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Synthesis and evaluation of 2,3-dihy...

Chinigo, Gary Michael.

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Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation./
Author:	Chinigo, Gary Michael.
Description:	225 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5069.
Contained By:	Dissertation Abstracts International67-09B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3235027
ISBN:	9780542881435

Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation.
Chinigo, Gary Michael.

Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation. - 225 p.

Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5069.

Thesis (Ph.D.)--University of Virginia, 2007.

Dual inhibitors of cancer cell proliferation and angiogenesis have recently shown remarkable potential for the clinical treatment of several cancers. Inspired by this success, we have employed traditional medicinal chemistry techniques to develop a 2,3-dihydroquinazolin-4-one lead molecule with promising anti-proliferative and anti-angiogenic activity. These molecules, which we originally derived from thalidomide, have evolved into an extremely effective (sub-nanomolar) prospective drug candidate for the treatment of cancer.

ISBN: 9780542881435Subjects--Topical Terms:

1017686
Biology, Cell.

Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation.
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100 1 $a Chinigo, Gary Michael. $3 1920287
245 1 0 $a Synthesis and evaluation of 2,3-dihydroquinazolinones as dual inhibitors of angiogenesis and cancer cell proliferation.
300 $a 225 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5069.
500 $a Adviser: Milton Brown.
502 $a Thesis (Ph.D.)--University of Virginia, 2007.
520 $a Dual inhibitors of cancer cell proliferation and angiogenesis have recently shown remarkable potential for the clinical treatment of several cancers. Inspired by this success, we have employed traditional medicinal chemistry techniques to develop a 2,3-dihydroquinazolin-4-one lead molecule with promising anti-proliferative and anti-angiogenic activity. These molecules, which we originally derived from thalidomide, have evolved into an extremely effective (sub-nanomolar) prospective drug candidate for the treatment of cancer.
520 $a Described herein is an account of the many structural modifications made to this lead compound along with the corresponding effects on competitive 3H colchicine displacement from tubulin, microtubule depolymerization, and cytotoxicity toward several human cancer and endothelial cell lines. From these evaluations we were able to design 3rd generation analogs with significantly enhanced potency. Subsequent animal testing suggests these molecules are relatively non-toxic, bio-available, and efficacious at treating tumors in vivo---evidence which supports the possibility of our most active analogs being evaluated clinically.
520 $a In addition to the SAR studies, we were compelled to develop synthetic methods enabling us to synthesize the enantiomers of these molecules. Exploration of several different approaches eventually led us to a chiral auxiliary based method of synthesis. Preliminary success led to a more thorough exploration of the scope and limitations of this methodology, and ultimately to the synthesis of the R and S enantiomers of both the lead and our most active molecule. Related X-ray crystal structure and biological studies conclusively point to the S isomer as the biologically active enantiomer. Finally, by using molecular modeling in conjunction with all the data gathered thus far, we have developed a hypothesis regarding the likely mode of interaction between tubulin and the molecules in this study.
590 $a School code: 0246.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Chemistry, Organic. $3 516206
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Health Sciences, Oncology. $3 1018566
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710 2 0 $a University of Virginia. $3 645578
773 0 $t Dissertation Abstracts International $g 67-09B.
790 1 0 $a Brown, Milton, $e advisor
790 $a 0246
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3235027