TY - JOUR
T1 - Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N, N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones
T2 - Influence on topoisomerase I-targeting activity and cytotoxicity
AU - Ruchelman, Alexander L.
AU - Kerrigan, John E.
AU - Li, Tsai Kun
AU - Zhou, Nai
AU - Liu, Angela
AU - Liu, Leroy F.
AU - LaVoie, Edmond J.
N1 - Funding Information:
This study was supported by AVAX Technologies, Inc. (E.J.L.), Grant CA098127 (E.J.L.), Grant CA039662 (L.F.L.) and Grant CA077433 (L.F.L.) from the National Cancer Institute.
PY - 2004/7/1
Y1 - 2004/7/1
N2 - Recently, 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3- methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one, 1, was identified as a TOP1-targeting agent with pronounced antitumor activity. In the present study, the effect on activity of substituting a single nitro or amino group in the A-ring in lieu of the methylenedioxy moiety of 1 was evaluated. The presence of either a nitro or amino substituent at the 4-position had a pronounced adverse affect on both TOP1-targeting activity and cytotoxicity. To a lesser extent, derivatives with a nitro or amino substituent at the 1-position were also less active than 1. Replacement of the methylenedioxy moiety of 1 with either a nitro or amino substituent at either the 2- and 3-position did result in analogues with potent TOP1-targeting activity and cytotoxicity.
AB - Recently, 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3- methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one, 1, was identified as a TOP1-targeting agent with pronounced antitumor activity. In the present study, the effect on activity of substituting a single nitro or amino group in the A-ring in lieu of the methylenedioxy moiety of 1 was evaluated. The presence of either a nitro or amino substituent at the 4-position had a pronounced adverse affect on both TOP1-targeting activity and cytotoxicity. To a lesser extent, derivatives with a nitro or amino substituent at the 1-position were also less active than 1. Replacement of the methylenedioxy moiety of 1 with either a nitro or amino substituent at either the 2- and 3-position did result in analogues with potent TOP1-targeting activity and cytotoxicity.
UR - http://www.scopus.com/inward/record.url?scp=2942513563&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2942513563&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2004.03.076
DO - 10.1016/j.bmc.2004.03.076
M3 - Article
C2 - 15186859
AN - SCOPUS:2942513563
SN - 0968-0896
VL - 12
SP - 3731
EP - 3742
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 13
ER -