In vitro and in vivo evaluation of select kahalalide F analogs with antitumor and antifungal activities

Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (−)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (−)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1–5 (TH 1–5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the afore-mentioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The prospects of employing them in clinical practice are promising in view of the wealth of these compounds from marine organisms. The compounds may also be used in agriculture and the food industry.

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“…These compounds displayed antifungal activities against C. albicans and C. neoformans both in vitro and in vivo (Shilabin and Hamann 2011). …”

Section: Antifungal Productsmentioning

confidence: 99%

Antifungal and antiviral products of marine organisms

Cheung

Wong

Pan

et al. 2014

Appl Microbiol Biotechnol

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“…Of the hundreds of KF analogues produced by different research groups, only two modifications on the L -Orn residue showed a similar or higher potency in selected cancer cell lines. [14],[15] Perhaps it will be necessary to reconsider the KF modification approach focusing on improving the short half-life instead of increasing its potency. Much has been learned about the optimization of half-life, metabolism and bioavailability from the 15 year journey leading to the development for capsofungin (Cancidas®), the first in class antifungal derived from the echinocandins.…”

Section: Discussionmentioning

confidence: 99%

“…Our group has modified natural KF at the Orn- residue which yielded two molecules with a similar or higher potency in selected cancer cell lines. [14],[15] In this report we provide an approach to produce modified KF analogues with additional amino acid residues on the N- terminal side chain after removal of the terminal fatty acid by selective hydrolysis between threonine and valine.…”

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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“…The original discoverer of this group of compounds published an interesting paper on selected kahalalide F analogs with antitumor and antifungal activities in 2011 [87], and recently in the middle of 2012, PharmaMar stopped development of the kahalalide derivative 1-[ N -[(4 S )-4-methyl-1-oxohexyl]- d -valine]-kahalalide F which they were developing as an antitumor agent under the generic name elisidepsin and trade name of Irvalec ® [82], even though it had activity in gastroesophageal tumors. This appeared to be a business decision due to the very low numbers of potential patients.…”

Section: Other Marine-derived Compounds In Clinical Trials Againstmentioning

confidence: 99%

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

2014

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The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.

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In vitro and in vivo evaluation of select kahalalide F analogs with antitumor and antifungal activities

Cited by 34 publications

References 19 publications

Antifungal and antiviral products of marine organisms

Antifungal and antiviral products of marine organisms

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

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

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