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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'''
| | ===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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16033260}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16033260 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16033260}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Poison]] | | [[Category: Poison]] |
| [[Category: Topoisomerase i]] | | [[Category: Topoisomerase i]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:05:15 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:07:14 2008'' |
