Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon.
In a continuation of our search for potential tumor inhibitors from plants, we found that a crude extract from Ocotea leucoxylon showed selective activity typical of inhibitors of the enzyme topoisomerase I in a yeast assay for DNA-damaging agents. Using a bioassay-directed fractionation approach, the major bioactive compound was isolated and identified as the known aporphine alkaloid dicentrinone (4); the inactive alkaloid dicentrine (3) was also isolated. Compound 4 showed selective bioactivity against the rad52 repair-deficient yeast strain RS322 (IC(12) 49 microg/mL) and was inactive against the rad52- and topo1-deficient strain RS321 (IC(12) > 2000 microg/mL) and against the repair-proficient strain RJ03 (IC(12) > 2000 microg/mL). Biochemical studies with recombinant human topoisomerase I indicated that dicentrinone (4) is an inhibitor of the human enzyme. Colony formation studies suggest that it is weakly cytotoxic, but that its mechanism of toxicity differs from that of camptothecin and its derivatives.
Zhou
B N
BN
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0212, USA.
Johnson
R K
RK
Mattern
M R
MR
Wang
X
X
Hecht
S M
SM
Beck
H T
HT
Ortiz
A
A
Kingston
D G
DG
D001060:Aporphines / Q000302:isolation & purification* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010946:Plants, Medicinal / Q000737:chemistry*; D011994:Recombinant Proteins / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet; D059004:Topoisomerase I Inhibitors
D001060:Aporphines; D004278:DNA, Superhelical; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; C067342:dicentrine; C406631:dicentrinone