Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 9, Pages 2587-2590Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.02.079
Keywords
Polyamine; Chemical stability; Combinatorial synthesis; Immunosuppression; Peptoid; Antibacterials
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Funding
- Cellular Biotechnology Training Grant [GM008353]
- NIH [NS059690]
- NSF [MCB-0844512]
- Biogerontology Training Grant [AG000114]
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Spergualin is a natural product that exhibits immunosuppressive, anti-tumor and anti-bacterial activities. Its derivatives, such as 15-deoxyspergualin (15-DSG), have been clinically approved for acute allograft rejection. However, the reported syntheses are cumbersome (>10 steps) and they suffer from low overall yields (similar to 0.3% to 18%). Moreover, spergualin and its derivatives are chemically unstable and rapidly hydrolyzed in aqueous buffer. Here, we have re-explored these issues and report a modified synthetic route with significantly improved overall yield (similar to 31% to 47%). The key transformation is a microwave-accelerated Ugi multi-component reaction that is used to generate the peptoid core in a single step. Using the products of this route, we found that modifications of the hemiaminal significantly increased chemical stability. Thus, we anticipate that this synthetic route will improve access to biologically active 15-DSG derivatives. (C) 2011 Elsevier Ltd. All rights reserved.
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