2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent

Salah M. Sami, Robert T Dorr, David S Alberts, William A. Remers

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.

Original languageEnglish (US)
Pages (from-to)765-770
Number of pages6
JournalJournal of Medicinal Chemistry
Volume36
Issue number6
StatePublished - 1993

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amonafide
Antineoplastic Agents
Nitrogen
lissamine rhodamine B
Cells
Leukemia P388
Imides
Experimental Melanomas
Poisons
Alkalinity
Rigidity
Colonic Neoplasms
Muscle Cells
Rats
Tumors
Assays
Coloring Agents
Atoms
Growth
isoquinoline

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent. / Sami, Salah M.; Dorr, Robert T; Alberts, David S; Remers, William A.

In: Journal of Medicinal Chemistry, Vol. 36, No. 6, 1993, p. 765-770.

Research output: Contribution to journalArticle

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AU - Alberts, David S

AU - Remers, William A.

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N2 - A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.

AB - A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.

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