Jy. Kim et al., CYCLOPENT[A]ANTHRAQUINONES AS DNA-INTERCALATING AGENTS WITH COVALENT BOND FORMATION POTENTIAL - SYNTHESIS AND BIOLOGICAL-ACTIVITY, Journal of medicinal chemistry, 39(14), 1996, pp. 2812-2818
A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone
derivatives, were synthesized via Diels-Alder cyclization of naphthoq
uinone with 1-vinylcyclopent-1-enes. These new compounds are planar st
ructures, 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, )carbonyl]met
hyl]cyclopent[a]anthracene-6,11-dione (4) was shown to have inhibitory
activity against several leukemic and solid tumor cell lines. Mice (B
DF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (ip
, 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 unwind
ing assay indicated that 4 is able to intercalate into DNA double stra
nds and is also a topoisomerase II inhibitor.