| 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation. | |
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MedLine Citation:
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PMID: 9371240 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity. |
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Authors:
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I Antonini; P Polucci; T C Jenkins; L R Kelland; E Menta; N Pescalli; B Stefanska; J Mazerski; S Martelli |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 40 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1997 Nov |
Date Detail:
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Created Date: 1997-12-15 Completed Date: 1997-12-15 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3749-55 Citation Subset: IM |
Affiliation:
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Department of Chemical Sciences, University of Camerino, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acridines
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chemical synthesis*,
metabolism,
pharmacology* Animals Antineoplastic Agents / chemical synthesis*, metabolism, pharmacology* Cattle DNA / drug effects, metabolism* Drug Screening Assays, Antitumor Humans Intercalating Agents / chemical synthesis*, metabolism, pharmacology* Mice Nucleic Acid Denaturation Spectrometry, Fluorescence Tumor Cells, Cultured / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Acridines; 0/Antineoplastic Agents; 0/Intercalating Agents; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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