Total Synthesis of Apratoxin A Analogues

Apratoxin A is a potent cytotoxic compound that was isolated from the marine cyanobacterium Lygbya majuscula by Moore, Paul, and co-workers and reported in 2001. Structurally, this natural product is a macrocyclic depsipeptide that contains an unprecedented polyketide domain and a heavily methylated polypeptide domain. The biological mode of action of apratoxin A, to date, has not been fully elucidated. In addition, the mode of action cannot be correlated with any of the standard anti-cancer agents in the National Cancer Institute’s library, which suggests a unique mode of action. Herein are reported our efforts towards discovering an apratoxin A analogue that retains its anti-cancer activity, but eliminates its action against normal cells. We have developed an efficient synthetic route towards the oxazoline analogue of apratoxin A that relies upon a late stage installation of the oxazoline moiety. The convergent nature of the synthetic route has provided us with access to several oxazoline analogues that will be assayed for anti-cancer activity. Also, a second generation synthesis of oxazoline analogues has been developed, which shortens the overall synthetic route and eliminates late stage epimerization problems seen in the original synthesis of oxazoline apratoxin A. In addition, we have developed a reliable synthetic route to an oxazoline analogue that contains a polyethylene glycol domain, which terminates with an azide. The azide has been successfully used in a 1,3-dipolar cycloaddition with a biotinylated alkyne, which will be assayed to help determine the molecular targets of apratoxin A. Furthermore, the polyethylene glycol azide provides us with a handle to install additional biological tags.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

The Ohio State University

Year dc:date

2012

Author dc:creator

• Jackel, Matthew D.

Contributors dc:contributor

• Forsyth, Craig

• Chemistry
• Organic Chemistry

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=osu1355865894

OAI identifier oai:identifier

oai:etd.ohiolink.edu:osu1355865894