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1tl8

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[[Image:1tl8.gif|left|200px]]
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[[Image:1tl8.png|left|200px]]
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{{STRUCTURE_1tl8| PDB=1tl8 | SCENE= }}
{{STRUCTURE_1tl8| PDB=1tl8 | SCENE= }}
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'''Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex'''
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===Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex===
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==Overview==
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Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I inhibitor and also displays very high cytotoxicity in the NCI cancer cell culture screen (mean graph midpoint of 50 nM). The X-ray crystal structure of norindenoisoquinoline 14 in complex with topoisomerase I and DNA has been solved, providing insight into the structure-activity relationships within this class of new anticancer agents. The number and position of the norindenoisoquinoline substituents have a significant influence on biological activity and demonstrate that substitution on the nitrogen atom is not an absolute requirement for the antitumor effect of the indenoisoquinolines. Removal of the 11-keto group from the lead compound 1 and replacement of the N-alkyllactam with an unsubstituted pyridine ring causes the indenoisoquinoline ring system to flip over in the DNA-enzyme-inhibitor ternary complex. This allows the nitrogen atom to assume the hydrogen bond acceptor role of the 11-keto group, resulting in hydrogen bonding to Arg364.
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(as it appears on PubMed at http://www.pubmed.gov), where 16033260 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16033260}}
==Disease==
==Disease==
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[[Category: Poison]]
[[Category: Poison]]
[[Category: Topoisomerase i]]
[[Category: Topoisomerase i]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:05:15 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:07:14 2008''

Revision as of 00:07, 28 July 2008

Image:1tl8.png

Template:STRUCTURE 1tl8

Contents

Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex

Template:ABSTRACT PUBMED 16033260

Disease

Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]

About this Structure

1TL8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis., Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M, J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:16033260

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