1 - cytosine mechanism

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Flucytosine-resistant strains can develop very rapidly. These mutants may have a disturbed 5-FC-metabohsm, or a compensatory mechanism for the disturbed nucleic acid functions. No cytosine permease was found in a resistant Cyptococcus neoformans strain, whereas cytosine deaminase was absent in resistant C. albicans strains. A deficiency of uridine monophosphate pyrophosphorylase occurs frequently in resistant C. albicans strains (1). 

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). 

The proton transfer in these clusters via the water bridge was found to be about three times as fast as a nonassisted transfer, underscoring the importance of the solvent for the reaction mechanism [98IJQ855]. In addition to the relative stabilities of the cytosine tautomers, the structures and properties of some cytosine derivatives have been investigated, mainly those of 5-hydroxycytosine 111 and 5,6-dihydroxycytosine 112 (Scheme 73) [99JST1, 99JST49]. 

The reaction mechanism of the DNA (cytosine-5)-methyltransferase-catalyzed cytosine methylation was investigated at the MP2 and DFT levels [98JA12895]. This system has been modeled by 1-methylcytosine 117, methylthiolate, and trimethylsulfonium. The cytosine methylation is initiated by an attack of the anionic methylthiolate at Cg of the cytosine ring (Scheme 77). The formation of the methylthiolate adduct 118 of the neutral 117 was found to be endothermic in the gas phase and in solution. However, the MP2 and DFT results differ... 

Cytosine was the first nucleobase whose radiationless decay was studied with quantum mechanical methods. Nevertheless, its first excited states are not so clearly separated as in uracil and thymine, and this causes complications in the computational studies of the photophysics. So, many computational studies have been reported to elucidate the mechanisms for radiationless decay to the ground state but, not always with the same conclusions. 

Kistler KA, Matsika S (2007) Radiationless decay mechanism of cytosine an ab initio study with comparisons to die fluorescent analogue 5-methyl-2-pyrimidinone. J Phys Chem A 111 2650—2661... 

Takatori S, et al. Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues, l-(3-C-ethynyl-P-D-ribo-pentofuranosyl) cytosine and 1-(3-C-ethynyl-P-D-ribo-pentofuranosyl)uracil. Cancer Chemother Pharmacol 1999 44 97. 

Cytosine can become deaminated spontaneously or by reaction with nitrous acid to form uracil. This leaves an improper base pair (G-U), which is eliminated by a base excision repair mechanism (Figure 1-2-5). Failure to repair the improper base pair can convert a normal G-C pair to an A-T pair. 

This quinone reacts in aqueous solution with OH and H adducts of cytosines and uracils by an electron transfer/addition mechanism, similar to Eq. 18 [28], Addition takes place at the quinone carbonyl oxygen to produce an anthroxyl radical. This then undergoes spontaneous C-O heterolysis ... 

---