Synthesis and biological evaluation of novel naphthoquinone fused cyclic aminoalkylphosphonates and aminoalkylphosphonic monoester

A series of novel naphthoquinone fused cyclic alpha-aminophosphonates, 2-alkoxy-3,4-dihydro-2H-naphtho2,3-e]1,4,2]oxazaphosphinane-5,10-dione 2-oxide 3-17 and naphthoquinone fused cyclic alpha-aminophosphonic monoester 18 were synthesized for the first time. These cyclic alpha-aminophosphonates were evaluated for antitumor activity on four human tumor cell lines, and three of them showed significant cytotoxicity (IC(50): 0.019-5.15 microM) comparable to that of the reference drug doxorubicin. Furthermore, inhibition assays for topoisomerase II-mediated relaxation of supercoiled DNA indicated that the naphthoquinone fused cyclic aminophosphonates were catalytic inhibitors of topoisomerase II.