2.13 – Pyrimidines and their Benzo Derivatives

The occurrence of DNA fragmentation in lymphocytes obtained from alloxan-induced diabetic rats and diabetic patients was investigated. A high proportion of apoptotic lymphocytes in diabetic states may explain the impaired immune function in poorly controlled diabetic patients. Rat mesenteric lymph node lymphocytes were analysed for DNA fragmentation by using flow cytometry and agarose gel, and for chromatin condensation by Hoescht 33342 staining under different situations. Immediately after being obtained, the proportion of lymphocytes with fragmented DNA was twofold higher in alloxan-induced diabetic rats than in cells from control rats. After 48 h in culture, the occurrence of DNA fragmentation was also higher (81%) in cells from diabetic rats. Hoescht staining and fragmented DNA visualized in agarose gel were also higher in lymphocytes from alloxan-induced diabetic rats than in control cells. To investigate if this phenomenon also occurs in humans, blood lymphocytes from 14 diabetic subjects were examined. Similar results to those of rat lymphocytes were found in cells from diabetic patients immediately after being obtained and after 48 h in culture. The high occurrence of apoptosis in lymphocytes was accompanied by a reduced number of blood-circulating lymphocytes in diabetic patients. The involvement of low insulinaemia for the occurrence of apoptosis in lymphocytes was also examined. Insulin treatment markedly reduced the proportion of lymphocytes with fragmented DNA in alloxan-induced diabetic rats.

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Diabetes induces apoptosis in lymphocytes.

Interest in pyrimidine nucleotide biosynthesis has stemmed largely from the importance of these molecules as components of nucleic acids. Regulation of pyrimidine biosynthesis has been most extensively investigated in micro-organisms in which cell division is effectively controlled by regulation of the activity of the enzymes of the d e n o v o pathway (77, 11 0). The relation between pyrimidine biosynthesis and cellular proliferation in mammals has become clearer with the accumulation of a considerable body of evidence which indicates that there is a close correlation between the activity of enzymes involved in pyrimidine biosynthesis and the rate of cellular proliferation. The d e n o v o pyrimidine biosynthetic pathway and the urea cycle bo th utilize carbamyl phosphate, and important nitrogen carrier. The biosynthesis of pyrimidine and purine nucleotides are connected by a common intermediate, phosphoribosyl pyrophosphate (PRPP). In addition, pyrimidine nucleotides act as sugar and phospholipid carriers and are important in lipopolysaccharide biosynthesis. The importance of these interrelations is most forcibly emphasized by certain clinical phenomena which will be discussed later. This paper will attempt t o review the broad biologic aspects of pyrimidine nucleotide biosynthesis. A detailed consideration of d e n o v o pyrimidine biosynthesis in eucaryotic cells is available in the recent review by Jones (81). Pyrimidine biosynthesis in procaryotes has been reviewed in depth by O'Donovan and Neuhard (1 10).

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A review: biological and clinical aspects of pyrimidine metabolism.

Synthesis and antimicrobial activity of 6,7-annulated pyrido[2,3-d]pyrimidines.

Suitably functionalised pyrimidines as potential antimycotic agents.

Publisher Summary The beginning of pyrimidine chemistry may be traced back to the isolation of alloxan, a pyrimidine derivative. The synthesis of barbituric acid from urea and malonic acid perhaps marked the next major event in the development. Since then pyrimidines have occupied a unique and important place in the fields of biological and medicinal chemistry. It is well known that uracil, thymine, and cytosine are essential constituents in nucleic acids; thiamine that possesses antiberiberi activity was the first vitamin discovered in the B series; barbiturates are widely used as sedatives; pyrimethamine is highly potent against erythrocytic parasites in antimalarial study; aminometradine (Mictine) is an orally effective diuretic; and the 5-halogen-substituted uracils and derivatives have recently been reported as antitumour or antiviral agents, or both. Other pyrimidine derivatives have been found to possess fungicidal, antibacterial, antimitotic, antithyroid and surface-anaesthesia activities. With the exception of pyrimidine antibiotics, in this chapter, pyrimidines are classified based on special structural features and functional groups. The chapter discusses the following areas: 2,4- diaminopyrimidines, halogenated pyrimidines, sulphur-substituted pyrimidines, 2-substituted 4-amino-5-hydroxymethylpyrimidines, pyrimidine sulphonamides and pyrimidine antibiotics.

Cheng Cc

Papers

Some pyrimidines of biological and medicinal interest. 3.