Nucleic Acids in Chemistry and Biology

7-methyl-2
-deoxyguanosine residue, treatment of the oligonucleotide with 1M piperidine at 90°C for
30min leads to opening of the imidazole ring followed by glycosylic bond cleavage and -elimination of
the phosphate residue. -Elimination of both phosphates leads to strand cleavage on bothsides of the
dG residue.^10

8.5.4 Metallation Reactions

Mercury(II) acetateand chloride readily substitute C-5 of uridine and cytidine nucleosides and nucleotides.
The products are easily converted into organo-palladiumspecies that are useful intermediates in the synthesis
of a range of 5-substituted pyrimidine nucleosides^26 and nucleotides (Section 3.1.4).^27 These include C-5 allyl-,
vinyl-, halovinyl- and ethynyl-uridines, all of which have been much studied for possible antiviral activity.
One of the most important recent applications of such chemistry is for the synthesis of fluorescent
chain-terminating dideoxynucleotides, used in a rapid DNA sequencing (Figure 8.11).^28 5-Iodo-2
,3
-
dideoxyuridine is coupled to N-trifluoroacetylpropargylamine using palladium(0) catalysis and the
resulting amine is then condensed with a protected succinylfluorescein dye. Deprotection provides the
dideoxythymidine terminator species T-526 (which has a fluorescent emission maximum at 526 nm).
Related fluorescent derivatives of dideoxycytidine, C-519, dideoxyadenosine, A-512 and dideoxyguano-
sine, G-505, (the latter are derived by related Heck coupling reactions from 7-deazapurines) provide a
complete family of chain-terminators (Figure 8.11). Such modified nucleotides are incorporated with effi-
ciencies comparable to those of unsubstituted ddNTPs and can be used for rapid, single-lane DNA
sequencing(Section 5.1).
Barnett Rosenberg’s discovery of the cytotoxicity ofcis-diaminedichloroplatinum(II)has been care-
fully developed to make cisplatin, the reagent of choice for the successful chemotherapy of testicular can-
cer(and some other cancers), being given FDA approval in 1978. Cisplatin bonds to N-7 in one guanine
residue and then links it to N-7 of a second purine. It is selective for d(pGpG) and d(pApG) sequences,
but not for d(pGpA) sites and forms predominantly 1,2-intra-strand cross-links. Cisplatin can also bind to
two guanines separated by another base, as in d(pGpNpGpG). Stephen Lippard solved X-ray structures
for a model complex of cisplatin with d(pGpG) in which the platinum iscis-linked to N-7 of both guanines
and these bases lie in planes almost at right angles.^29

302 Chapter 8

N

N N

N

pentose

N

ethenoadenosine

N

N

N

pentose

O

ethenocytidine

N

N

N

N

DNA

N H

H

O

H N

N

O DNA

Me

N

N

N

N

DNA

O H N

H N

N

N H O DNA

H

H

A T G C

O

P

O

O

O

DNA

DNA

17%

0.1%

0.4% 6%

0.1%

SN 1

♠

♠

♠

20%

ss

10%

ss

♠

2%

10%

SN 2

70%♠

1%

Most agents Methyl radicals

a

b

Figure 8.10 (a) Alkylation of adenosine and cytidine with chloroacetaldehyde to give fluorescent etheno-derivatives.
(b) Sites for the methylation of the DNA bases and sugar-phosphate backbone^24

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