Angewandte
Chemie
c) E. Ferrer, M. Wiersma, B. Kazimierczak, C. W. Müller, R.
work on the etiology of nucleic acid structure can be
interpreted to indicate that it may have been mainly the
structure of the recognition elements and not so much the
structure of the oligomer backbone that had been critical in
natureꢀs choice of the molecular basis of a genetic system.
Although a variety of backbone alternatives of generational
complexity and base-pairing capability similar to that of RNA
would have been available for natureꢀs choice, there seems to
be a distinct scarcity of potential natural alternatives to the
two pairs of Watson–Crick nucleobases. Our observations
indicate that 2,4-disubstituted 1,3,5-triazines and 2,4-disub-
stituted-5-aminopyrimidines, two families of heterocycles
deemed to be of generational simplicity comparable with
that of the canonical nucleobases, yet offering chemically
wider opportunities for backbone tagging, are clearly func-
tionally inferior to the family of Watson–Crick bases by
reasons that seem intrinsically chemical in nature. The
findings provide a chemical illustration of the view that the
canonical nucleobases represent a functional optimum with
respect to informational base pairing in aqueous solution. Our
observations, however, should not be interpreted as excluding
the possibility that functionally less-than-optimal recognition
elements, such as the 5-aminopyrimidines, may have played a
role in the self-organization of organic matter.
Eritja, Bioconjugate Chem. 1997, 8, 757; d) V. S. Rana, K. N.
Ganesh, Nucleic Acids Res. 2000, 28, 1162; e) M. J. Storek, A.
Suciu, G. L. Verdine, Org. Lett. 2002, 4, 3867.
[8] For an early constitutional analysis of alternative nucleobase
pairs, see: a) J. A. Piccirilli, T. Krauch, S. E. Moroney, S. E.
Benner, Nature 1990, 343, 33; b) S. A. Benner, Acc. Chem. Res.
2004, 37, 784.
[9] a) T. Otzen, E. G. Wempe, B. Kunz, R. Bartels, G. L. -Yvetot, W.
Hänsel, K.-J. Schaper, J. K. Seydel, J. Med. Chem. 2004, 47, 240;
b) C. Bamford, K. Al-Lamee, J. Chem. Soc. Chem. Commun.
1993, 1580; c) D. J. Brown, K. Mori, Aust. J. Chem. 1985, 38, 467.
An amino group in position 5 of a pyrimidine is, together with
the NH group in position 1, part of a vinylogous hydrazine
system, whereas amino groups at position 2 or 4 are part of a
guanidine or an amidine system, respectively.
[10] a) P. Wipf, A. Cunningham, R. L. Rice, J. S. Lazo, Bioorg. Med.
Chem. 1997, 5, 165. b) The procedure used in the preparation for
the d enantiomer was used: K. L. Webster, A. B. Maude, M. E.
OꢀDonnell, A. P. Mehorotra, D. Gani, J. Chem. Soc. Perkin
Trans. 1 2001, 1673.
[11] S. Nakabayashi, C. D. Warren, R. W. Jeanloz, Carbohydr. Res.
1988, 174, 279.
[12] All compounds were characterized by 1H and 13C NMR and
mass spectral data following purification by column chromatog-
raphy on silica gel. Oligodipeptides were synthesized on an
Expedite 8909 Nucleic Acid Synthesizer (Perseptive Biosys-
tems) by using a modified PNA protocol, purified by HPLC (ion
exchange) to a minimal purity of 95%, and checked by MALDI-
TOF-MS (see the Supporting Information). RNA and DNA
oligonucleotides were purchased from commercial sources;
TNA sequences were available from our previous work.[13]
[13] K.-U. Schoening, P. Scholtz, X. Wu, S. Guntha, G. Delgado, R.
Krishnamurthy, A. Eschenmoser, Helv. Chim. Acta 2003, 86,
1259.
Received: August 7, 2006
Published online: November 17, 2006
Keywords: 5-aminopyrimidines · base pairing · DNA ·
.
nucleic acid hybridization · oligonucleotides
[14] The similarity between the UV spectra of cytosine (lmax
=
267 nm, e = 6100)[15a] and 1-methyl-cytosine (lmax = 273 nm, e =
8100)[15a] or 1-ribofuranosylcytosine (lmax = 270 nm, e = 8800)[15b]
closely corresponds to the similarity between the UV spectra of
the 5-aminocytosine (lmax = 292 nm, e = 3800)[15c] and of its 1-
ribofuranosyl derivative (lmax = 298 nm, e = 6200)[15b] in buffer
solution pH 7. This indicates that the 5-aminocytosine nucleus
prefers the position 1 NH tautomer in aqueous solution. In the 5-
aminoisocytosine series we observe UV spectra of quite differ-
ent structure for the free base 2 (lmax = 287 nm, e = 4100; 240 nm
(shoulder), e = 6400; e220nm = 10,500) and its N3 methyl deriva-
tive (lmax = 308 and 242 nm, e = 7300 and 6800; e220nm = 3500;
both spectra in aqueous phosphate buffer solution, pH 7). The
absorption maxima of the UV spectrum of the 5-formyl amino
derivative of 3-methyl-isocytosine (for its preparation and for
the X-ray structure analysis of the corresponding N,N-dimethyl-
formamidine derivative, see the Supporting Information) are
hypsochromically shifted (lmax = 295 and 235 nm, e = 8800 and
7000; e220nm = 5200) relative to the maxima of the 3-methyl-
isocytosine derivative. The spectrum is, however, of the same
type as for the free N-3-methylated base. These findings point to
the conclusion that 5-aminoisocytosine disfavors its NH(3)-
tautomer in aqueous solution. The conclusion remains tentative
as the necessary UV comparison with the 1-methylisocytosine
derivative is lacking.
[1] G. K. Mittapalli, K. R. Reddy, H. Xiong, O. Munoz, B. Han, F.
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[5] For alternative (potentially prebiotic) formation of canonical
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Lundmark, F. Rise, S. Sundell, Tetrahedron 1995, 51, 3655; b) A.
Holy, Collect. Czech. Chem. Commun. 1979, 44, 2846; c) C. O.
Johns, Am. Chem. J. 1911, 45, 79. For 5-aminoisocytosine, see:
d) T. B. Johnson, C. O. Johns, Am. Chem. J. 1905, 34, 554; e) J. L.
Kelly, E. W. Mclean, J. Heterocycl. Chem. 1981, 18, 671. For
2,4,5-triaminopyrimidine, see f) D. J. Brown, J. Appl. Chem.
1957, 7, 109. 5-Aminouracil is commercially available.
[15] a) A. R. Katritzky, A. J. Warring, J. Chem. Soc. 1963, 3046; b) J.
Fox, D. V. Praag, J. Org. Chem. 1961, 26, 526; c) S. F. Mason, J.
Chem. Soc. 1954, 2071.
[16] See, for example, R. Krishnamurthy, S. Pitsch, M. Minton, C.
Miculka, N. Windhab, A. Eschenmoser,Angew. Chem. 1996, 108,
1619; Angew. Chem. Int. Ed. Engl. 1996, 35, 1537.
[7] a) J.-W. Chern, D. S. Wise, W. Butler, L. B. Townsend, J. Org.
Chem. 1988, 53, 5622; b) M. A. Sofan, A. E.-S. Abdel-Megied,
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Angew. Chem. Int. Ed. 2007, 46, 2478 –2484
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