Synthesis of DNA

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

Mitomycin C was found to have broad activity against a range of tumors and has been used clinically since the early 1960s [14, 15]. It causes many specific cellular effects, including inhibition of DNA synthesis, recombination, chromosome breakage, sister chromatid exchange, induction of DNA repair, and induction of... 

Macrocytic or magaloblastic anemia is caused by disturbances of DNA synthesis. It occurs, for example, in both folic acid and vitamin B12 deficiencies. Hematopoesis is slowed down due to reduced DNA synthesis and a reduced number of abnormally large (macrocytic) and hemaglobin-rich (hyperchromic) erythrocytes is released. 

Deoxy-3 -fluorothymidine (813), a selective inhibitor of DNA synthesis, was prepared " in moderate yields from 3 -0-mesyl- or 3, 5 -di-O-mesyl-thymidine, through 2,3 -anhydro-1 -(2-deoxy- -D-t/2reopentofur-anosyl)thymine (808), by treatment with hydrogen fluoride (0.1% HF in l,4-dioxane-AlF3, 3.764 hf in DMF-AlFj, or 10% HF in DMF ),... 

Human tissues can synthesize purines and pyrimidines from amphibolic intermediates. Ingested nucleic acids and nucleotides, which therefore are dietarily nonessential, are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. The purine bases are then oxidized to uric acid, which may be absorbed and excreted in the urine. While little or no dietary purine or pyrimidine is incorporated into tissue nucleic acids, injected compounds are incorporated. The incorporation of injected [ H] thymidine into newly synthesized DNA thus is used to measure the rate of DNA synthesis. 

Figure 36-14. The initiation of DNA synthesis upon a primer of RNA and the subsequent attachment of the second deoxyribonucleoside triphosphate.

Figure 36-17. The generation of "replication bubbles" during the process of DNA synthesis. The bidirectional replication and the proposed positions of unwinding proteins at the replication forks are depicted.

Othet cyclins and CDKs are involved in different aspects of cell cycle progression (Table 36-7). Cychn E and CDK2 form a complex in late Gl. Cychn E is tapidly degraded, and the released CDK2 then fotms a complex with cyclin A. This sequence is necessaty fot the initiation of DNA synthesis in S phase. A complex between cychn B and CDKl is tate-hmiting fot the G2/M transition in eukatyotic cells. 

Klaunig JE, Siglin JC, Schafer ED, et al. 1991. Correlation between species and tissue sensitivity to chemical carcinogenesis in rodents and the induction of DNA synthesis. Prog Clin Biol Res 369 185-194. 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

The copper(II) complexes of 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazone) and related compounds are active in vivo agents [151, 158, 159]. The metal complexes of 2-heterocyclic thiosemicarbazones were evaluated for their cytotoxicities [160, 161]. Further studies have revealed that these ligand s iron and copper complexes are effective inhibitors of DNA synthesis at much lower concentrations than the free thiosemicarbazones without apparent cytotoxicity [127]. Although the iron(III) complex of 2-isoformylquinoline thiosemicarbaz-one, 21, is considerably more active than free 21, the copper(II) complex is only moderately more active [127]. 

Rossi, P., Dolci, S., Albanesi, C., Grimaldi, P., Ricca, R., and Geremia, R. (1993). Follicle-stimulating hormone induction of Steel factor (SLF) mRNA in mouse sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Dev. Biol. 155 68-74. 

Bidentate sites may be available in DNA itself. In the binding of Hg2+ and Ag+ we surmise that the binding is to amino-groups of cytidine and adenine and possibly the N(7) of guanine as all these positions are accessable in DNA. The introduction of a more kinetically permanent group such at [Pt(NH3)2]2+ attached to two such groups, e.g. two amino groups could lead to the formation of an inter-strand cross-link and an inhibition of DNA synthesis (90). 

Sirover, MA, Loeb LA. 1976. Infidelity of DNA synthesis in vitro Screening for potential metal mutagens or carcinogens. Science 194 1434-1436. 

Figure 5.15 The filamentous single-stranded DNA bacteriophage fd. Orientation of the proteins and genes in the virion. Note the intergenic space which contains the origin of DNA synthesis. Gene cloning is done in this intergenic space.

DNA has two broad functions replication and expression. First, DNA must be able to replicate itself so that the information coded into its primary structure is transmitted faithfully to progeny cells. Second, this information must be expressed in some useful way. The method for this expression is through RNA intermediaries, which in turn act as templates for the synthesis of every protein in the body. The relationships of DNA to RNA and to protein are often expressed in a graphic syllogism called the central dogma. The concept was proposed by Crick in 1958 and was revised in 1970 to accommodate the discovery of the RNA-dependent DNA polymerase. Crick s original theory suggested that the flow of information was always from RNA to protein and could not be reversed, yet it allowed for the possibility of DNA synthesis from RNA. 

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