title: An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pharmacognosy, Department of BioMolecular Sciences, The University of Mississippi, University, MS 38677, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Pharmacognosy, Department of BioMolecular Sciences, The University of Mississippi, University, MS 38677, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Waters
authors.affiliation: Henry Ford Health System, Department of Internal Medicine, Division of Hematology and Oncology, Detroit, MI 48202, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.affiliation: Division of Pharmacognosy, Department of BioMolecular Sciences, The University of Mississippi, University, MS 38677, USA; Division of Pharmacology, Department of BioMolecular Sciences, The University of Mississippi, University, MS 38677, USA; Department of Chemistry and Biochemistry and National Center for Natural Products Research, The University of Mississippi, University, MS 38677, USA. Electronic address: mthamann@olemiss.edu.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Hamann
mesh_terms: D000460:Chlorophyta / Q000378:metabolism*; D003362:Cost-Benefit Analysis; D047630:Depsipeptides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D005068:Eutrophication; D006868:Hydrolysis; D013329:Structure-Activity Relationship
chemical_list: D047630:Depsipeptides; C097897:kahalalide F
keywords: Kahalalide F; N-terminal modification; Partial hydrolysis