DNA damage by fasicularin.
Fasicularin is a structurally novel thiocyanate-containing alkaloid isolated from the ascidian Nephteis fasicularis. Early biological experiments suggested that this compound's cytotoxic properties may stem from its ability to damage cellular DNA. Sequence gel analysis reveals that treatment of a 5'-32P-labeled DNA duplex with fasicularin in pH 7.0 buffer causes strand cleavage selectively at guanine residues. Further experiments indicate that production of these base-labile lesions in DNA involves alkylation of guanine residues by a fasicularin-derived aziridinium ion. This work reveals fasicularin as the first natural product found to generate a DNA-alkylating aziridinium ion via a mechanism analogous to the clinically used anticancer drugs mechlorethamine, melphalan, and chlorambucil.
Dutta
Sanjay
S
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Abe
Hideki
H
Aoyagi
Sakae
S
Kibayashi
Chihiro
C
Gates
Kent S
KS
D001483:Base Sequence; D004249:DNA Damage / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D007553:Isotope Labeling; D013058:Mass Spectrometry; D008956:Models, Chemical; D013861:Thiocyanates / Q000494:pharmacology*
D006575:Heterocyclic Compounds, 3-Ring; D013861:Thiocyanates; C448329:fasicularin