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Synthetic study of C-1027-CHR.

Jiang, Yu.

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Synthetic study of C-1027-CHR.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Synthetic study of C-1027-CHR./
Author:	Jiang, Yu.
Description:	265 p.
Notes:	Source: Dissertation Abstracts International, Volume: 63-10, Section: B, page: 4681.
Contained By:	Dissertation Abstracts International63-10B.
Subject:	Chemistry, Organic. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3067150
ISBN:	0493866280

Synthetic study of C-1027-CHR.
Jiang, Yu.

Synthetic study of C-1027-CHR. - 265 p.

Source: Dissertation Abstracts International, Volume: 63-10, Section: B, page: 4681.

Thesis (Ph.D.)--Princeton University, 2003.

The enediyne natural products are potent cytotoxins which target DNA as a primary biological substrate, causing double or single stranded cleavage. Cycloaromatization of the enediyne unit to a 1,4-arene diradical, which subsequently abstracts hydrogen atoms from the DNA sugar-phosphate backbone is the accepted mechanism by which these compounds render cytotoxicity.

ISBN: 0493866280Subjects--Topical Terms:

516206
Chemistry, Organic.

Synthetic study of C-1027-CHR.
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035 $a (UnM)AAI3067150
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100 1 $a Jiang, Yu. $3 1028945
245 1 0 $a Synthetic study of C-1027-CHR.
300 $a 265 p.
500 $a Source: Dissertation Abstracts International, Volume: 63-10, Section: B, page: 4681.
500 $a Adviser: Martin Semmelhack.
502 $a Thesis (Ph.D.)--Princeton University, 2003.
520 $a The enediyne natural products are potent cytotoxins which target DNA as a primary biological substrate, causing double or single stranded cleavage. Cycloaromatization of the enediyne unit to a 1,4-arene diradical, which subsequently abstracts hydrogen atoms from the DNA sugar-phosphate backbone is the accepted mechanism by which these compounds render cytotoxicity.
520 $a The mechanism of activation for C-1027 is still not clear. Several proposed mechanisms of activation for C-1027 are reviewed in chapter 1, which are based both on molecular modeling and incomplete experimental support. Our goal is the synthesis of the natural enediyne C-1027-chr and its functional analogs. A total synthesis would alleviate the problem of the limited supply of the natural product while the designed models offer an opportunity to test possible mechanisms of activation. New enediyne analogies based on a full understanding of the mechanism might improve potency and selectivity in the action of these compounds.
520 $a The synthesis of the beta-amino acid C is presented in chapter 2. The key steps include the enantioselective Michael addition of an amide anion to an alpha,beta-unsaturated ester and selective debenzylation. The structure of the final compound was confirmed by X-ray crystallography. An efficient coupling reaction between the beta-amino acid and the enediyne core structure A under mild conditions was demonstrated on a model system.
520 $a A study of the synthesis of the enediyne core structure A and its analogs is presented in chapter 3. The key step is the cyclization step to form a highly strained cyclic 9-membered enediyne molecule. Several model enediynes were synthesized. Among several cyclization methodologies tested on those models, the chromium chloride/nickel chloride mediated cyclization between an aldehyde and an iodoacetylene showed the highest efficiency and consistency. Nevertheless, the technology for the key cyclization step is not fully satisfactory. The Bergman rearrangement of the model enediynes was demonstrated to he fast at room temperature by NMR study. The masked cyclopentene moiety of the part A was synthesized.
520 $a The synthesis of the amino sugar B is presented in chapter 4. The key steps include an oxidation of a primary alcohol at C-6 to either aldehyde or ester in the presence of a 4-amino group and double methylation at the C-5 position with an ester at the alpha position. The structure of an unexpected beta-lactam product was established by X-ray diffraction. The structure of the final product was confirmed by comparison NMR spectra data with that of the natural product.
590 $a School code: 0181.
650 4 $a Chemistry, Organic. $3 516206
650 4 $a Health Sciences, Oncology. $3 1018566
690 $a 0490
690 $a 0992
710 2 0 $a Princeton University. $3 645579
773 0 $t Dissertation Abstracts International $g 63-10B.
790 1 0 $a Semmelhack, Martin, $e advisor
790 $a 0181
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3067150