Cyclopent[a]anthraquinones as DNA intercalating agents with covalent bond formation potential: synthesis and biological activity.
A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone derivatives, were synthesized via Diels-Alder cyclization of naphthoquinone with 1-vinylcyclopent-1-enes. These new compounds are planar structures, like MMC, and bear an aziridine ring and a methyl carbamate side chain. After bioreduction, they are anticipated to be capable of intercalating into double-stranded DNA and bind covalently. Structure-activity relationships were studied. Of these compounds, 2,3-aziridino-4-[[(methylamino)carbonyl]methyl] cyclopent[alpha]anthracene-6,11-dione (4) was shown to have inhibitory activity against several leukemic and solid tumor cell lines. Mice (BDF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (i.p., QD x 5). At a dose of 30.0 mg/kg, compound 4 was as effective as MMC (0.8 mg/kg). Compound 4 appears to be less toxic than MMC. DNA unwinding assay indicated that 4 is able to intercalate into DNA double strands and is also a topoisomerase II inhibitor.
Kim
J Y
JY
Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division of Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
Su
T L
TL
Chou
T C
TC
Koehler
B
B
Scarborough
A
A
Ouerfelli
O
O
Watanabe
K A
KA
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D008937:Mitomycins; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D008937:Mitomycins; D016685:Mitomycin; D004247:DNA