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The design and synthesis of anti-inf...

Londregan, Allyn Timothy.

The design and synthesis of anti-infective agents based on manzamine A.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The design and synthesis of anti-infective agents based on manzamine A.
Author:	Londregan, Allyn Timothy.
Description:	381 p.
Notes:	Adviser: Jeffrey D. Winkler.
Notes:	Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3803.
Contained By:	Dissertation Abstracts International67-07B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3225495
ISBN:	9780542799709

The design and synthesis of anti-infective agents based on manzamine A.
Londregan, Allyn Timothy.

The design and synthesis of anti-infective agents based on manzamine A. - 381 p.

Adviser: Jeffrey D. Winkler.

Thesis (Ph.D.)--University of Pennsylvania, 2006.

*Please refer to dissertation for diagrams.

ISBN: 9780542799709Subjects--Topical Terms:

193634
Chemistry, Organic.

The design and synthesis of anti-infective agents based on manzamine A.
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245 1 4 $a The design and synthesis of anti-infective agents based on manzamine A.
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500 $a Adviser: Jeffrey D. Winkler.
500 $a Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3803.
502 $a Thesis (Ph.D.)--University of Pennsylvania, 2006.
520 # $a *Please refer to dissertation for diagrams.
520 # $a Manzamine A is a complex polycyclic alkaloid that demonstrates potent anti-infective activity against a wide array of infectious diseases and pathogens. Most notably, manzamine A demonstrates high activity (IC50 = 1.55 ng/mL) against the chloroquine-resistant malaria-causing pathogen, Plasmodium falciparum. The promising anti-infective activity of manzamine A provoked us to design and synthesize a series of analogs based on the ABCDE pentacyclic ring system of the natural product.*
520 # $a Our first approach to the synthesis of analog structures utilized a de novo synthetic construction, in which a series of simplified structures were created to analyze systematically the effects of each of the five rings (ABCDE) of manzamine A on the observed anti-malarial activity. A [2+2] photocycloaddition/rearrangement sequence previously developed in our laboratories was used as the key step in the synthesis of the ABCE and BCE systems. Biological evaluation indicated that none of the truncated analogs were more potent than manzamine A against P. falciparum. It seems likely that simplified analogs with complexity comparable to those discussed are unlikely to display activity comparable to that of manzamine A. It likewise appears that manzamine A retains an anti-malarial pharmacophore that is relatively unforgiving with respect to structural simplification.
520 # $a The second approach to the synthesis of analogs relied on the covalent modification of natural manzamine A. The olefins of the D and E rings of manzamine A were subjected to a series of calculated and engineered ring opening metathesis/ring-closing metathesis transformations in an effort to synthesize new analog structures. Some of the new structures demonstrated significant anti-bacterial and anti-protozoal activity with respect to manzamine A. Biological evaluation indicated that analogs created by the covalent modification protocol were superior to those of the de novo-based approach.
520 # $a We have initiated the first serious study into the design and synthesis of manzamine A analogs. The new manzamine-like structures serve as viable chemotherapeutic leads for a variety of infectious diseases. We have also demonstrated the viability of metathesis chemistry as a means of creating novel analogs from a natural product.
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