Nucleic acid derivatives, action

XVI. The Action of Ionizing Radiation on Nucleic Acid Derivatives. . 283... 

XVI. THE ACTION OF IONIZING RADIATION ON NUCLEIC ACID DERIVATIVES... 

The unique properties of oligonucleotides create crosslinking options that are far different from any other biological molecule. Nucleic acids are the only major class of macromolecule that can be specifically duplicated in vitro by enzymatic means. The addition of modified nucleoside triphosphates to an existing DNA strand by the action of polymerases or transferases allows addition of spacer arms or detection components at random or discrete sites along the chain. Alternatively, chemical methods that modify nucleotides at selected functional groups can be used to produce spacer arm derivatives or activated intermediates for subsequent coupling to other molecules. 

Administration203 to chicks of acetic acid labeled with C14 (in the carboxyl group) gave D-glucose (from the glycogen) labeled equally at C3 and C4, but the D-ribose (from nucleic acids) had more label at C3 than at C2, indicating that in vivo D-ribose does not arise exclusively from hexose by loss of Cl. The 20-30% isotope content of D-ribose formed from D-glucose-l-C14 by Escherichia coli indicates that direct conversion is the major pathway but that a part is probably derived from transketolase action.204 206... 

Bergman AM, et al. Antiproliferative activity and mechanism of action of fatty acid derivatives of gemcitabine in leukemia and solid tumor cell lines and in human xenografts. Nucleosides Nucleotides Nucleic Acids 2004 23 1329. 

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]. 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

This subject has been of continuing interest for several reasons. First, the present concepts of the chemical constitution of such important biopolymers as cellulose, amylose, and chitin can be confirmed by their adequate chemical synthesis. Second, synthetic polysaccharides of defined structure can be used to study the action pattern of enzymes, the induction and reaction of antibodies, and the effect of structure on biological activity in the interaction of proteins, nucleic acids, and lipides with polyhydroxylic macromolecules. Third, it is anticipated that synthetic polysaccharides of known structure and molecular size will provide ideal systems for the correlation of chemical and physical properties with chemical constitution and macromolecular conformation. Finally, synthetic polysaccharides and their derivatives should furnish a large variety of potentially useful materials whose properties can be widely varied these substances may find new applications in biology, medicine, and industry. 

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 ... 

In relation with resistance of weeds to herbicides, Duke et al. (2000) mentioned that new mechanisms of action for herbicides are highly desirable to fight evolution of resistance in weeds, to create or exploit unique market niches, and to cope with new regulatory legislation. Comparison of the known molecular target sites of synthetic herbicides and natural phytotoxins reveals that there is little redundancy. Comparatively little effort has been expended on determination of the sites of action of phytotoxins from natural sources, suggesting that intensive study of these molecules will reveal many more novel mechanisms of action. These authors gave some examples of natural products that inhibit unexploited steps in the amino acid, nucleic acid, and other biosynthetic pathways AAL-toxin, hydantocidin, and various plant-derived terpenoids. 

No partly methylated ribose derivatives have been isolated from natural sources up to the present, for although such nucleic acids as yeast nucleic acid contain D-ribose phosphate residues, the methylation technique fails in structural studies in this group because of the hydrolytic action of alkaline reagents. Trimethyl-D-ribofuranose has, how-... 

In comparison with the penicillin and cephalosporin derivatives, the peptide antibiotics are not numbered among the major antibiotics . Their action mechanisms vary, e.g. inhibition of cell-wall synthesis, increased permeability of the cell wall, or influence on nucleic acid synthesis. 

Bergman AM, Ruiper CM, Noordhuis P, Smid K, Voorn DA, Comijn EM, Myhren F, Sandvold ML, Hendriks HR, Fodstad O, Breistol K, Peters Gf (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of gemcitabine in leukemia and solid tumor cell lines and in human xeno-grafrs. Nucleosides Nucleotides Nucleic Acids 23 1329-1333... 

In the body, the energy derived from food is released as body heat and also used in the synthesis of ATP. The energy captured in ATP is then transformed into other forms, i.e., chemical (synthesis of new compounds), mechanical (muscle contraction), electrical (nerve activity), electrochemical (various ion pumps), thermal (maintenance of body temperature), and informational (base sequences in nucleic acids, amino acids in proteins). In general, the energy of food provides for the specific dynamic action of food, the maintenance of the body s basal metabolism, and the energy expenditure associated with various types of activity. 

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