AHPG [electronic resource] : 9-((1-amino-3-hydroxy-2-propoxy)methyl);guanine. Synthesis, biological evaluation, and biochemical mechanism of action in the L1210 cell system.

1989

1 online resource (151 p.)

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Source: Dissertation Abstracts International, Volume: 50-11, Section: B, page: 5037.

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This thesis involved the synthesis, biological evaluation, and determination of the mechanism of cytotoxicity of 9- ((1-amino-3-hydroxy-2-propoxy)methyl) guanine, AHPG. This acyclic nucleoside was synthesized by a novel route and purified by state-of-the-art chromatography. The antimetabolite was screened for cytotoxic activity and was found to be most effective against L1210 cells among those systems tested. Initial biochemical studies in this system indicated that AHPG significantly decreased the incorporation of amino acids into L1210 acid-insoluble material without altering the incorporation of precursor molecules into DNA or RNA. Electrophoretic analysis of the nuclear and cytoplasmic proteins formed in the presence of drug indicated that this effect was a generalized phenomenon. Additionally, AHPG was found not to alter amino acid transport into L1210 cells. Since AHPG is a modified precursor of DNA and RNA, it was essential to evaluate the influence of this agent on these macromolecules. DNA and RNA were isolated from L1210 cells which had been treated with radiolabeled AHPG (tritium in the guanine base). HPLC analysis indicated that native AHPG was not present in the nucleic acids and phosphorylated AHPG was not found in cytosolic fractions. Since all the data suggested that the primary effect of AHPG might be directed at the level of translation, ribosomes and polysomes were isolated in the presence and absence of drug. After sixty minutes of exposure to AHPG there was a significant decrease in the levels of these complexes, suggesting that AHPG invokes its initial cytotoxic action directly at the level of protein synthesis. In summary, AHPG produces toxicity in L1210 cells by altering protein metabolism. Specifically, this alteration is expressed as an initial decrease in ribosome and short polysome content with a subsequent, nearly complete loss of ribosomes and a decrease in polysomes of all lengths.

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English

July 12, 2011

Thesis (Ph.D.)--Yale University, 1989.

Yale University.