Abstract
5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a β-methyl group or a β-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C2H5 or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3× week at a dose of 2.0 mg/kg. Compound 4a when administered orally 5× weekly at a dose of 40 mg/kg also suppressed tumor growth.
| Original language | English |
|---|---|
| Pages (from-to) | 2061-2073 |
| Number of pages | 13 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 11 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - May 1 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
5H-Dibenzo[c,h]1,6-naphthyridin-6-ones : Novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity. / Ruchelman, Alexander L.; Singh, Sudhir K.; Ray, Abhijit; Wu, Xiao Hua; Yang, Jin Ming; Li, Tsai Kun; Liu, Angela; Liu, Leroy-Fong; LaVoie, Edmond J.
In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 9, 01.05.2003, p. 2061-2073.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 5H-Dibenzo[c,h]1,6-naphthyridin-6-ones
T2 - Novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity
AU - Ruchelman, Alexander L.
AU - Singh, Sudhir K.
AU - Ray, Abhijit
AU - Wu, Xiao Hua
AU - Yang, Jin Ming
AU - Li, Tsai Kun
AU - Liu, Angela
AU - Liu, Leroy-Fong
AU - LaVoie, Edmond J.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a β-methyl group or a β-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C2H5 or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3× week at a dose of 2.0 mg/kg. Compound 4a when administered orally 5× weekly at a dose of 40 mg/kg also suppressed tumor growth.
AB - 5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a β-methyl group or a β-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C2H5 or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3× week at a dose of 2.0 mg/kg. Compound 4a when administered orally 5× weekly at a dose of 40 mg/kg also suppressed tumor growth.
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UR - http://www.scopus.com/inward/citedby.url?scp=0037401629&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(03)00051-8
DO - 10.1016/S0968-0896(03)00051-8
M3 - Article
C2 - 12670657
AN - SCOPUS:0037401629
VL - 11
SP - 2061
EP - 2073
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 9
ER -