Isocytosines

The direct formation of dipyrimidin-5-yl sulfides occurs on treatment of appropriate 5-unsubstituted pyrimidine substrates with sulfur mono- or di-chloride. Thus, reaction of uracil (83 R = H) with sulfur monochloride in boiling formic acid gives diuracil-5-yl sulfide in good yield sulfur dichloride gives a poor yield. Simple derivatives of uracil and barbituric acid undergo similar reactions but not cytosine, isocytosine, 2,4-bismethylthiopyrimidine or pyrimidine-4,6-dione (59). The mechanism is unknown (72AJC2275). 

Owing to the increasing efficiency of computational methods, it has become possible to investigate base pairs in the gas phase and solution simulated by super-molecular approaches with up to six water molecules [98IJQ37, 98JPC(A) 10374, 98JPC(B)9109, 99JST107]. In the cytosine-isocytosine Watson-Crick base pair. 

In tautomeric equilibria of some functionalized pyrimidine derivatives, such as isocytosine 52 (R = H) [77ZN(C)894] or pseudocytidine 52 (R = furanosyl) (99MI1), the potentially tautomeric oxo and amino groups are practically not involved, and only annular tautomeric interconversions N(1)H N(3)H are ob-... 

A large variety of nucleobases have also been used and developed in a PNA backbone context (Tab. A4). Several of these are routinely used in PNA applications. The pseudo isocytosine (Nl) is employed in the Hoogsteen strand of tri-... 

Kwiatkowski, J. S., Leszczynski, J., 1997, Density Functional Theory Study on Molecular Structure and Vibrational IR Spectra of Isocytosine , Int. J. Quant. Chem., 61, 453. 

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... 

Cyclizations of 6-(l-alkylhydrazino)isocytosine 260 with the appropriate a-haloketones or ethyl bromopyruvate under acidic conditions gave (80JOC3919) exclusively the 6-amino-l,4-dihydro-8H-pyrimido[6,l-c]-[l, 2,4]triazin-8-ones 261. 

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... 

Complete clustering, or segregation, of tautomers may occur during crystal growth. This can lead, for example, to crystals that consist of two tautomers in equal proportions and located at crystallographically independent sites. This is the case for isocytosine, 47 (104). Similarly, in crystalline anthranilic acid the neutral molecule and the zwitterion coexist (10S). Another example, 39, has been mentioned already (82). 

In isocytosine and anthranilic acid it seems that any given molecule is always of the same tautomeric form in the crystal that is, the proton is not moving from site to site in the hydrogen bond. In general, however, the question of whether the proton is localized or not was difficult to answer until the advent of solid-state NMR Thus, for example, there has been much controversy as regards imidazole, 48. On the one hand there were the proponents of delocalization on this basis Zimmerman introduced his controversial theory of proto-merism (106). Others argued for localization. Recently evidence from high-resolution l3C NMR of the solid has provided evidence in support of the latter (107). A similar situation exists for pyrazole, 49 (107). 

Figure 6 15 Important hydrogen-bonding positions for (A) cytosine and (B) isocytosine in hammerhead ribozymes.

Other interesting examples of intermolecular N-C-N transfragment replacement are the ones being found when 1,3-dimethyluracil (113, R = R" = H) and several of its C-5/C-6 mono-substituted or C-5,6 di-substituted derivatives react with different 1,3-ambident nucleophiles (77JHC537 84H(2)89). Reaction of (113, R = R" = H) with guanidine gives isocytosine 115 (R = R = H) in reasonable-to-good yields. 

Variation of the ring portion of acyclovir has been achieved. Compounds include monocyclic (isocytosine, triazole, imidazole), bicyclic (adenine, 8-azapurine, pyrrolo[2,3-c/]-pyrimidine, pyrazolo[3,4-[Pg.131]

Similar problems were not observed with isocytosine derivatives 366, and isocytosine 5-boronic acids 367 were successfully obtained <1998J(P2)841>. 

An interesting feature was discovered by Sharma and co-workers494,495 in the crystal structure of isocytosine. Two tautomers of isocytosine (42 and 43) exist in an exact 1 1 ratio in the crystal. The tautomers are hydrogen-bonded to each other in a manner analogous to that proposed by Watson and Crick496,497 for the guanine-cytosine pair in DNA. It is worth underlining that the base pair of isocytosine was not obtained by expedient cocrystallization of the two components. It seems therefore probable that both forms 42 and 43 of isocytosine are of approximately equal stability and are present in comparable amounts in solution. 

Figures 18 and 19 collect the averaged geometrical parameters for thiouracils and thiocytosine. The geometrical structures of the two isocytosine tautomers can be found in the paper by Sharma and...

The X-ray crystallographic studies show that thiouracils and 2-thiocytosine exists in the crystalline state in forms 51 and 52, respectively, and that isocytosine exists as a mixture of two amine-lactam forms, 42 and 43. Several experimental studies on these pyrimidines in solution confirm the conclusions from the crystal. However, studies on the tautomerism of the minor pyrimidine bases are few. In a number of cases the conclusions about the dominant structures are intuitive rather than proved. We present the essential experimental data on the structure of the minor pyrimidine bases. 

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