A new 7,8-euphadien-type triterpenoid from Brackenridgea nitida and Bleasdalea bleasdalei that inhibits DNA polymerase beta.
Bioassay-guided fractionation of extracts prepared from Brackenridgea nitida and Bleasdalea bleasdalei, using an assay to detect DNA polymerase beta inhibition, resulted in the isolation of the inhibitory principle, (24E)-3beta-hydroxy-7,24-euphadien-26-oic acid (1), a new euphane triterpenoid. The structure of 1 was established on the basis of HRMS and 1D and 2D NMR spectroscopic methods and was confirmed further by X-ray crystallographic analysis. Compound 1 inhibited rat DNA polymerase beta with an IC(50) value of 23 microM in the presence of bovine serum albumin (BSA) and 9.7 microM in the absence of BSA, consistent with the possibility that 1 may be of utility in vivo. This possibility was further supported by the finding that 1 potentiated the inhibitory action of the anticancer drug bleomycin in cultured P-388D(1) cells, reducing the number of viable cells by 48% when employed at a concentration of 25 microM in the presence of an otherwise nontoxic (75 nM) concentration of bleomycin. Compound 1 is the first euphane-type triterpenoid found to inhibit DNA polymerase beta.
Deng
J Z
JZ
Departments of Chemistry and Biology, University of Virginia, Charlottesville, Virginia 22901, USA.
Starck
S R
SR
Sun
D A
DA
Sabat
M
M
Hecht
S M
SM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification*; D007941:Leukemia P388; D019684:Magnoliopsida / Q000737:chemistry*; D051379:Mice; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification*; D014407:Tumor Cells, Cultured
C416465:3-hydroxy-7,24-euphadien-26-oic acid; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D014315:Triterpenes; D001761:Bleomycin; D019951:DNA Polymerase beta