Biochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates.

2.50
Hdl Handle:
http://hdl.handle.net/10541/97469
Title:
Biochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates.
Authors:
Meikle, I; Cummings, Jeffrey; Macpherson, J S; Hadfield, John A; Smyth, J F
Abstract:
Mono-conjugation of an anthraquinone nucleus with a range of naturally occurring amino acids chemically modified at their C-terminus has been adopted as a synthetic approach in the rational design of novel topoisomerase (topo) inhibitors. The biochemistry of topo I and II inhibition has been investigated for a series of 16 new compounds (NU/ICRF 500-515) from which structure-activity relationships have been investigated. Only three compounds could be demonstrated to bind to DNA: two serine derivatives (NU/ICRFs 500 and 506) and an arginine derivative (NU/ICRF 510). In decatenation and relaxation assays with purified enzyme, several compounds were shown to be potent catalytic inhibitors of topo II (100% inhibition at 5 micrograms/mL (10-15 microM) or less) without stabilizing cleavable complex formation. These included the three DNA binding species (of which NU/ICRF 506 was the most active) and a dihydroxyphenylalanine analogue (NU/ICRF 513). Both NU/ICRFs 500 and 506 were further shown to antagonize DNA cleavage induced by amsacrine. Only NU/ICRF 506 unequivocally inhibited the catalytic activity of topo I without induction of DNA cleavage, and was the only combined topo I and II catalytic inhibitor. One compound, NU/ICRF 505 (tyrosine conjugate), stabilized topo I cleavable complexes without inhibiting the catalytic activity of topo I and II. Modifications to the structure of NU/ICRF 505 revealed that the presence of an unhindered hydroxyl on the tyrosine ring and a more hydrophobic ethyl ester at the amino acid C-terminal were both essential, suggesting a highly specific interaction between drug, enzyme and DNA in the ternary complex. Molecular modelling studies suggested that the observed differences in topo inhibition are a consequence of major conformational alterations brought about by small changes in the amino acid substituent, and confirmed a rigid structural requirement for the induction of topo I cleavage, in addition to a less rigid structural requirement for topo II inhibition. A strong correlation was observed between topo inhibition and in vitro cytotoxicity against the human ovarian cancer cell line A2780 (IC50 range 3.4-11.6 microM), suggesting a mechanism of cell kill, at least in part, involving topo inhibition.
Affiliation:
Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Citation:
Biochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates. 1995, 49 (12):1747-57 Biochem. Pharmacol.
Journal:
Biochemical Pharmacology
Issue Date:
16-Jun-1995
URI:
http://hdl.handle.net/10541/97469
DOI:
10.1016/0006-2952(95)00086-F
PubMed ID:
7598737
Type:
Article
Language:
en
ISSN:
0006-2952
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMeikle, Ien
dc.contributor.authorCummings, Jeffreyen
dc.contributor.authorMacpherson, J Sen
dc.contributor.authorHadfield, John Aen
dc.contributor.authorSmyth, J Fen
dc.date.accessioned2010-04-27T14:48:48Z-
dc.date.available2010-04-27T14:48:48Z-
dc.date.issued1995-06-16-
dc.identifier.citationBiochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates. 1995, 49 (12):1747-57 Biochem. Pharmacol.en
dc.identifier.issn0006-2952-
dc.identifier.pmid7598737-
dc.identifier.doi10.1016/0006-2952(95)00086-F-
dc.identifier.urihttp://hdl.handle.net/10541/97469-
dc.description.abstractMono-conjugation of an anthraquinone nucleus with a range of naturally occurring amino acids chemically modified at their C-terminus has been adopted as a synthetic approach in the rational design of novel topoisomerase (topo) inhibitors. The biochemistry of topo I and II inhibition has been investigated for a series of 16 new compounds (NU/ICRF 500-515) from which structure-activity relationships have been investigated. Only three compounds could be demonstrated to bind to DNA: two serine derivatives (NU/ICRFs 500 and 506) and an arginine derivative (NU/ICRF 510). In decatenation and relaxation assays with purified enzyme, several compounds were shown to be potent catalytic inhibitors of topo II (100% inhibition at 5 micrograms/mL (10-15 microM) or less) without stabilizing cleavable complex formation. These included the three DNA binding species (of which NU/ICRF 506 was the most active) and a dihydroxyphenylalanine analogue (NU/ICRF 513). Both NU/ICRFs 500 and 506 were further shown to antagonize DNA cleavage induced by amsacrine. Only NU/ICRF 506 unequivocally inhibited the catalytic activity of topo I without induction of DNA cleavage, and was the only combined topo I and II catalytic inhibitor. One compound, NU/ICRF 505 (tyrosine conjugate), stabilized topo I cleavable complexes without inhibiting the catalytic activity of topo I and II. Modifications to the structure of NU/ICRF 505 revealed that the presence of an unhindered hydroxyl on the tyrosine ring and a more hydrophobic ethyl ester at the amino acid C-terminal were both essential, suggesting a highly specific interaction between drug, enzyme and DNA in the ternary complex. Molecular modelling studies suggested that the observed differences in topo inhibition are a consequence of major conformational alterations brought about by small changes in the amino acid substituent, and confirmed a rigid structural requirement for the induction of topo I cleavage, in addition to a less rigid structural requirement for topo II inhibition. A strong correlation was observed between topo inhibition and in vitro cytotoxicity against the human ovarian cancer cell line A2780 (IC50 range 3.4-11.6 microM), suggesting a mechanism of cell kill, at least in part, involving topo inhibition.en
dc.language.isoenen
dc.subject.meshAmino Acids-
dc.subject.meshAnthracenes-
dc.subject.meshBase Sequence-
dc.subject.meshCatalysis-
dc.subject.meshCell Survival-
dc.subject.meshDNA-
dc.subject.meshDNA Topoisomerases, Type I-
dc.subject.meshDNA Topoisomerases, Type II-
dc.subject.meshHela Cells-
dc.subject.meshHumans-
dc.subject.meshHydrolysis-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMolecular Structure-
dc.subject.meshStructure-Activity Relationship-
dc.titleBiochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates.en
dc.typeArticleen
dc.contributor.departmentImperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.en
dc.identifier.journalBiochemical Pharmacologyen

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