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Ruthenium half-sandwich complexes as...

Pagano, Nicholas.

Ruthenium half-sandwich complexes as protein kinase inhibitors.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Ruthenium half-sandwich complexes as protein kinase inhibitors.
作者:	Pagano, Nicholas.
面頁冊數:	606 p.
附註:	Source: Dissertation Abstracts International, Volume: 70-10, Section: B, page: .
附註:	Adviser: Eric Meggers.
Contained By:	Dissertation Abstracts International70-10B.
標題:	Chemistry, Biochemistry.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3381770
ISBN:	9781109430141

Ruthenium half-sandwich complexes as protein kinase inhibitors.
Pagano, Nicholas.

Ruthenium half-sandwich complexes as protein kinase inhibitors. - 606 p.

Source: Dissertation Abstracts International, Volume: 70-10, Section: B, page: .

Thesis (Ph.D.)--University of Pennsylvania, 2009.

Since 2004, the Meggers group has established strategies for the design of protein kinase inhibitors by morphing indolocarbazole alkaloids (i.e. staurosporine) into chemically inert metallo-organic compounds. Ruthenium half-sandwich constructions bearing pyridocarbazole, cyclopentadienyl and carbon monoxide building blocks have been identified as highly potent and extremely selective inhibitors for Pim-1 and GSK-3. Synthetic modification of this scaffold for the development of improved inhibitors for these and other kinases is the topic of this thesis.*

ISBN: 9781109430141Subjects--Topical Terms:

226900
Chemistry, Biochemistry.

Ruthenium half-sandwich complexes as protein kinase inhibitors.
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245 1 0 $a Ruthenium half-sandwich complexes as protein kinase inhibitors.
300 $a 606 p.
500 $a Source: Dissertation Abstracts International, Volume: 70-10, Section: B, page: .
500 $a Adviser: Eric Meggers.
502 $a Thesis (Ph.D.)--University of Pennsylvania, 2009.
520 $a Since 2004, the Meggers group has established strategies for the design of protein kinase inhibitors by morphing indolocarbazole alkaloids (i.e. staurosporine) into chemically inert metallo-organic compounds. Ruthenium half-sandwich constructions bearing pyridocarbazole, cyclopentadienyl and carbon monoxide building blocks have been identified as highly potent and extremely selective inhibitors for Pim-1 and GSK-3. Synthetic modification of this scaffold for the development of improved inhibitors for these and other kinases is the topic of this thesis.*
520 $a In Chapter 2, a third generation strategy for the synthesis of the pyridocarbazole ligand is presented. From this, the synthesis of over a dozen modified complexes is described. The influence of new pyridocarbazole substituents on potency and selectivity for GSK-3 and Pim-1 is also investigated. From this, ruthenium pyridocarbazole 2.48 was discovered as the first organometallic picomolar inhibitor for GSK-3 (0.3 nM, 100 muM ATP), also displaying an excellent cellular potency against certain cancer cell lines.*
520 $a In Chapter 3, work towards the synthesis of a potential femtomolar inhibitor for GSK-3 is disclosed. With an IC50 value of at least 40 pM, ( RRu)-3.1 is one of the highest affinity ligands for a protein kinase known to date. Furthermore, a co-crystal structure of (RRu)-3.1 bound in the ATP-site of GSK-3beta was successfully solved and refined to 2.4 A.*
520 $a In Chapter 4, utilization of a library of organometallic scaffolds assists in the discovery of two novel kinase targets. Ruthenium pyridocarbazole ( RRu)-4.5 was determined to be a 45 nM inhibitor for MST-1 (100 microM ATP) and displays a promising selectivity profile when compared to other closely related Ste-20 kinases. In addition, ruthenium pyridocarbazole (SRu)-4.13a was determined to be a 30 nM inhibitor for TrkA (100 muM ATP) displaying an outstanding selectivity profile in a panel of 50 kinases.*
520 $a In Chapter 5, synthetic access to the class of lactam ruthenium pyridocarbazoles is presented. Previous binding preferences of the half-sandwich scaffold have switched from GSK-3/Pim-1 selectivity to MLCK/TrkA and CLK-2/PKG-1beta selectivity. In addition, with an IC50 value of 6 nM against TrkA (100 muM ATP) and remarkable selectivity over GSK-3, MLCK, and Pim-1, lactam ruthenium pyridocarbazole (RRu)-5.28 has the potential to be the most selective inhibitor for TrkA yet reported.*
520 $a *Please refer to dissertation for diagrams.
590 $a School code: 0175.
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650 4 $a Chemistry, Inorganic. $3 197298
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