Chemistry and Biology of Kahalalides

Gao, Jiangtao; Hamann, Mark T.

doi:10.1021/cr100187n

Cited by 68 publications

(69 citation statements)

References 76 publications

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“…KF is a promising anticancer compound that has been extracted from both Elysia rufescens and Bryopsis species (44). The bioactive compounds associated with E. rufescens are well investigated (45)(46)(47), and preliminary data revealed that two strains of Vibrio species isolated from E. rufescens produce the compound KF, with production confirmed by liquid chromatography-mass spectrometry (LCMS) and nuclear magnetic resonance (NMR) (48). However, recent attempts to isolate KF from cultured Vibrio strains have given inconsistent results, and more studies are needed to unequivocally determine the organism(s) responsible for the production of KF.…”

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confidence: 99%

Characterization of the Bacterial Community of the Chemically Defended Hawaiian Sacoglossan Elysia rufescens

Davis

Fricke

Hamann

et al. 2013

Appl Environ Microbiol

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dSacoglossans are characterized by the ability to sequester functional chloroplasts from their algal diet through a process called kleptoplasty, enabling them to photosynthesize. The bacterial diversity associated with sacoglossans is not well understood. In this study, we coupled traditional cultivation-based methods with 454 pyrosequencing to examine the bacterial communities of the chemically defended Hawaiian sacoglossan Elysia rufescens and its secreted mucus. E. rufescens contains a defense molecule, kahalalide F, that is possibly of bacterial origin and is of interest because of its antifungal and anticancer properties. Our results showed that there is a diverse bacterial assemblage associated with E. rufescens and its mucus, with secreted mucus harboring higher bacterial richness than entire-E. rufescens samples. The most-abundant bacterial groups affiliated with E. rufescens and its mucus are Mycoplasma spp. and Vibrio spp., respectively. Our analyses revealed that the Vibrio spp. that were highly represented in the cultivable assemblage were also abundant in the culture-independent community. Epifluorescence microscopy and matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS) were utilized to detect the chemical defense molecule kahalalide F on a longitudinal section of the sacoglossan.

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confidence: 99%

Characterization of the Bacterial Community of the Chemically Defended Hawaiian Sacoglossan Elysia rufescens

Davis

Fricke

Hamann

et al. 2013

Appl Environ Microbiol

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“…The activity of KF was then investigated in Phase II clinical studies with patients having liver, non-small-cell lung cancer (Provencio et al, 2009) and melanoma. KF has also been tested in Phase II clinical trials for severe psoriasis (Gao and Hamann, 2011). IsoKF (elisidepsin, PM02734; Irvalec), the 4S-methylhexanoic isomer of KF, currently obtained via synthetic process, has been developed by PharmaMar in a Phase II clinical study (Serova et al, 2013).…”

Section: Kahalalide F: a Study In Chemical Ecology As A Starting Poinmentioning

confidence: 99%

“…The exposure of breast, vulval and hepatic human tumor cell lines to KF induced a downregulation of protein expression levels of ErbB3 (Janmaat et al, 2005). Detailed information on the biological activities, mechanism of action and clinical status of KF is provided in an excellent review (Gao and Hamann, 2011).…”

Section: Kahalalide F: a Study In Chemical Ecology As A Starting Poinmentioning

confidence: 99%

Marine Peptide Secondary Metabolites

Banaigs

Bonnard

Witczak

et al. 2014

Outstanding Marine Molecules

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A large pro port ion of the marine natural produc ts actu ally u n der clinical inve stigat ion are pept ide sec ondary metabolites with unusual amino acids re sidues. This growing f amily of compounds can be produced via tw o major p athw ays, r ibosomal and nonribosomal. In this c hapt er a re p re sent ed a nd illu strated, with a fe w f amou s examples, ribosomal-and n onribosomal-d erived pe ptides. Atte ntion is focused on fi ve families of biological ly a ctive marine p eptides of d iverse origin, ranging from the old est living ce ll of the world, the cyanobact eria, to more sophisticat ed organisms s uch a s tu nicates or mol lusk s. T he discu ssed pe ptides illu strate d iff erently th e s tructural fe atu re s and diversity f ound in mari ne-derived peptid es; laxaphycins as an example o f true pept ide s; dolast atins, didemnins and kahalalides are discuss ed in connectio n wit h their cl inical trials; a nd azole/azoli ne-c ontaining cyanobactins to exe m plif y the extra ord ina ry c hemi cal dive rs it y wit hin a single organism. Information abou t their biol ogical properties and mec hanisms of a ctio n is disc uss ed when available .

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“…Unfortunately, the lead was dropped from phase II clinical trials due to a lack of efficacy despite results indicating a limited number of patients achieved a positive response. [11] The pharmacokinetic studies suggested that KF has a short half-life (approximately 30 min),[11] which could in part be the reason for its poor efficacy. However, no further studies have provided evidence of KF degradation products in vivo.…”

Section: Introductionmentioning

confidence: 99%

An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata

Wang¹,

Waters²,

Valeriote³

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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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 dVal13 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. 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. This approach is economical, efficient and amendable to large-scale production while eliminated a nuisance algal bloom.

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Chemistry and Biology of Kahalalides

Cited by 68 publications

References 76 publications

Characterization of the Bacterial Community of the Chemically Defended Hawaiian Sacoglossan Elysia rufescens

Characterization of the Bacterial Community of the Chemically Defended Hawaiian Sacoglossan Elysia rufescens

Marine Peptide Secondary Metabolites

An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata

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