DNA cleavage characteristics of non-protein enediyne antibiotic N1999A2.
N1999A2 (NA2) is a new non-protein antitumor antibiotic that contains a stable 9-membered ring enediyne chromophore similar to a neocarzinostatin chromophore (NCS-chr). We have compared DNA cleavage reactions between NA2 and NCS-chr, and also clarified some characteristics of DNA strand scission by NA2. It was found that: (1) NA2 is considerably stable in nature, (2) the compound intercalates into base pairs of a DNA minor groove and decreases its base-attacking frequency in the order of T>A>> C>G, (3) the base-sequence specificity 5(')-GGT/3(')-CCA presented by NA2 is significantly related to recognition of the base pair with the naphthoate moiety, and (4) the different cleavage property between NCS-chr and NA2 is associated with the presence or absence of an aminoglycoside residue. Based on the results of the site-specific cleavage by NA2 for certain bulged DNAs and a fluorescence study of NA2-DNA oligomer complexes, the DNA interaction mode of NA2 has also been examined. These results provide important information to design a new enediyne molecule for a DNA target.
Miyagawa
Naoko
N
Institute for Chemical Research, Kyoto University, Uji, 611-0011, Kyoto, Japan.
Sasaki
Daisuke
D
Matsuoka
Mieko
M
Imanishi
Miki
M
Ando
Toshihiko
T
Sugiura
Yukio
Y
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004269:DNA, Bacterial / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004214:Distamycins / Q000494:pharmacology; D004355:Drug Stability; D053281:Enediynes; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013696:Temperature; D014466:Ultraviolet Rays; D009353:Zinostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004214:Distamycins; D053281:Enediynes; D004852:Epoxy Compounds; C437375:N1999-A2; D009281:Naphthalenes; D013438:Sulfhydryl Compounds; C030000:stallimycin; C032372:neocarzinostatin chromophore; D009353:Zinostatin