XIV International Symposium on Marine Natural Products

Cubierta 4:Abstracts 01/08/13 20:01 Página 1

on Marine Natural Products

on Marine Natural Products

14th International Symposium 8th European Conference

14th International Symposium 8th European Conference

September 15th - 20th, 2013 La Toja Island, Galicia Organized by:

Spain

Posters Session 1

Interior POSTERS 1:Abstracts 02/08/13 11:28 Página 62


Monday 16th September, 2013

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THIOCORALINE-TRIOSTIN HYBRIDS Fernando Albericio, Judit Tulla-Puche, Sara Auriemma, Chiara Falciani Institute for Research in Biomedicine, IRB Barcelona, Baldiri Reixac, 10, 08028, Barcelona, Spain E-mail: [email protected]

Posters Session 1

The synthesis and biological activity of hybrid bisintercalators based on triostin A and thiocoraline, and of thiocoraline analogues with decreased hydrophobicity is described. The design of the hybrid analogues was focused on three main aspects: i) the combination of the amino acid sequences; ii) the intercalating heterocycle; iii) the replacement of the natural thioester and also ester moieties by either esters, in the first case, or bridged NMe amides. This last substitution granted, in the case of thiocoraline, an analogue (NMe-azathiocoraline) which retained the same activity as the natural product. The incorporation of “solubilizing residues” in NMe-azathiocoraline, was based on the replacement of the NMe-Cys(Me) moiety, which is thought not to participate in the binding, by an amino side-chain-containing residue [such as diaminopropionic (Dap) or diaminobutiric (Dab) acids], that could remain as a free amino group or be coupled to a PEG group. Solid-phase synthetic strategies based on the concourse of six different amino protecting groups: Fmoc, Boc Alloc, pNZ, o-NBS, and Troc and of a broad range of coupling reagents have been developed. In vitro biological activity as well as structure-activity relationships is discussed.

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14th International Symposium on Marine Natural Products / 8th European Conference on Marine Natural Products


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FIRST SOLID-PHASE SYNTHESIS OF NATURAL ANTITUMORAL THIOCORALINE Fernando Albericio1, Judit Tulla-Puche1, Miriam Gongora-Benítez1, Nuria BayóPuxan1, Andrés M. Francesch2, Carmen Cuevas2 1

Institute for Research in Biomedicine, IRB Barcelona, Baldiri Reixac, 10, 08028 - Barcelona, Spain. 2 PharmaMar, S. A., Avenida de los Reyes, 1, 28770 - Colmenar Viejo, Madrid, Spain. E-mail: [email protected]

The potent antitumoral thiocoraline isolated in 1997 by PharmaMar1 presents a challenging structure: a sequence highly rich in Cys, the presence of consecutive NMeamino acids, and a bicyclic structure formed by a disulfide bridge flanked by two thioester moieties. In addition to the -amino protection, the occurrence of six Cys, combined with the presence of the bisintercalating chromophore, requires the concourse of several protecting groups. However, synthetic strategies totally based on chemicallabile protecting groups have failed for this molecule. The main limitation resides in the formation of the fragile thioester function, which needs to be postponed until the final stages of the synthesis, and usually this formation is incompatible with that of the disulfide bridge. We report herein the first solid-phase synthesis of thiocoraline by using the key enzyme-labile protecting group phenylacetamidomethyl (Phacm).2 Its mild removal conditions allow the formation of the disulfide bridge at the last step of the synthesis in the presence of the already formed thioester moieties.3

1.

(a) F. Romero, F. Espliego, J. Pérez Baz, T. García de Quesada, D. Gravalos, F. De la Calle, J. L. Fernández-Puentes J. Antibiot. 1997, 50, 734-737; (b) J. Pérez Baz, L. M. Canedo, J. L. Fernández Puentes, M. V. Silva Elipe, J. Antibiot. 1997, 50, 738-741.

2.

M. Góngora-Benítez, A. Basso, T. Bruckdorfer, M. Royo, J. Tulla-Puche, F. Albericio, Chem. Eur. J. 2012, 18, 16166-16176.

3.

J. Tulla-Puche, M. Góngora-Benítez, N. Bayó-Puxan, A. M. Francesch, C. Cuevas, F. Albericio, Angew. Chem. Int. Ed. 2013, 52, 5726-5730.


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References

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UNUSUAL U NUSUAL POLYKETIDES POLYKETIDES E F FROM ROM TH THE ES SPONGE-DERIVED PONGEE DERIVED F FUNGUS UNGUS Staachylidium sp. Stachylidium Celso Almeida Allmeida1,1,22, Stefan Steffan Ke Kehraus hraus1 and and Gabriele Gabr a iele Kön König ig2 Celso 1

Institute In stitute ffor or P Pharmaceutical harmaceutical B Biology, iology, University University of of Bonn, Bonn, Germany; Germany; 2Ce Center C nter for for Biodiversity, Biodiversity, Functional F u n c tio n a l Integrative Genomics Genomi m cs (BioFig), (BioFig), University University ooff L isbon, Portugal. Portugal. & Integrative Lisbon, E-maail: [email protected] [email protected] E-mail:

Posters Session 1

Inspired Ins pired by the the impressive impressive level leve v l of biodiversity biodiversity in in the the h marine marrine environment, environment, the the pha arrmacological pot ential of natural n tural produc na ts from from r marrine organisms orgaannisms has has been b en be pharmacological potential products marine iinvestigated nvestigated eenthusiastically nthusiastically [[1] ]. The The marine-derived marrine-derived fungus fuungus g St achyylidium sp. spp. w as [1]. Stachylidium was iisolated solated ffrom rom r tthe he ssponge ponge Cal lyspongi p a cf. cf. C. flammea. flammea. Che C mical iinvestigation nvestigattion off the the Callyspongia Chemical bi oactive v ffungal unga u l extract extract lled ed ttoo tthe hee iisolation solation of 15 novel novel polyketides, pollyketides, namely namely mariline marrilinee AAbioactive C [2], [2], marilones marrilones A-C A-C [3], [3], maristachones marristachones A-E, A-E, marilactone marilactonne and and ciclomarinone ciclomarrinone (3) (3) [4]. T he sskeleton keeleton of tthese hese pol yketidees iiss unus ual, aand nd ttheir heir bi osyntthhesis iiss ssuggested uggested ttoo The polyketides unusual, biosynthesis require re quire unusual u ual biochemical unus biochemical reactions reactions in in fungal funga u l secondary secondaarryy metabolism. metabbolism. Cyclomarinone Cyclomarrinone n (3 presents a novel novel carbon carrbon skeleton, skeeleton, possibly possibly created creatted by b ann unprecedented unprecedented type typee of (3)) presents rearrangement re arrranggement iinn pol polyketide yketide biosynthesis. biossynthesis. Biosynthetic Biosynthetic pathway pathway analysis analysis and and feeding feedi d ng eexperiments xperiments led led ttoo the the ccreation reationn of the the unnatural unnaatural natural naaturaal product product mariquinoline marriquinoline (4, unpubl ished). Enantiomers Enanntiomers mariline marriline A1/A2 (1, 2) 2) inhibited inhibited human human leucocyte leucocyte elastase elastase unpublished). (HLE) with (HLE) w ith aan n IC50 value value of 0.86 μ μM, M, aand nnd aacetylcholinesterase cetylcholinesterase (A (AChE) ChE) w with ith IC50 va values lues off 0.18 μM (offset (offfset = 49%) and and 0.63 0.663 μM (of ffset = 54%), respectively. respectively. (offset

Figure Formulae Compounds Figure 1. 1. Structural Struuctural F ormulae off Com poounds 1-4 14 References: References: 1. 2. 3. 4.

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Glaser G aser K.B. Gl K.B. and and Mayer Mayer A.M.S., A.M.S., Biochem. Biochem. Ph Pharmacol. armacol. 2009, 78, 7 440 440-448. -448. Almeida A m e id a C Al C., ., et al., al., Chem. Chem. Eur. Eur. J., J., . 2012, 18, 8827 8827-8834. -8834. Almeida A m e id a C Al C., ., et al., al., Beilstein Beilstein JJ.. O Organic r g a n ic C Chem., hem., 2011, 2011, 77,, 11636-1642. 636-1642. Almeida A meida C., Al C., et al., al., J. nnat. at. Pr Prod., od., 2013, 22; 76, 3, 322-326. 322-326.



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MARINE TOXINS POTENTIAL FOR THE DEVELOPMENT OF NEW THERAPIES AGAINST NEURODEGENERATIVE DISORDERS Eva Alonso, Paz Otero, Carmen Vale and Luis M. Botana Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain. Phone/Fax: +34 982822233.

[email protected]

Posters Session 1

Oceans are a unique and rich source for active compounds for the pharmaceutical industry, with the association of a great genetic diversity of marine organism and ecological variety, ranging from accessible beaches to extreme oceans depth. Nowadays, neurological and neurodegenerative diseases are a growing problem in industrialized countries due to the rise of life expectancy with important socioeconomic consequences. Among these marine organisms, marine biotoxins form a wide and heterogeneous group with a wide chemical and pharmacological variety that make them a good opportunity for the drug pursuit. Some of these marine biotoxins are classified as neurotoxins. These compounds are highly specific for ion and ligand gated channels, being them their main cellular targets. For example, spirolides and gymodimines act at cholinergic receptors level, whereas other neurotoxins as gambierol and its analogs interact with the voltage gated potassium channel, targets intimately linked to neurological disorders as Alzheimer´s disease or immune disorders. These mechanism of action variety opens a wide window of new and promising chemical products for further investigations in the successful development of new medicines.


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ENANTIOSELECTIVE EN ANTIOSELECTI T VE SYNTHESIS SYNTHESIS OF OF LEP L LEPADINS A DI NS A A-C -C M ercedes Am att, t, Al Alexandre lexxandre P Pinto, into, o Ros Rosaa G Griera riera an andd Joan Bosch Bosch Mercedes Amat, Laboratory L La boratory ooff O Organic rganic Chemistry, Chemistry, Faculty Faculty of of Pharmacy, Pharmacy, University University of of Barcelona, Barcelona, Spain S p a in E-mail: E-mail:

The lepadin lepa p din alkaloids, alkaloids, comprising compriising eight eight cis-decahydroquinoline cis-decahhydrroquinoline members, membbers, were were The identified ffrom rom r 1991 ttoo 2002 ffrom rom r different marine marrine ssources o es ssuch ourc uch aass tthe he ttunicate unicate identified different Clavelina n lepadinformis, leppadinffoormis, flatworm flattworrm Prostheceraeus Prostheceraeus villatus, villaattus, tropical tropical marine marrine tunicate tunicate Clavelina Didemnun sp., sp., and annd Australian Australian Great Greatt Barrier Barrier Reef Reef ascidian ascidian Aplidium Applidium ttabascum. abascum. u 1 Didemnun Lepadins L epadins n A and annd B have haavve been been shown shoown to to exhibit exhibit significant significantt iinn vvitro itro cytotoxicity cytotoxicity aagainst gaainst 1a,b ,b human sseveral everal hum ann ccancer anncer ccell ell llines. ines.1a In addition, addition, lepadin lepadin B is is a potent potent blocker blocker for foor neuronal receptors neuronaal nicotinic nicotinic acetylcholine acetylcholinee re ceptors (nAChR's). (nAChR's).2 L Lepadins epadins D D-F -F ha have avve llow ow ccytotoxicity ytotoxiicity but ssignificant ignificannt and annd selective selective aantiplasmodial nntiplasmodial aand nd nd an ntitrypanosomal activity. activity.3 antitrypanosomal

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Posters Session 1

In the the context context of our studies studies on o the the use use of phenylglycinol-derived phenylglyccinol-derived chiral chiral tricyclic tricyc y lic lactams aass eenantiomeric products, wee will present nanntiomeric sscaffolds caffooldss ffor or o the the ssynthesis ynthesis of natural naatura u l produc ts, w will pre sent an efficient efficient synthesis synthesis of the the marine marrine n aalkaloids lkaloids llepadin epadin A-C. an

References R eferences 1 a) S 1. Steffan, tefffaan, B B.. Tetrahedron Tetrahedron 1991, 1991 47, 477, 88729-8732; 729-8732; b) Kubanek, Kubanek, k J.; J.; Williams, Williams, D. D. E.; E.;; de de Silva, Silva, E. E. D.; D.;; Allen, T .; An d erso n , R Tetrahedron Lett. L tt. 1995, 36, Le 36, 66189-6192; 189-6192; c) c) W right, A D.; Goclik, Goclik, E.; E.; König, König, g G Allen, T.; Anderson, R.. JJ.. Tetrahedron Wright, A.. D.; G.. M.; Kaminsky, Kaminsky, R. R. J. M eed. C hem. 2002, 2002, 45, 45, 33067-3072; 067-3072; d) Davis, Davis, R A.; Carroll, Carroll, A. A. R.; R .; Q uinn, R. R. J. J. J. M.; Med. Chem. R.. A.; Quinn, Nat. P rod. 2002, 65, 65, 4454-457. 54-457. Nat. Prod. Tsuneki, H.; H.; You, You, Y.; Y.; Toyooka, Toyooka, N.; N.; Sasaoka, Sasaoka, T.; T.; Nemoto, Nemoto, H.; H.; Dani, Dani, J. J. A.; A.; Kimura, Kimura, I. I. Biol. Biol. Ph arm. Bull. B ll . Bu 2. Tsuneki, Pharm. 11-614. 2005, 28, 6611-614. ig h t, A D.; Goclick, G o c lic k , E .; K ö n ig , G .; K a m in s k y , R ed e . Ch em. 2002, 45, 45, 33067-3072. 067-3072. 3. Wr Wright, A.. D.; E.; König, G.. M M.; Kaminsky, R.. J. M Med. Chem. 4. a) Amat, Amat a , M.; M.; Griera, Griera, R.; R .; F abregat, R.; R.; Molins, Molins, E.; E.; Bosch, Bosch, J. J. An gew. Chem. Chem. Int. Int. Ed 348Fabregat, Angew. Ed.. 2008, 47 47,, 333483351; b) Amat, Amat, M.; M.; Fabregat, Fabregat, R.; R.; Griera, Griera, R.; R.; Bosch, Bosch, J. J. J. O rg . C hem. 2009, 2 74 794-1797; Amat, Amat, M.; M.; c) c) Org. Chem. 74,, 11794-1797; Fa bregat, R.; R.; Griera, Griera, R.; R.; Florindo, Florindo, P.; P.; Molins, Molins, E.; E.; Bosch, Bosch, J. J. J. O rg. Chem. Chem. e 2010, 75, 75, 33797-3805. 797-3805. Fabregat, Org.

Acknowledgments A cknow wledgments Financial ssupport Financial upport ffrom rom tthe he M MICINN, ICINN, Spain Spain ((CTQ CTQ 2012-35250), 2012-35250), aand nd tthe hee A AGAUR, GAUR, Generalitat Generalitat de de Ca talunya ((2009-SGR-1111). 2009-SGR-1111). Catalunya


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CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THE ANTITUMOR ACTIVITIES EXERTED BY Hypocrea jecorina sp. A MARINE ENDOPHYTIC FUNGUS Siti Alwani Ariffin1,3, Kalavathy Ramasamy2, and Paul Davis3 1 Marine Pharmaceutical Research Group (MaReG), 2Collaborative Drug Discovery Research (CCDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Selangor, Malaysia; 3Department of Medicine, University of Otago, Wellington New Zealand. E-mail: [email protected]

Posters Session 1

Seaweeds have been extensively used as traditional medicine due to the presence of their bioactive compounds. Endophytes from seaweeds however, have not been widely explored or documented. A marine endophytic fungal extract (S2) isolated from brown seaweed Turbinaria conoides in our previous study has shown promising ability to inhibit cancer cells in particular colon and lung cell lines. It was relatively inactive against the normal fibroblast (D551) and liver (WRL-68) cells. The toxicity profile of S2 was further confirmed by acute toxicity studies. However the precise mechanism(s) by which S2 exerts the antitumor effects are not known. This study therefore aimed to determine the possible molecular mechanisms of extract S2 that is involved in the induction of cell death in colon cancer cells using microarray. Several genes that were related to the apoptosis-regulatory pathway, DNA damage and cell cycle arrest (ATF3, DDIT3, PPPIR15A, CASP4, TP53INPI, TNFSRF10B and BTG1) were significantly (p