| Investigation of the mechanism of the interaction of tubulin with derivatives of 2-styrylquinazolin-4(3H)-one. | |
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MedLine Citation:
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PMID: 1944246 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A new class of antimitotic agents, derivatives of 2-styrylquinazolin-4(3H)-one (SQZ), was recently described [J. Med. Chem. 33:1721-1728 (1990)]. Because they appeared to interact at a new ligand binding site on tubulin, we attempted to determine their mechanism of action as inhibitors of tubulin polymerization. Although in initial studies inhibition of colchicine binding was negligible, substantial and competitive inhibition of this reaction could be demonstrated with very short incubation times (less than 5 min), provided that a relatively low colchicine to tubulin ratio was used. The initial apparent failure to inhibit colchicine binding resulted from extremely rapid binding to tubulin and dissociation from tubulin by the SQZ derivatives, in comparison with the slow, temperature-dependent, poorly reversible binding of colchicine. The most inhibitory of the SQZ derivatives in the colchicine binding assay was 6-methyl-2-styrylquinazolin-4(3H)-one (NSC 379310), and its interaction with tubulin, particularly as an inhibitor of colchicine binding, was compared with that of 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (MTPT), because the binding parameters of MTPT with tubulin have been well described. The data indicate that NSC 379310 binds to tubulin and dissociates from the protein about 3 times as rapidly as MTPT. The other SQZ derivatives with equal or greater potency as inhibitors of tubulin polymerization but apparently less potency as inhibitors of colchicine binding presumably bind to and/or dissociate from tubulin even more rapidly than does NSC 379310. |
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Authors:
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C M Lin; G J Kang; M C Roach; J B Jiang; D P Hesson; R F Luduena; E Hamel |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Molecular pharmacology Volume: 40 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 1991 Nov |
Date Detail:
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Created Date: 1991-12-19 Completed Date: 1991-12-19 Revised Date: 2000-12-18 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 827-32 Citation Subset: IM |
Affiliation:
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Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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metabolism* Binding Sites Colchicine / metabolism Guanosine Triphosphate / metabolism Quinazolines / metabolism* Styrenes / metabolism* Tropolone / analogs & derivatives, metabolism Tubulin / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Quinazolines; 0/Styrenes; 0/Tubulin; 4765-58-6/2-styrylquinazolin-4(3H)-one; 533-75-5/Tropolone; 60423-21-4/2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone; 64-86-8/Colchicine; 86-01-1/Guanosine Triphosphate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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