Isocytosine, synthesis

Until the 1980s, yields of nucleobases obtained in prebiotic syntheses were very small. Thus, some scientists assumed that in earlier phases of molecular evolution, the nucleic acids used other bases in their information-transmitting substances. Piccirilli et al. (1990) suggested isocytosine and diaminopyridine, while Wachtershauser (1988) suggested that the first genetic material possibly consisted only of purines. However, pyrimidine (about a fifth of the total amount of purines present) had been detected in the Murchison meteorite, so that an effective pyrimidine synthesis should have been possible. 

Roberts et al. (1966) described a similar synthesis cyanoacetaldehyde and guanidine hydrochloride gave 40-80% yields of 2,4-diaminopyrimidine under the conditions of the lagoon model mentioned above. Hydrolysis of diaminopyrimi-dine leads to cytosine, isocytosine and uracil. Thiourea reacts with cyanoacetylene to give 2-thiocytosine however, the yield is considerably lower than with urea or... 

David and Lubineau191 reported the synthesis of pseudocytidine [5-/3-D-ribofuranosylcytosine (270)] and its a anomer by a procedure analogous to that used in preparing pseudouridine.155-157 Thus, 2,4 3,5-di-O-benzylidene-a/de/iydo-D-ribose (223) was condensed with the dilithio derivative of 2-0,4-N-(trimethylsilyl)cytosine, and the resulting, epimeric, acyclic derivatives were subjected to acid-catalyzed cyclization. The anomeric configuration of the free C-nucleosides was ascertained by spectroscopic methods and by their transformation into a- and /3-pseudouridine in the presence of nitrous acid. The anomeric 5-(/3-D-ribofuranosyl)isocytosines have also been prepared by Fox and coworkers.1913... 

Schuchmann MN, Naumov S, Schuchmann H-P, von Sonntag J, von Sonntag C (2005) 4-Amino-3Ff-pyrimidin-2-one ("isocytosine") is a short-lived non-radical intermediate formed in the pulse radiolysis of cytosine in aqueous solution. Radiat Phys Chem 72 243-250 Schulte-Frohlinde D, Hildenbrand K (1989) Electron spin resonance studies of the reactions of OH and SO4 radicals with DNA, polynucleotides and single base model compounds. In Minisci F (ed) Free radicals in synthesis and biology. Kluwer, Dordrecht, pp 335-359 Schulte-Frohlinde D, Behrens G, Onal A (1986) Lifetime of peroxyl radicals of poly(U), poly(A) and single- and double-stranded DNA and the rate of their reaction with thiols. Int J Radiat Biol 50 103-110... 

About 2 years later, a Stanford Research Institute group described the synthesis of the first true pyrimidine analogue of FA (303) which incorporated all of the structural features of FA except the pyrazine ring (see Scheme 3.55) [159], They envisioned that (303) could be assembled from appropriately protected derivatives of isocytosine, glyoxal and p-aminobenzoyl L-glutamic... 

Further studies on hydrophobicity were carried out by adding hydrophobic substituents to the isocytosine analogue (Fig. 13.45). These studies showed that there was an optimum hydrophobicity for activity corresponding to the equivalent of a butyl or pentyl substituent. A benzyl substituent was particularly good for activity, but proved to have toxic side-effects. These side-effects could be reduced by adding alkoxy substituents to the aromatic ring and this led to the synthesis of oxmetidine (Fig. 13.48) which had enhanced activity over cimetidine. Oxmetidine was considered for clinical use, but was eventually withdrawn since it still retained undesirable side-effects. 

A new facile reaction for the synthesis of S,6,7,8-S-deaza-5-thiapterins (30) is afforded by the reaction of S-bromo-6-chloro-isocytosine with cysteamines via the aliphatic S-N Smiles rearrangement in ethanolic pH7 buffer solution [94CPB806]. 

Liu LJ, Hong JH (2010) Design and synthesis of novel sate derivatives of acyclic isocytosine and 9-deazaadenine C-nucleosides. Nucleosides Nucleotides Nucleic Acids 29 257-266... 

The discovery that arabino-cytxddae shows antileukaemic activity has prompted the synthesis of 5-(j8-D-arabinofuranosyl)-isocytosine (71) and some related C-nucleosides. The ara mo-nucleoside was synthesized from the corresponding antileukaemic 5-(j3-D-ribofuranosyl)-isocytosine by epimeriza-tion at C-2 via a 2, 4-anhydro-arabinosyl nucleoside intermediate. The a-anomer of (71) was also obtained. None of the new products showed any antileukaemic activity. ... 

Synthesis of mono UPy s from isocytosine and an isocyanate is also unproblematic, and if the interest in UPy s would be restricted to monofunctional derivatives, there would probably be no need for improved synthetic procedures. However, for the preparation of bis-UPy s for linear supramolecu-lar polymers, and for multifunctional UPy derivatives, the addition reaction is not trivial anymore, because molecules with multiple isocyanate groups suffer from hydrolytic instability leading to higher molecular weight species, and therefore are most favorably prepared in situ [13]. 

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