Nucleic Acid Biosynthesis Inhibition

Nucleic acid metabolism is a feature that is common to all living things and few steps in the process in fungi are sufficiently different from those in other organisms to be used as an effective target for selective fungicides. Consequently, few compounds have been discovered that are not limited by their lack of specificity. In those fungicides known to inhibit nucleic acid biosynthesis the basis for the observed specificity is not understood. 

Several compounds may interfere with nucleic acid metabolism but commonly their effects are secondary to their primary mode of action, for example, the benzimidazoles. Compounds that inhibit nucleic acid biosynthesis directly are either phenylamides, pyrimidines or hydroxy-pyrimidines. Recently, the phenoxyquinolines were identified as exhibiting a novel mode of action in purine biosynthesis and are potentially useful fungicides. 

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The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

FIGURE 36-3 Sites of anticancer antimetabolite action. Various drugs interfere with DNA/RNA production by inhibiting nucleic acid biosynthesis at specific sites indicated by the dashed lines. 

Fluorouracil interferes with nucleic acid biosynthesis, thus inhibiting subsequent DNA synthesis and RNA synthesis.2... 

Dimayuga et al. (1991) reported activity of camosol against B. subtilis and Candida albicans, and supported results on S. aureus and E. coli. The authors used 4 mg per disc. Significant activity was also found for camosic acid and its 12-O-methyl ester to inhibit S. aureus. The inhibitive action is due to the inhibition of the nucleic acid biosynthesis pathway, as camosic acid prevents the incorporation of thymidine and uridine into the DNA and RNA of S. aureus (Wagner, 1993). 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

The antineoplastic activity of naphthomycin A (56) and its mode of action were reported. The antibiotic caused neither metaphase arrest nor prevented tubulin polymerization, and it was suggested that the mechanism of cytotoxicity of 56 was the inhibition of various SH enzymes, particularly those involved in nucleic acid biosynthesis [228,229]. 

Methotrexate, a folate antagonist, interferes vAth nucleic acid biosynthesis. Would you expect it to inhibit purine or pyrimidine biosynthesis or both processes Explain. 

Gray, G.D., Camiener, G.W., Bhuyan, B.K. 1966. Nogalamycin effects in rat liver inhibition of tryptophan pyrrolase induction and nucleic acid biosynthesis. Cancer Res. 26(12) 2419-2424. 

Telomerase is a multicomponent highly specialized enzyme responsible for the synthesis of telomeres. Its catalytic subunit (TERT, telomerase reverse transcriptase) utilizes the RNA component of the enzyme (TR) as a template to synthesizes telomeric DNA repeats. A number of strategies for telomerase inhibition by low-moleeular dmgs have been proposed. They include the application of nucleoside and non-nucleoside reverse transcriptase inhibitors, antisense oligonucleotides and their analogues against TR RNA, ribozymes and siRNA directed against TR and TERT components of the enzyme, etc. [5-9]. These approaches are rather traditional for the inhibition of enzymes of nucleic acids biosynthesis. Totally different approach is based on the presence of unique stmctural motifs in telomeric DNA called G-quadmplexes (G4). 

Camptothecin is currently one of the most important compounds in cancer research due to its activity against leukaemias and other cancers resistant to vincristine. Camptothecin inhibits nucleic acid biosynthesis and topoisomerase I, which is necessary for the relaxation of DNA during vital cellular processes. However, camptothecin is relatively unstable under physiological conditions prompting the preparation of more stable derivatives. Camptothecin also inhibits the replication of DNA viruses by disrupting the normal function of DNA in cellular ontogenesis. Side effects of camptothecin include haematopoietic depression, diarrhoea, alopecia, haematuria, and other urinary tract irritations. 

The Li+-induced inhibition of the production of the HSV virus may be related to its actions upon viral DNA polymerase production and activity. Li+ reduces both the synthesis of DNA polymerase in tissue culture and the activity of DNA polymerase in vitro, each by about 50%. It has been proposed that Li+ reduces the biosynthesis of viral polypeptides and nucleic acids, and hence inhibits viral DNA replication by competition with Mg2+, a cofactor of many enzymes [243]. However, the inhibitory effect of Li+ on HSV replication in tissue culture is not affected by Mg2+ levels. A more likely hypothesis is the alteration of the intracellular K+ levels, possibly modifying levels of the high-energy phosphate compounds by replacement of either Na+ or K+ in Na+/K+-ATPase [244]. In tissue culture, HSV replication has been shown to be affected by the... 

A wide variety of other biochemical effects has been reported to be associated with treatment of cells with vinblastine, vincristine, and related compounds (S). These effects include inhibition of the biosynthesis of proteins and nucleic acids and of aspects of lipid metabolism it is not clear whether such effects contribute to the therapeutic or toxic actions of vincristine and vinblastine. Vinblastine and vincristine inhibit protein kinase C, an enzyme system that modulates cell growth and differentiation (9). The pharmacological significance of such inhibition has not been established, however, and it must be emphasized that the concentrations of the drugs required to inhibit protein kinase C are several orders of magnitude higher than those required to alter tubulin polymerization phenomena (10). 

The significance of these in vitro enzyme inhibition studies is uncertain, in view of the evidence that has been presented concerning the sensitivity of cancer cells to feedback inhibition by these nucleotides. On the other hand, 6-chloropurine inhibits the de novo biosynthesis of nucleic acid guanine but not of nucleic acid adenine in sarcoma 180 ascites cells [319],... 

The pyrimidine antagonists inhibit the biosynthesis of pyrimidine nucleotides or interfere with vital cellular functions, such as the synthesis or function of nucleic acids. The analogues of deoxycytidine and thymidine that are used are inhibitors of DNA synthesis while 5-fluorouracil (5-FU) an analogue of uracil, is an inhibitor of both RNA function and of the synthesis of thymidylate (see Fig. 2). PALA (N-phosphonoacetyl-L-aspartate), an inhibitor of as-... 

Trimethoprim (Proloprim, Trimpex) interferes with the bacterial folic acid pathway by inhibiting the dihydrofolate reductase enzyme in susceptible bacteria (see Fig. 33-2). This enzyme converts dihydrofolic acid to tetrahydrofolic acid during the biosynthesis of folic acid cofactors. By inhibiting this enzyme, trimethoprim directly interferes with the production of folic acid cofactors, and subsequent production of vital bacterial nucleic acids is impaired. 

Chemotherapeutic agents, useful in me treatment of neoplastic diseases, exert their therapeutic effects by modifying me synthesis or functions of nucleic acids (see Chapter 51 and Chapter 58). For example, 6-mercaptopurine inhibits purine-ring biosynthesis, cytarabine inhibits DNA polymerase, alkylating agents crosslink DNA, and hydroxyurea inhibits the conversion of ribonucleotides into deoxyribonucleotides. However, other pharmacologic agents such as chlorpromazine, a... 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU)... 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) must first be converted to nucleotide derivatives such as 5-fluorodeoxyuridylate (5-FdUMP). Similarly, floxuridine (FUdR) is also converted to FdUMP by the following reactions ... 

Ribosomal protein biosynthesis is often inhibited by alkaloids that interact with nucleic acids [23]. There are also more specific inhibitors, such as emetine. 

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