An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata
| Autor: | Amanda L. Waters, Frederick A. Valeriote, Bin Wang, Mark T. Hamann |
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| Rok vydání: | 2015 |
| Předmět: |
Natural product
Stereochemistry Cost-Benefit Analysis Hydrolysis Biophysics Eutrophication Biochemistry Semisynthesis Coupling reaction Article chemistry.chemical_compound Structure-Activity Relationship chemistry Succinimide Chlorophyta Amide Yield (chemistry) Depsipeptides Peptide synthesis Molecular Biology |
| Zdroj: | Biochimica et biophysica acta. 1850(9) |
| ISSN: | 0006-3002 |
| Popis: | Background Kahalalide F (KF) and its isomer iso-kahalalide F (isoKF), both of which can be isolated from the mollusk Elysia rufescens and its diet alga Bryopsis pennata , are potent cytotoxic agents that have advanced through five clinical trials. Due to a short half-life, narrow spectrum of activity, and a modest response in patients, further efforts to modify the molecule are required to address its limitations. In addition, due to the high cost in producing KF analogues using solid phase peptide synthesis (SPPS), a degradation and reconstruction approach was employed using natural KF from a seasonal algal bloom to generate KF analogues. Methods N -protected KF was carefully hydrolyzed at the amide linkage between l -Thr12 and d -Val13 using dilute HCl. The synthesis of the C -terminal fragment began with the formation of hexanoic succinimide ester, followed by a reaction with dipeptides. The final coupling reaction was performed between the semisynthesized Fmoc–KF hydrolysis product and the C -terminal fragment, followed by the deprotection of the Fmoc group. Results Six KF analogues with an addition of an amino acid residue on the N -terminal chain, d -Val14–isoKF (2) , Val13–Val14–isoKF (3) , d -Leu14–isoKF (4) , d -Pro14–isoKF (5) , d -Phe14–isoKF (6) , and 3,4-2F- d -Phe14-isoKF (7) were prepared using semisynthesis at the exposed N -terminal chain. Conclusions The overall yield of the medication was 45%. This approach is economical, efficient and amendable to large-scale production while eliminated a nuisance algal bloom. General significance B. pennata blooms are capable of producing KF in good yields. The semisynthesis from the natural product produced N -terminal modifications for the construction of inexpensive semisynthetic KF libraries. |
| Databáze: | OpenAIRE |
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