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-Fong Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2061-2073
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number9
DOIs
Publication statusPublished - May 1 2003
Externally publishedYes

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

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 journalArticle

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. / 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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