Cytosine synthesis

Shapiro, R. 1999. Prebiotic cytosine synthesis A critical analysis. Implications for die origin of life. Proc. Natl. Acad. Sci. U.S.A. 96 4396-4401. 

The exocychc nitrogens on cytosine and the purine bases must be protected during the synthesis. The search is ongoing for protecting groups that are subject to fewer side reactions and that can be removed more easily in the final deprotection step (34). 

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

Cytarabine, 4-amino-l-/3-D-arabinofuranosylpyrimidin-2(lif)-one or cytosine arabino-side (1033 R = H, X = NH2), is an established drug for the treatment of acute leukaemias of childhood and adult granulocytic leukaemia. It must be given intravenously and much of the drug becomes the corresponding inactive uracil derivative in vivo by virtue of a deaminase in the liver it interferes with DNA but not RNA synthesis, and it has incidental... 

The steps involved in automated oligonucleotide synthesis illustrate the current use of protective groups in phosphate chemistry (Scheme 1). Oligonucleotide synthesis involves the protection and deprotection of the 5 -OH, the amino groups on adenine, guanine, and cytosine, and -OH groups on phosphorus. 

Because synthesis of l-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)cytosine (744, FAC), an elementary arabino type of nucleoside having a growth-inhibitory effect against L 1210 leukemia in mice, through direct introduction of a fluorine atom in the 2 - up (arabino) position was difficult, compound 744 was prepared by condensation of trimethylsilylated A -acetylcytosine with 3-0-acetyl-5-(7-benzoyl-2-deoxy-2-fluoro-D-arabin-ofuranosyl bromide (742), which had been prepared by periodate oxidation of 6-0-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (741). Similar condensa-... 

Many yeasts are inhibited by 5-fluorocytosine and a block in the synthesis of 5-fluorouridylic acid by loss of cytosine deaminase or of nracil phosphoribosyltransferase is sufficient to cause resistance. Mntational loss of pyrimidine salvage enzymes has been frequently observed. 

Many years later, Schwartz (Schwartz and Goverde, 1982 Voet and Schwartz, 1983) discovered that the synthesis of adenine via polymerisation of HCN can be accelerated by adding formaldehyde and other aldehydes. Reactions in the gas phase (nitrogen/methane atmosphere) promoted by electrical discharges led to the formation of cyanoacetylene in relatively good yields the latter reacts with urea to give various products, including cytosine (Sanchez et al., 1968). 

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... 

The same problem, the stability of the nucleobases, was taken up by Levi and Miller (1998). They wanted to show that a synthesis of these compounds at high temperatures is unrealistic, and thus they took a critical look at the high temperature biogenesis theories, such as the formation of biomolecules at hydrothermal vents (see Sect. 7.2). The half-life of adenine and guanine at 373 K is about a year, that of uracil about 12 years and of the labile cytosine only 19 days. Such temperatures could have easily been reached when planetoids impacted the primeval ocean. 

Shapiro published a critical analysis of the availability of the nucleobase cytosine on the primeval Earth in the highly-regarded Proceedings of the National Academy of Science (Shapiro, 1999). Some biogeneticists still believe that all the substances necessary for the synthesis of a nucleic acid were available in the much-cited (but hypothetical) primeval soup . Shapiro directs these optimists to the following problems ... 

Reports of the synthesis of cytosine from cyanoacetylene (or its hydrolysis product cyanoacetaldehyde) with cyanate, cyanogens or urea show that these substances react faster with nucleophilic compounds to give side products than to give the required main product. In addition, the formation of cytosine requires concentrations which are unrealistic in prebiotic environments. 

The dilemma described above, that cytosine-rich matrices lead to (complementary) sequences which are low in cytosine and are themselves ineffective matrices, makes the synthesis of nucleic acids in the absence of enzymes almost impossible. Thus, other models and model experiments must be looked for. 

Fig. 6.13 Reaction routes for the synthesis of other components of PNA, such as cytosine- and uracilacetic acid (see Fig. 6.12) from hydantoic acid and cyanoacetaldehyde (Nelson et al., 2000b)...

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