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The design, synthesis, and prelimina...

Horan, Joshua Courtney.

The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs.
Author:	Horan, Joshua Courtney.
Description:	302 p.
Notes:	Adviser: Paul A. Wender.
Notes:	Source: Dissertation Abstracts International, Volume: 66-11, Section: B, page: 5983.
Contained By:	Dissertation Abstracts International66-11B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3197444
ISBN:	9780542431418

The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs.
Horan, Joshua Courtney.

The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs. - 302 p.

Adviser: Paul A. Wender.

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

An optimized synthesis to an important intermediate in the production of a lead analog was developed. The optimized route was used to produce gram amounts of the intermediate, which have been used to synthesize additional quantities of the lead analog as well as to supply further analog development. Additionally, new simplified analogs with modified A-ring regions were designed and synthesized. These analogs incorporate a sterically demanding tert-butyl, phenyl, or bromo-phenyl substituent as an isosteric replacement for the A-ring of the natural product. The bromo-phenyl group was used as a handle for late-stage diversification to generate additional analogs in a single step using cross-coupling chemistry. The A-ring modified analogs all exhibit low nanomolar affinity for PKC. Two analogs with modified B-ring regions were also designed and synthesized. These analogs incorporate a substituent on the B-ring to mimic an unsaturated ester found in the natural product. These compounds were synthesized using a common synthetic route that diverged at a late stage to provide access to the two analogs. These analogs exhibit greater affinity for PKC than bryostatin 1.

ISBN: 9780542431418Subjects--Topical Terms:

193634
Chemistry, Organic.

The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs.
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100 0 $a Horan, Joshua Courtney. $3 244994
245 1 4 $a The design, synthesis, and preliminary biological evaluation of structurally simplified bryostatin analogs.
300 $a 302 p.
500 $a Adviser: Paul A. Wender.
500 $a Source: Dissertation Abstracts International, Volume: 66-11, Section: B, page: 5983.
502 $a Thesis (Ph.D.)--Stanford University, 2006.
520 # $a An optimized synthesis to an important intermediate in the production of a lead analog was developed. The optimized route was used to produce gram amounts of the intermediate, which have been used to synthesize additional quantities of the lead analog as well as to supply further analog development. Additionally, new simplified analogs with modified A-ring regions were designed and synthesized. These analogs incorporate a sterically demanding tert-butyl, phenyl, or bromo-phenyl substituent as an isosteric replacement for the A-ring of the natural product. The bromo-phenyl group was used as a handle for late-stage diversification to generate additional analogs in a single step using cross-coupling chemistry. The A-ring modified analogs all exhibit low nanomolar affinity for PKC. Two analogs with modified B-ring regions were also designed and synthesized. These analogs incorporate a substituent on the B-ring to mimic an unsaturated ester found in the natural product. These compounds were synthesized using a common synthetic route that diverged at a late stage to provide access to the two analogs. These analogs exhibit greater affinity for PKC than bryostatin 1.
520 # $a The bryostatins are a family of polyketide natural products isolated from the marine bryozoan Bugula neritina. Bryostatin 1, which is currently in Phase I and II clinical trials for the treatment of cancer, has been shown to elicit a remarkable array of biological activities, including the ability to inhibit cancer cell growth, induce apoptosis, reverse multi-drug resistance, stimulate the immune system, synergize with other agents, reduce amyloid beta-protein formation, and enhance memory and learning. Despite its promising activity, the widespread use of bryostatin as a therapeutic agent is limited by its low natural abundance, which prohibits its large-scale isolation. Furthermore, the complexity of the natural product prohibits its practical production through total synthesis. The supply problem can be addressed through the development of simplified analogs that retain the function of the natural product and that can be synthesized in a practical manner. Analog design could not only provide material for therapeutic use, but also allow for the synthesis of compounds optimized for therapeutic efficacy.
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791 $a Ph.D.
792 $a 2006
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