Polyketides represent a class of small molecules that has had an enormous impact on the human condition. Several natural products and derivatives of this class possess a wealth of pharmacological properties from anti-cancer to antibiotic and even anti-cholesterol activity. Standard methods to prepare these molecules include fermentation and total synthesis. This proposal outlines a new method for the general synthesis of polyketides that is inspired by polyketide synthase, the enzymatic machinery that is utilized in Nature to prepare molecules of this class. This method would capitalize on the use of a solid-supported template to elongate a growing polyketide chain via decarboxylative Claisen reactions between thioesters. If successful, this method could lay the groundwork for an iterative, standardized method for the synthesis polyketides, opening avenues for automated synthesis of natural products and derivatives thereof.

Public Health Relevance

Polyketides such as the tetracyclines, the erythromycins, and the epothilones possess a wealth of pharmacological properties including anti-cancer, antibiotic and anti-cholesterol activity. This proposal outlines a new method for the general synthesis of polyketides that is designed to lay the groundwork for a standardized way to access these molecules to further advance their medicinal potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM099233-03
Application #
8539048
Study Section
Special Emphasis Panel (ZRG1-F04A-G (20))
Program Officer
Lees, Robert G
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$52,190
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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Wright, Peter M; Seiple, Ian B; Myers, Andrew G (2014) The evolving role of chemical synthesis in antibacterial drug discovery. Angew Chem Int Ed Engl 53:8840-69