The effects of alpha-methylene-gamma-lactone purines and pyrimidines on L1210 lymphoid leukemia nucleic acid metabolism.
Purine and pyrimidine adducts of alpha-methylene-gamma-lactone demonstrated potent cytotoxicity against murine L1210 lymphoid leukemia growth as well as a variety of human tissue cultured tumors. The most potent compound, 9-[(2-methyl-4-methylene-5-oxotetrahydrofuran-2-yl)-methyl 1] adenine 1 demonstrated significant inhibition of DNA synthesis in L1210 leukemic cells with moderate inhibition of protein synthesis. The major enzyme activities inhibited by 1 were DNA polymerase alpha, ribonucleoside reductase and t-RNA polymerase with marginal inhibition of thymidine kinase, TMP kinase, PRPP amidotransferase and IMP dehydrogenase. The inhibition of DNA polymerase alpha activity by 1 was evident at the lowest concentration 25 microM and was evident within 15 min incubation at 100 microM. The magnitude of enzyme inhibition was consistent with the observed DNA synthesis inhibition by 1. The only deoxyribonucleotide level reduced by 1 was the dATP pool level. U.V. absorption of DNA after interacting with 1 demonstrated a hyperchromic effect and L1210 DNA strand scission was observed after 24 hr incubation with 1 suggesting some type of interference with the DNA template by the drug.
Hall
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Lee
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KH
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D003854:Deoxyribonucleotides / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000187:drug effects
D004273:DNA, Neoplasm; D003854:Deoxyribonucleotides; D007783:Lactones; D009363:Neoplasm Proteins; D011687:Purines; D011743:Pyrimidines; D012334:RNA, Neoplasm