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Synthetic and biosynthetic studies t...

Lee, Taek Soon.

Synthetic and biosynthetic studies toward novel aromatic polyketides.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Synthetic and biosynthetic studies toward novel aromatic polyketides.
Author:	Lee, Taek Soon.
Description:	316 p.
Notes:	Adviser: Chaitan Khosla.
Notes:	Source: Dissertation Abstracts International, Volume: 67-05, Section: B, page: 2558.
Contained By:	Dissertation Abstracts International67-05B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3219319
ISBN:	9780542707544

Synthetic and biosynthetic studies toward novel aromatic polyketides.
Lee, Taek Soon.

Synthetic and biosynthetic studies toward novel aromatic polyketides. - 316 p.

Adviser: Chaitan Khosla.

Thesis (Ph.D.)--Stanford University, 2006.

Mumbaistatin is an anthraquinone natural product isolated in 1997 from cultures of soil bacteria with a very poor yield (70 mg/1000 L). It is the most potent known natural inhibitor (IC50 = 5 nM) of glucose-6-phosphate translocase (G6P-T1) which is an important target for the treatment of type 2 diabetes. Total synthesis of mumbaistatin has not been successful so far due to the congested structure of the natural product and the complex substituents pattern of the anthraquinone ring moiety. Interestingly, the substituents pattern of this anthraquinone is identical to 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid (DMAC), an aromatic polyketide produced by a genetically engineered strain of Streptomyces coelicolor CH999 with a high yield (&sim; 200 mg/L). In this study, several semisynthetic analogues of mumbaistatin have been prepared from biosynthesized DMAC for the structure-activity relationship study of mumbaistatin. As a synthetic model for total synthesis of mumbaistatin, the analogues containing a 6-methylsalicylic acid southern block have been synthesized. Total synthesis of mumbaistatin has also been attempted using DMAC and an advanced precursor for the coupling reaction has been synthesized. However, the further study on the coupling reaction was deterred due to insufficient supply of the material. The optimization of the precursor preparation needs to be further explored.

ISBN: 9780542707544Subjects--Topical Terms:

193634
Chemistry, Organic.

Synthetic and biosynthetic studies toward novel aromatic polyketides.
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100 0 $a Lee, Taek Soon. $3 264150
245 1 0 $a Synthetic and biosynthetic studies toward novel aromatic polyketides.
300 $a 316 p.
500 $a Adviser: Chaitan Khosla.
500 $a Source: Dissertation Abstracts International, Volume: 67-05, Section: B, page: 2558.
502 $a Thesis (Ph.D.)--Stanford University, 2006.
520 # $a Mumbaistatin is an anthraquinone natural product isolated in 1997 from cultures of soil bacteria with a very poor yield (70 mg/1000 L). It is the most potent known natural inhibitor (IC50 = 5 nM) of glucose-6-phosphate translocase (G6P-T1) which is an important target for the treatment of type 2 diabetes. Total synthesis of mumbaistatin has not been successful so far due to the congested structure of the natural product and the complex substituents pattern of the anthraquinone ring moiety. Interestingly, the substituents pattern of this anthraquinone is identical to 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid (DMAC), an aromatic polyketide produced by a genetically engineered strain of Streptomyces coelicolor CH999 with a high yield (&sim; 200 mg/L). In this study, several semisynthetic analogues of mumbaistatin have been prepared from biosynthesized DMAC for the structure-activity relationship study of mumbaistatin. As a synthetic model for total synthesis of mumbaistatin, the analogues containing a 6-methylsalicylic acid southern block have been synthesized. Total synthesis of mumbaistatin has also been attempted using DMAC and an advanced precursor for the coupling reaction has been synthesized. However, the further study on the coupling reaction was deterred due to insufficient supply of the material. The optimization of the precursor preparation needs to be further explored.
520 # $a Polyketides are a large class of structurally and pharmacologically diverse molecules which include a variety of antibiotics and anticancer drugs. Type II polyketide synthases (PKSs) are responsible for the biosynthesis of aromatic polyketides such as frenolicin, and doxorubicin. Synthesis of analogues of existing potent natural products is important due to the need for new drug molecules that have better properties and might be effective against drug-resistant bacteria. In this study, the biosynthesis of known natural products has been engineered to produce analogues of the natural products by regioselective introduction of unnatural primer into the molecule. Engineered bimodular aromatic PKSs have been constructed from a heterologous initiation module and elongation module, and several novel aromatic polyketides were biosynthesized from these engineered enzymes. The biosynthetic potential of bimodular aromatic PKSs has been further exploited through a precursor-directed biosynthesis and novel cyclopropyl-incorporated anthraquinone compound was isolated by supplementation of cyclopropyl alanine.
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650 # 0 $a Chemistry, Organic. $3 193634
650 # 0 $a Engineering, Chemical. $3 226989
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690 $a 0542
710 0 # $a Stanford University. $3 212607
773 0 # $g 67-05B. $t Dissertation Abstracts International
790 $a 0212
790 1 0 $a Khosla, Chaitan, $e advisor
791 $a Ph.D.
792 $a 2006
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