5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: Novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity

Alexander L. Ruchelman, Sudhir K. Singh, Abhijit Ray, Xiao Hua Wu, Jin Ming Yang, Tsai Kun Li, Angela Liu, Leroy F. Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2061-2073
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number9
DOIs
StatePublished - May 1 2003

Fingerprint

Naphthyridines
Type I DNA Topoisomerase
Antineoplastic Agents
Tumors
Nude Mice
Cytotoxicity
Neoplasms
Growth
Tumor Cell Line
Heterografts
Human Activities
Breast Neoplasms
Assays
Injections
Cells
Derivatives
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Ruchelman, Alexander L. ; Singh, Sudhir K. ; Ray, Abhijit ; Wu, Xiao Hua ; Yang, Jin Ming ; Li, Tsai Kun ; Liu, Angela ; Liu, Leroy F. ; LaVoie, Edmond J. / 5H-Dibenzo[c,h]1,6-naphthyridin-6-ones : Novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity. In: Bioorganic and Medicinal Chemistry. 2003 ; Vol. 11, No. 9. pp. 2061-2073.
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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.",
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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 F.; LaVoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 9, 01.05.2003, p. 2061-2073.

Research output: Contribution to journalArticle

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 F.

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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