic
nucleosides (lower)

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