title: Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells.
abstract: The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360.
authors.forename: I H
authors.initials: IH
authors.lastname: Hall
authors.forename: E S
authors.initials: ES
authors.lastname: Hall
authors.forename: L K
authors.initials: LK
authors.lastname: Chi
authors.forename: B R
authors.initials: BR
authors.lastname: Shaw
authors.forename: A
authors.initials: A
authors.lastname: Sood
authors.forename: B F
authors.initials: BF
authors.lastname: Spielvogel
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000737:chemistry / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D013942:Thymine Nucleotides / Q000737:chemistry / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C076050:5'-O-((triphenylphosphine-boryl)carbonyl)-3'-O-acetylthymidine; C076051:5'-diethylphosphite-cyanoborane-3'-acetylthymidine; D001896:Boron Compounds; D004273:DNA, Neoplasm; D013942:Thymine Nucleotides; D012321:DNA-Directed RNA Polymerases; D013936:Thymidine