Synthesis of cyclopentanthraquinones: analogs of mitomycin C

Abstract

2,3-Dihydro-1H-cyclopent[a]anthracene-6,11-dione (cyclopentanthraquinone) derivatives bearing a mustard side chain at C-4 and an aziridine ring at the cyclopentene moiety were synthesized. Such a compound may be viewed as an analogue of mitomycin C (MC) and may exhibit bifunctional DNA-alkylating and DNA-intercalating agent. The key intermediate, 4-hydroxy-2,3-di-O-substituted cyclopentanthraquinone, was synthesized by Diels-Alder reaction of naphthoquinone with various 4,5-dihydroxy-1-vinylcyclopent-1-ene derivatives.Introduction of a mustard side chain to the OH group at C-4 and subsequent construction of an aziridine-ring on C 2 -C 3 of the cyclopentanthroquinone molecule furnished the target compound, 2,3-aziridino-4-[2-[N,N-bis(2-chloroethyl)amino]ethoxy]-2,3-dihydro-1H-cyclopenta[a]anthrcene-6,11-dione.It was found that both the aziridine function and the mustard side chain play a significant role in their cytotoxicity against leukemic L1210 and HL-60 cell growth in culture and the inhibition of topoisomerase II kDNA decatenation