2,6-Di(ω-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones: Novel, Potent, Cytotoxic, and DNA-Binding Agents
- 21 December 2001
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 45 (3) , 696-702
- https://doi.org/10.1021/jm011004x
Abstract
DNA-binding agents with potential antitumor activities bearing two cationic side chains, the 2,6-di(ω-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4a − r), have been prepared either by reaction of the appropriate 2-(ω-aminoalkyl)-6-chloro-2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione with the appropriate (ω-aminoalkyl)hydrazine or by cyclization of the requisite N-6,2-di(ω-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-6-carboxamide with phosgene. In vitro cytotoxic properties of these derivatives against three human colon adenocarcinoma cell lines (HT29, LoVo, and LoVo/Dx) and against some cell lines of the NCI panel are described and compared to that of reference drugs. Some of the new compounds showed outstanding potency while lacking cross-resistance with anthracyclines. Structure−activity relationships are discussed, and a mechanistic analysis is performed using the COMPARE procedure. The mechanism and efficiency of noncovalent DNA binding of these compounds are examined using gel electrophoresis and fluorometric techniques. The 2,6-di(ω-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4) constitute a new class of potent, cytotoxic DNA-binding agents not cross-resistant with doxorubicin.Keywords
This publication has 11 references indexed in Scilit:
- N4-(ω-Aminoalkyl)-1-[(ω-aminoalkyl)amino]-4-acridinecarboxamides: Novel, Potent, Cytotoxic, and DNA-Binding AgentsJournal of Medicinal Chemistry, 2000
- 2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione Derivatives, a Class of Cytotoxic Agents Active on Multidrug-Resistant Cell Lines: Synthesis, Biological Evaluation, and Structure−Activity RelationshipsJournal of Medicinal Chemistry, 1999
- 1-[(ω-Aminoalkyl)amino]-4-[N-(ω-aminoalkyl)carbamoyl]-9-oxo-9,10-dihydro- acridines as Intercalating Cytotoxic Agents: Synthesis, DNA Binding, and Biological EvaluationJournal of Medicinal Chemistry, 1997
- Novel Acridine-Triazenes as Prototype Combilexins: Synthesis, DNA Binding, and Biological ActivityJournal of Medicinal Chemistry, 1995
- Synthesis of (Dialkylamino)alkyl-Disubstituted Pyrimido[5,6,1-de]acridines, a Novel Group of Anticancer Agents Active on a Multidrug Resistant Cell LineJournal of Medicinal Chemistry, 1995
- 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A Novel Class of Chromophore-Modified Antitumor Anthracene-9,10-diones: Synthesis and Antitumor EvaluationsJournal of Medicinal Chemistry, 1994
- 2-(Aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines, a new class of anticancer agentsJournal of Medicinal Chemistry, 1992
- Chromophore-modified antineoplastic imidazoacridinones. Synthesis and activity against murine leukemiasJournal of Medicinal Chemistry, 1992
- Potential antitumor agents. 46. Structure-activity relationships for acridine monosubstituted derivatives of the antitumor agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamideJournal of Medicinal Chemistry, 1986
- Potential antitumor agents. 12. 9-AnilinoacridinesJournal of Medicinal Chemistry, 1972