Interference with Nucleic Acid Synthesis and Function

3 Interference with Nucleic Acid Synthesis and Function 

Many compounds do not directly interact with intact DNA but are nonetheless able to affect normal DNA function in a cell. All the following examples are drugs that bind proteins or enzymes. 

---

Antibacterial agents can interfere with nucleic acid synthesis at a number of junctures including replication and/or transcription of DNA through preferential binding or insertion into the DNA. They may also influence the proteins involved with the replication. Other antibacterial agents interfere with the RNA synthesis, action, or proteins associated with these functions. They may also interfere with the coiling and uncoiling necessary for appropriate action. 

Phase I and II clinical trials indicated that acronycine reduced pain of the spine in some patients with multiple myeloma [280,282,283]. Acronycine has been reported to cause leukopoenia and to have CNS-depressant activity [284], Biochemically, acronycine inhibits incorporation of extracellular nucleosides into the RNA and DNA of leukaemia L-5178Y cell culture. There is, however, no evidence of interaction between acronycine and DNA or inhibition of template activity of DNA. This alkaloid does not inhibit nucleic acid synthesis in the cell, but rather inhibits the accumulation of extracellular uridine or thymidine, as nucleotides, in the intracellular precursor pool [285, 286], Acronycine, acting primarily on membranous organelles [287], seems to interfere with the structure, function and/or turnover of cell membrane components, thereby changing the fluidity of the plasma membrane [288]. 

So, by competing with natural pyrines and pyrimidines in metabolic schemes, they interfere with the synthesis of nucleic acids, thus being included in place of ordinary metabolites. This leads to the formation of cellular products, which cannot function normally. Thus, cellular processes of division and multiplication are disrupted. 

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-... 

An antimetabolite is a compound that is (1) similar to a compound required for normal cellular function and (2) interferes with cellular processes. Based on this definition, many drugs technically qualify as antimetabolites. The term antimetabolite is, however, most closely associated with drugs that interfere with the synthesis or action of nucleic acids. Antimetabolites are commonly discussed in the treatment of cancer, viruses, and bacterial infections. 

Mechanism of action Griseofulvin interferes with microtubule function in dermatophytes (Figure 48-2) and may also inhibit the synthesis and polymerization of nucleic acids. Sensitive dermatophytes take up the drug by an energy-dependent mechanism, and resistance can occur via decrease in this transport. 

---