Nucleic acid synthesis, inhibition

After metabolic activation, it depoly-merizes DNA and causes chromosomal damage and also nucleic acid synthesis inhibition. It is found to be effective in Hodgkin s disease and carcinoma of lungs. 

It has been found that viruses (Appendix 10) utilize a number of virus specific enzymes during replication. These enzymes and the processes they control are significantly different from those of the host cell to make a useful target for medicinal chemists. Consequently, antiviral drugs usually act by either inhibiting viral nucleic acid synthesis, inhibit attachment to and penetration of the host cell or inhibit viral protein synthesis. 

An understanding of the biochemistry of peptidoglycan (PG murein) that comprises bacterial cell walls is very important medically since blockage of its synthesis was the first, and continues to be a primary, point of attack in the control of bacterial infection. In addition to inhibition of cell wall synthesis, antimicrobial drug s main mechanisms are interference with nucleic acid synthesis, inhibition of folate metabolism, and binding to ribosomes to disrupt protein synthesis (Table 16-2). 

Even though early work indicated that the drug was having effects on the fungal cell wall, nucleic acid synthesis inhibition, and alterations of cytoplasmic microtubles, later studies all point toward a specific inhibition of mitotic spindle formation. 

Bredinin, Neosidomycin, and SF-2140. Bredinin (62), isolated from the culture filtrates of Eupenicillium brefeldianum (1,4), inhibits the multiplication of L5178Y, HeLa S3, RK-13, mouse L-ceUs, and Chinese hamster cells. GMP can reverse the inhibition by (62), but (62) is not incorporated into the nucleic acids. The inhibition of nucleic acid synthesis and chromosomal damage in the S and G 2 phases that is caused by (62), is reversed by GMP. It blocks the conversion of IMP to XMP and XMP to GMP. In combination with GMP, (62) interferes with intracellular cAMP levels and thereby inhibits cell division. 

Quinacrine concentrates in the scolex of the parasite and causes the muscles needed for holding onto the intestinal wall to relax. The worms are stained yellow and pass from the body, still aUve. Quinacrine can intercalate with DNA and inhibit nucleic acid synthesis. It creates fluorescent bands in deoxyadenylate—deoxythmidylate-rich regions of DNA and has been used as a stain in the study of human genetics. 

Phenoxazines — The microbial phenoxazines like actinomycins are well-known antibiotics. Actinomycin D produced by Streptomyces anibioticus is an effective antineoplastic agent that inhibits nucleic acid synthesis. The main function of ommochromes is to act as screening pigments in the eyes of insects and other arthropods, as pattern pigments in the integument, and as excretion products of excess tryptophan. ... 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Vinblastine suppresses cell growth during metaphase, affects amino acid metabolism, in particular at the level of including glutamine acid into the citric acid cycle and preventing it from transformation into urea, and it also inhibits protein and nucleic acid synthesis. 

Asparaginase Asparaginase is an enzyme that hydrolyzes L-asparagine to L-aspartic acid, which causes a depletion of reserves of L-asparagine, thus inhibiting protein and nucleic acid synthesis. It is effective for severe lymphocyte leukemia [154]. A synonym of this drug is elspar. 

Many cytostatics inhibit nucleic acid synthesis or functions such as replication or transcription. There... 

The only antimalarial drugs whose mechanisms of action are reasonably well understood are the drugs that inhibit the parasite s ability to synthesize folic acid. Parasites cannot use preformed folic acid and therefore must synthesize this compound from the following precursors obtained from their host p-aminobenzoic acid (PABA), pteridine, and glutamic acid. The dihydrofolic acid formed from these precursors must then be hydrogenated to form tetrahydrofoUc acid. The latter compound is the coenzyme that acts as an acceptor of a variety of one-carbon units. The transfer of one-carbon units is important in the synthesis of the pyrimidines and purines, which are essential in nucleic acid synthesis. 

Antimetabolites are analogues of normal DNA components or of coenzymes involved in nucleic acid synthesis. They get incorporated or competitively inhibit utilization of normal substrate to form dysfunctional nucleic acid molecules. 

Two other features deserve mention. First, there is evidence, especially in the de novo purine pathway, that the enzymes are present as large, multienzyme complexes in the cell, a recurring theme in our discussion of metabolism. Second, the cellular pools of nucleotides (other than ATP) are quite small, perhaps 1% or less of the amounts required to synthesize the cell s DNA. Therefore, cells must continue to synthesize nucleotides during nucleic acid synthesis, and in some cases nucleotide synthesis may limit the rates of DNA replication and transcription. Because of the importance of these processes in dividing cells, agents that inhibit nucleotide synthesis have become particularly important to modern medicine. 

The glycoside/aminoglycoside antibiotics, like the macrolides, exert a bacteriostatic effect due to selective inhibition of bacterial protein synthesis, with the exception of novobiocin (26). The compounds neomycin (27), spectinomycin (28) and streptomycin (29) bind selectively to the smaller bacterial 30S ribosomal subunit, whilst lincomycin (30) binds to the larger 50S ribosomal subunit (cf. macrolides). Apramycin (31) has ribosomal binding properties, but the exact site is uncertain (B-81MI10802). Novobiocin (26) can inhibit nucleic acid synthesis, and also complexes magnesium ion, which is essential for cell wall stability. 

Predecessors to praziquantel as the preferred treatment for schistosomiasis include oxamniquine, and the related compound hycanthone (Cioli et al., 1995). These drugs act by inhibiting nucleic acid synthesis, but only after parasite-mediated biotransformation of the drug by a schistosome enzyme (Cioli et al., 1993, 1985). Until relatively recently, oxamniquine continued to be the primary drug used to treat schistosomiasis in Brazil. 

Several antibacterial drugs inhibit bacterial nucleic acid synthesis by inhibiting the production of folic acid.17 Folic acid serves as an enzymatic cofactor in a number of reactions, including synthesis of bacterial nucleic acids and certain essential amino acids. The pathway for synthesis of these folic acid cofactors is illustrated in Figure 33-2. Certain antibacterial drugs block specific steps in the folate pathway, thus impairing the production of this enzymatic cofactor and ultimately impairing the production of nucleic acids and... 

The sulfonamides include sulfadiazine, sulfamethizole, and similar agents (see Table 33-4). Sulfonamides interfere with bacterial nucleic acid production by disrupting folic acid synthesis in susceptible bacteria. Sulfonamide drugs are structurally similar to PABA, which is the substance used in the first step of folic acid synthesis in certain types of bacteria (see Fig. 33-2). Sulfonamides either directly inhibit the enzyme responsible for PABA utilization or become a substitute for PABA, which results in the abnormal synthesis of folic acid. In either case, folic acid synthesis is reduced, and bacterial nucleic acid synthesis is impaired. 

Mechanism of Action. Atovaquone appears to selectively inhibit electron transport in susceptible microorganisms.6 This inhibition directly decreases production of ATP in the microorganism and may interfere with nucleic acid synthesis, ultimately resulting in death of the parasite. 

Mechanism of Action. The exact mechanism of this drug is not clear, and pentamidine may affect different parasites in different ways. Some possible antiprotozoal actions of this drug include the inhibition of protein and nucleic acid synthesis, cellular metabolism, and oxidative phosphorylation in susceptible parasites. 

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