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Design, synthesis and application of...

Liu, Fei.

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Design, synthesis and application of an adenosine-anchored library in protein kinase recognition.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Design, synthesis and application of an adenosine-anchored library in protein kinase recognition./
作者:	Liu, Fei.
面頁冊數:	180 p.
附註:	Director: David J. Austin.
Contained By:	Dissertation Abstracts International63-03B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046187
ISBN:	0493603999

Design, synthesis and application of an adenosine-anchored library in protein kinase recognition.
Liu, Fei.

Design, synthesis and application of an adenosine-anchored library in protein kinase recognition. - 180 p.

Director: David J. Austin.

Thesis (Ph.D.)--Yale University, 2002.

This dissertation work addresses the issue of specific protein kinase recognition by small molecules at the ATP-binding site.

ISBN: 0493603999Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Design, synthesis and application of an adenosine-anchored library in protein kinase recognition.
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245 1 0 $a Design, synthesis and application of an adenosine-anchored library in protein kinase recognition.
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502 $a Thesis (Ph.D.)--Yale University, 2002.
520 $a This dissertation work addresses the issue of specific protein kinase recognition by small molecules at the ATP-binding site.
520 $a A library of adenosine-anchored small molecules was synthesized using a Rh(II)-mediated 1,3-diploar cycloaddition sequence. This sequence was developed to stereospecifically and convergently bring four building blocks, which are primary amines, carboxylic acids, malonates, and vinyl ethers, to form the [2.2.1] bicyclic core with the four epitopes rigidly projected for space sampling. In order to accommodate biologically relevant structures such as adenosine, necessary synthetic methodologies were developed to allow first efficient access and appropriate protection schemes of the adenosine-containing building blocks and second the incorporation of the nucleoside structures into the transition metal mediated sequence. The deprotection and purification protocols were also optimized to furnish the final library, with the adenosine anchor displayed at each of the four diversity positions. Computational analysis of the conformational properties of a representative library member suggested potentials of ATP-site recognition (Chapter 2).
520 $a This adenosine-anchored library was screened for activity against HER-2 and HER-4, two members of the epidermal growth factor receptor tyrosine protein kinase (EGFR-TPK). HER-2 is a validated molecular target for breast cancer therapy and shares 77% primary sequence identity with HER-4. While adenosine itself shows identical inhibitory activity against HER-2 and HER-4, the attachment of the bicyclic moiety has allowed this library to exhibit different structure-activity profiles against these two sister proteins. The position of anchor attachment onto the [2.2.1] rigid core and the stereochemistry of the probes were found to be influential on both activity and specificity. More detailed kinetic analysis revealed that these molecules interact with the kinases in a competitive manner. One library member exhibited preincubation time-dependent deactivation behavior that may be ATP-site directed, potentially through an irreversible inhibitory mechanism. The activity characteristics of the library strongly suggest stereoselective probing at the triphosphate subsite and establish the initial ground for further computational simulation and future library design (Chapter 3). (Abstract shortened by UMI.)
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