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Targeting topoisomerase II: Two nove...

Godfrey, Murrell.

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Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function./
作者:	Godfrey, Murrell.
面頁冊數:	147 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-07, Section: B, page: 3257.
Contained By:	Dissertation Abstracts International64-07B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3099272

Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function.
Godfrey, Murrell.

Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function. - 147 p.

Source: Dissertation Abstracts International, Volume: 64-07, Section: B, page: 3257.

Thesis (Ph.D.)--The University of Mississippi, 2003.

The focus of this dissertation research is to probe the interactions and targeting strategies of small molecules that have been demonstrated to modulate the catalytic activities of topoisomerase II, one of the most targeted enzymes in the treatment of cancer. Eukaryotic topoisomerases (I and II) are nuclear enzymes that are critical for nuclear functions including replication, transcription, and nucleosome assembly (Bjornsti, 1991; Wang, 1996). Small molecules that alter the catalytic activities of topoisomerase II have been demonstrated to be highly effective as anticancer agents. Anticancer agents may exert their influence on topoisomerase II activity through interactions with DNA or through direct interactions with the enzyme.Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function.
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245 1 0 $a Targeting topoisomerase II: Two novel approaches toward evaluation of drug-induced catalytic changes to topoisomerase II function.
300 $a 147 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-07, Section: B, page: 3257.
500 $a Adviser: David E. Graves.
502 $a Thesis (Ph.D.)--The University of Mississippi, 2003.
520 $a The focus of this dissertation research is to probe the interactions and targeting strategies of small molecules that have been demonstrated to modulate the catalytic activities of topoisomerase II, one of the most targeted enzymes in the treatment of cancer. Eukaryotic topoisomerases (I and II) are nuclear enzymes that are critical for nuclear functions including replication, transcription, and nucleosome assembly (Bjornsti, 1991; Wang, 1996). Small molecules that alter the catalytic activities of topoisomerase II have been demonstrated to be highly effective as anticancer agents. Anticancer agents may exert their influence on topoisomerase II activity through interactions with DNA or through direct interactions with the enzyme.
520 $a Hence, although the targeting of topoisomerase II can occur through markedly different mechanisms the ultimate effects of these interactions result in the enhancement in topoisomerase 11 mediated DNA strand cleavage. This dissertation research probes two mechanisms associated with ligand-induced topoisomerase II poisoning. The objective of the first approach is to design, synthesize and characterize an ethidium-DNA adduct that has been demonstrated to be highly effective in stimulating enzyme-mediated DNA cleavage. In this work, the photoreactive analog of ethidium was directed and covalently attached to the central C-G binding site in the deoxyoligonucleotide duplex, d(ATATCGATAT)2 under controlled experimental conditions. Quantitative and stoichiometric calculations suggest an approximate 1:1 ethidium-d(ATATCGATAT)2 ratio. These studies do demonstrate that the adduct can be prepared in sufficient quantities. As mentioned earlier, not all topoisomerase II poisons bind DNA. The objective of the second part of this dissertation research is to examine the ligand-enzyme interactions of the potent anticancer agent, etoposide (NSC 141540), and selected analogs. The STD-NMR data reported here provide novel information regarding the topoisomerase II-binding epitope of etoposide to the enzyme.
520 $a The results of these studies reveal strong interactions of the A, B, and pendent rings of etoposide with the protein while little or no interactions were observed for the C and D rings nor the sugar or N-alkyl sidechains of etoposide or etoposide analogs. The results of this study provide pivotal insight into the future directions of etoposide design and development.
520 $a The research described in this dissertation investigates the two distinct mechanisms associated with ligand-induced topoisomerase II poisoning. Through this research we hope to gain insights into the basic properties needed to target topoisomerase II that may lead to the design and synthesis of more effective anticancer agents.
590 $a School code: 0131.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Chemistry, Pharmaceutical. $3 550957
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690 $a 0992
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710 2 0 $a The University of Mississippi. $3 1019522
773 0 $t Dissertation Abstracts International $g 64-07B.
790 1 0 $a Graves, David E., $e advisor
790 $a 0131
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3099272