Cancer pyrimidine analogs

Nucleic-acid-related molecules (nucleotides, nucleosides, purines, pyrimidines) may also be used as dmgs themselves (and not only as dmg receptors). Once again, as discussed in chapters 7 and 9, this is most relevant in the areas of cancer and infectious disease, with purine/pyrimidine analogs being exploited as antimetabolites. 5-Fluorouracil is a well-described antineoplastic agent. Analogously, 5-fluorocytosine is used as an antifungal... 

A number of purine and pyrimidine analogs are useful as anti-cancer drugs. For example, 5-fluorouracil blocks the enzyme that produces thymidine, a key base in DNA, and kills many cancer cells as well as some healthy cells. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

Hitchings G, Elion G (1967) Mechanisms of action of purine and pyrimidine analogs. In Brodsky I, Kahn S, Moyer J et al (eds) Cancer chemotherapy I. Grune and Stratton, New York, NY, p 26... 

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy. 

In the nucleoside field, the use of calorimetric, volumetric, and structural data for describing the properties of pyrimidine nucleic acid bases and their derivatives was the subject of a specialized review <03MI155>, and pyrimidine nucleoside analogs as cancer chemotherapeutics <03MI717>... 

PRPP was also utilized in the formation of 5 -ribonucleotides from naturally occurring purine and pyrimidine bases (73, 80, 83, 84) and from synthetically prepared analogs (86). It was required in purine biosynthesis (86) and its precise role will be described below. PRPP also served as a substrate in the de novo synthesis of DPN (87). Its ability to condense with purine analogs to form analogs of 5 -ribonucleotides suggests many possibilities for fundamental studies of cancer chemotherapy. 

One of the current approaches to the treatment of cancer involves the disruption of kinase activity and signal transduction pathways. For example, protein kinase C (PKC) plays a crucial role in signal transductions, cellular proliferation, and differentiation. PKC is the term for a whole family of cytosolic serine/threonine kinases. Phenylamino-pyrimidines like 3- 4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]pyridin-2-yl-amino propanol (159, CGP 60474) represent a promising class of inhibitors of PKC with a high degree of selectivity versus other serine/threonine and tyrosine kinases and show competitive kinetics relative to ATP. Analogs of CGP 60474 were synthesized as useful models for the evaluation of structure-activity relationships of phenylamino-pyrimidine-type protein kinase C inhibitors. 

The utility of pyrimidine and purine analogs in cancer chemotherapy (e.g. 6-mercaptopurine, 5-fluorouracil, arabinosyl cytosine) serves as a continued stimulus for the preparation of new compounds of this type. Among these,3-deaza-uridine [l-(j3-p-ribofuranosyl)-4-hydroxy-2-pyridone] was markedly active... 

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