Planta Med 2021; 87(01/02): 49-70
DOI: 10.1055/a-1257-8402
Biological and Pharmacological Activities
Reviews

Anticancer Potential of Compounds from the Brazilian Blue Amazon

Diego V. Wilke
1   Núcleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil
,
Paula C. Jimenez
2   Departamento de Ciências do Mar, Instituto do Mar, Universidade Federal de São Paulo, Santos, SP, Brazil
,
Paola C. Branco
3   Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
,
Paula Rezende-Teixeira
3   Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
,
Amaro E. Trindade-Silva
1   Núcleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil
,
Anelize Bauermeister
3   Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
,
4   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
,
3   Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
› Institutsangaben
Gefördert durch: ArboControl Brasil Project FNS/UnB TED74/2016 and TED42/2017
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo 2014/50926-0
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo 2015/17177-6
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo 2017/09022-8
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo 2017/17646-4
Gefördert durch: Conselho Nacional de Desenvolvimento Científico e Tecnológico 465637/2014-0

Abstract

“Blue Amazon” is used to designate the Brazilian Economic Exclusive Zone, which covers an area comparable in size to that of its green counterpart. Indeed, Brazil flaunts a coastline spanning 8000 km through tropical and temperate regions and hosting part of the organisms accredited for the countryʼs megadiversity status. Still, biodiversity may be expressed at different scales of organization; besides species inventory, genetic characteristics of living beings and metabolic expression of their genes meet some of these other layers. These metabolites produced by terrestrial creatures traditionally and lately added to by those from marine organisms are recognized for their pharmaceutical value, since over 50% of small molecule-based medicines are related to natural products. Nonetheless, Brazil gives a modest contribution to the field of pharmacology and even less when considering marine pharmacology, which still lacks comprehensive in-depth assessments toward the bioactivity of marine compounds so far. Therefore, this review examined the last 40 years of Brazilian natural products research, focusing on molecules that evidenced anticancer potential–which represents ~ 15% of marine natural products isolated from Brazilian species. This review discusses the most promising compounds isolated from sponges, cnidarians, ascidians, and microbes in terms of their molecular targets and mechanisms of action. Wrapping up, the review delivers an outlook on the challenges that stand against developing groundbreaking natural products research in Brazil and on a means of surpassing these matters.



Publikationsverlauf

Eingereicht: 16. Juni 2020

Angenommen nach Revision: 01. September 2020

Artikel online veröffentlicht:
03. November 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Ab Saber AN. Litoral do Brasil/Brazilian Coast. 1st edition. São Paulo: Metalivros; 2001: 1-281
  • 2 Snelgrove PVR. An ocean of discovery: biodiversity beyond the census of marine life. Planta Med 2016; 82: 790-799
  • 3 Mora C, Tittensor DP, Adl S, Simpson AGB, Worm B. How many species are there on earth and in the ocean?. PLoS Biol 2011; 9: e1001127
  • 4 Miloslavich P, Klein E, Díaz JM, Hernández CE, Bigatti G, Campos L, Artigas F, Castillo J, Penchaszadeh PE, Neill PE, Carranza A, Retana MV, Díaz de Astarloa JM, Lewis M, Yorio P, Piriz ML, Rodríguez D, Valentin YY, Gamboa L, Martín A. Marine biodiversity in the Atlantic and Pacific coasts of South America: knowledge and gaps. PLoS One 2011; 6: e14631
  • 5 Longo LL, Amado-Filho GM. Knowledge of Brazilian benthic marine fauna throughout time. Hist Cienc Saude Manguinhos 2014; 21: 995-1010
  • 6 Moura RL, Amado-Filho GM, Moraes FC, Brasileiro PS, Salomon PS, Mahiques MM, Bastos AC, Almeida MG, Silva JM, Araujo BF, Brito FP, Rangel TP, Oliveira BCV, Bahia RG, Paranhos RP, Dias RJS, Siegle E, Figueiredo AG, Pereira RC, Leal CV, Hajdu E, Asp NE, Gregoracci GB, Neumann-Leitão S, Yager PL, Francini-Filho RB, Fróes A, Campeão M, Silva BS, Moreira APB, Oliveira L, Soares AC, Araujo L, Oliveira NL, Teixeira JB, Valle RAB, Thompson CC, Rezende CE, Thompson FL. An extensive reef system at the Amazon River mouth. Sci Adv 2016; 2: e1501252
  • 7 Bruce T, Meirelles PM, Garcia G, Paranhos R, Rezende CE, de Moura RL, Filho RF, Coni EOC, Vasconcelos AT, Amado-Filho G, Hatay M, Schmieder R, Edwards R, Dinsdale E, Thompson FL, De RL, Filho RF, Coni EOC, Vasconcelos AT, Filho GA, Hatay M, Schmieder R, Edwards R, Dinsdale E, Thompson FL. Abrolhos bank reef health evaluated by means of water quality, microbial diversity, benthic cover, and fish biomass data. PLoS One 2012; 7: e36687
  • 8 Leão ZMAN, Kikuchi RKP, Testa V. Corals and Coral Reefs of Brazil. In: Cortés J. ed. Latin American Coral Reefs. Amsterdam: Elsevier Science B. V.; 2003: 9-52
  • 9 Thompson F, Krüger R, Thompson CC, Berlinck RGS, Coutinho R, Landell MF, Pavão M, Mourão PAS, Salles A, Negri N, Lopes FAC, Freire V, Macedo AJ, Maraschin M, Pérez CD, Pereira RC, Radis-Baptista G, Rezende RP, Valenti WC, Abreu PC, Francini-Fo R, Asp N, Siegle E, Rezende CE, Schenkel E, Lhullier C, Dias J, Broetto L, Gomes PB, Cordeiro RT, Melo LFA, Vasconcelos AT, Gadelha L, Soares A, Meirelles P, Tschoeke D, Garcia G, Vicente AC, Vieira V, Miranda M, Gregoracci G, Cartaxo ANS, Frattini NAC, Georges S, Polejack A, Chimetto L, de Oliveira L, Leomil L, Reis L, Calegario G, Moreira AP, Soares AC, Costa AC, Silva BS, Lima AW, Otzuki K, Walter JM, Bahiense L, Machado A, Santos E, Nobrega MS, Coutinho F, Vidal L, Mattoso M, Thompson M, Campeão M, Varaste T, Pitta G, Paixão R, Mattsson H, Venas T, Hadelk C, Freitas T, Lopes G, Paz P, Silveira C, Cavalcanti G, Fróes AM, Freitas L, Vizzotto C, Pinto O, Vilegas W, Costa TM, de Castro LM, Augusto AS, Rorig L, Derner RB, Hajdu E, Leal C. Marine biotechnology in Brazil: recent developments and its potential for innovation. Front Mar Sci 2018; 5: e236
  • 10 Costa-Lotufo LV, Pessoa C, Moraes MEA, Paixão Almeida AM, de Moraes MO, da Cruz Lotufo TM. Marine organisms from Brazil as source of potential anticancer agents. Adv Phytomed 2006; 2: 181-196
  • 11 Ióca LP, Nicacio KJ, Berlinck RGS. Natural products from marine invertebrates and microorganisms in Brazil between 2004 and 2017: still the challenges, more rewards. J Braz Chem Soc 2018; 29: 998-1031
  • 12 Ióca LP, Allard PM, Berlinck RGS. Thinking big about small beings-the (yet) underdeveloped microbial natural products chemistry in Brazil. Nat Prod Rep 2014; 31: 646-675
  • 13 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
  • 14 Jimenez PC, Wilke DV, Branco PC, Bauermeister A, Rezende-Teixeira P, Gaudêncio SP, Costa-Lotufo LV. Enriching cancer pharmacology with drugs of marine origin. Br J Pharmacol 2020; 177: 3-27
  • 15 Dias DA, Urban S, Roessner U. A historical overview of natural products in drug discovery. Metabolites 2012; 2: 303-336
  • 16 Pye CR, Bertin MJ, Lokey RS, Gerwick WH, Linington RG. Retrospective analysis of natural products provides insights for future discovery trends. Proc Natl Acad Sci U S A 2017; 114: 5601-5606
  • 17 Wilson MC, Mori T, Rückert C, Uria AR, Helf MJ, Takada K, Gernert C, Steffens UA, Heycke N, Schmitt S, Rinke C, Helfrich EJ, Brachmann AO, Gurgui C, Wakimoto T, Kracht M, Crüsemann M, Hentschel U, Abe I, Matsunaga S, Kalinowski J, Takeyama H, Piel J. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 2014; 506: 58-62
  • 18 Wilson MC, Piel J. Metagenomic approaches for exploiting uncultivated bacteria as a resource for novel biosynthetic enzymology. Chem Biol 2013; 20: 636-647
  • 19 Cooper ED, Bentlage B, Gibbons TR, Bachvaroff TR, Delwiche CF. Metatranscriptome profiling of a harmful algal bloom. Harmful Algae 2014; 37: 75-83
  • 20 Miller IJ, Vanee N, Fong SS, Lim-Fong GE, Kwan JC. Lack of overt genome reduction in the bryostatin-producing bryozoan symbiont Candidatus Endobugula sertula . Appl Environ Microbiol 2016; 82: 6573-6583
  • 21 Aksenov AA, Da Silva R, Knight R, Lopes NP, Dorrestein PC. Global chemical analysis of biology by mass spectrometry. Nat Rev Chem 2017; 1: e0054
  • 22 Brunetti AE, Carnevale Neto F, Vera MC, Taboada C, Pavarini DP, Bauermeister A, Lopes NP. An integrative omics perspective for the analysis of chemical signals in ecological interactions. Chem Soc Rev 2018; 47: 1574-1591
  • 23 Berlinck RGS, Hajdu E, Da Rocha RM, De Oliveira JHHL, Hernández ILC, Seleghim MHR, Granato AC, De Almeida ÉVR, Nuñez CV, Muricy G, Peixinho S, Pessoa C, Moraes MO, Cavalcanti BC, Nascimento GGF, Thiemann O, Silva M, Souza AO, Silva CL, Minarini PRR. Challenges and rewards of research in marine natural products chemistry in Brazil. J Nat Prod 2004; 67: 510-522
  • 24 Kobayashi M. Search for biologically active substances from marine sponges. In: Fusetani N. ed. Drugs from the Sea. Basel: Karger; 2004: 46-58
  • 25 Perdicaris S, Vlachogianni T, Valavanidis A. Bioactive natural substances from marine pponges: new developments and prospects for future pharmaceuticals. Nat Prod Chem Res 2013; 01: e1000115
  • 26 da Frota LCM, Silva RB, Mothes B, Henriques AT, Moreira JCF. Current status on natural products with antitumor activity from Brazilian marine sponges. Curr Pharm Biotechnol 2011; 13: 235-244
  • 27 Bergmann W, Feeney RJ. Contributions to the study of marine products. XXXII. The nucleosides of sponges. I. J Org Chem 1951; 16: 981-987
  • 28 Schwartsmann G. Marine organisms and other novel natural sources of new cancer drugs. Ann Oncol 2000; 11: 235-243
  • 29 Hirata Y, Uemura D. Halichondrins–antitumor polyether macrolides from a marine sponge. Pure Appl Chem 1986; 58: 701-710
  • 30 Cortes J, Schöffski P, Littlefield BA. Multiple modes of action of eribulin mesylate: Emerging data and clinical implications. Cancer Treat Rev 2018; 70: 190-198
  • 31 Rocha-Lima CM, Bayraktar S, MacIntyre J, Raez L, Flores AM, Ferrell A, Rubin EH, Poplin EA, Tan AR, Lucarelli A, Zojwalla N. A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors. Cancer 2012; 118: 4262-4270
  • 32 van Soest RWM, Boury-Esnault N, Vacelet J, Dohrmann M, Erpenbeck D, de Voogd NJ, Santodomingo N, Vanhoorne B, Kelly M, Hooper JNA. Global diversity of sponges (Porifera). PLoS One 2012; 7: e35105
  • 33 Muricy G, Lopes D, Hajdu E, Carvalho MS, Moraes FC, Klautau M, Menegola C, Pinheiro U. Catalogue of Brazilian Porifera. Rio de Janeiro: Museu Naci. Universidade Federal do Rio de Janeiro; 2011
  • 34 Berlinck RGS, Ogawa CA, Almeida AMP, Sanchez MAA, Malpezzi ELA, Costa LV, Hajdu E, De Freitas JC. Chemical and pharmacological characterization of halitoxin from Amphimedon viridis (porifera) from the southeastern Brazilian coast. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1996; 115: 155-163
  • 35 Rangel M, De Sanctis B, De Freitas JC, Polatto JM, Granato AC, Berlinck RGS, Hajdu E. Cytotoxic and neurotoxic activities in extracts of marine sponges (Porifera) from southeastern Brazilian coast. J Exp Mar Bio Ecol 2001; 262: 31-40
  • 36 Prado MP, Torres YR, Berlinck RGS, Desiderá C, Sanchez MA, Craveiro MV, Hajdu E, Da Rocha RM, Machado-Santelli GM. Effects of marine organisms extracts on microtubule integrity and cell cycle progression in cultured cells. J Exp Mar Bio Ecol 2004; 313: 125-137
  • 37 Muricy G, Ribeiro SM. Shallow-water Haplosclerida (Porifera, Demospongiae) from Rio de Janeiro State, Brazil (Southwestern Atlantic). Beaufortia 1999; 49: 83-108
  • 38 Stankevicins L, Aiub C, Maria LCS, Lobo-Hajdu G, Felzenszwalb I. Genotoxic and antigenotoxic evaluation of extracts from Arenosclera brasiliensis, a Brazilian marine sponge. Toxicol Vitr 2008; 22: 1869-1877
  • 39 Stankevicins L, Aiub CAF, Mazzei JL, Lobo-Hajdu G, Felzenszwalb I. Cytotoxic, mutagenic and antimutagenic screening of Arenosclera brasiliensis acetone and ethanol extracts. Genet Mol Res 2008; 7: 542-548
  • 40 Torres YR, Berlinck RGS, Magalhães A, Schefer AB, Ferreira AG, Hajdu E, Muricy G. Arenosclerins A–C and haliclonacyclamine E, new tetracyclic alkaloids from a Brazilian endemic Haplosclerid sponge Arenosclera brasiliensis . J Nat Prod 2000; 63: 1098-1105
  • 41 Torres YR, Berlinck RGS, Nascimento GGF, Fortier SC, Pessoa C, de Moraes MO. Antibacterial activity against resistant bacteria and cytotoxicity of four alkaloid toxins isolated from the marine sponge Arenosclera brasiliensis . Toxicon 2002; 40: 885-891
  • 42 Andersen RJ, Van Soest RWM, Kong F. 3-Alkylpyridine Alkaloids isolated from marine Sponges in the order Haposclerida. In: Pelletier SW. ed. Alkaloids: Chemical and biological Perspectives. London: Pergamon; 1996: 301-355
  • 43 Trindade-Silva AE, Rua CPJ, Andrade BGN, Vicente ACP, Silva GGZ, Berlinck RGS, Thompson FL. Polyketide synthase gene diversity within the microbiome of the sponge Arenosclera brasiliensis, endemic to the southern Atlantic Ocean. Appl Environ Microbiol 2013; 79: 1598-1605
  • 44 Hajdu E, Muricy G, Custodio M, Russo C, Peixinho S. Geodia corticostylifera (Demospongiae, Porifera) new astrophorid from the Brazilian coast (southwestern Atlantic). Bull Mar Sci 1992; 51: 204-217
  • 45 Rangel M, Konno K, Brunaldi K, Procopio J, De Freitas JC. Neurotoxic activity induced by a haemolytic substance in the extract of the marine sponge Geodia corticostylifera . Comp Biochem Physiol C Toxicol Pharmacol 2005; 141: 207-215
  • 46 Rangel M, Prado MP, Konno K, Naoki H, Freitas JC, Machado-Santelli GM. Cytoskeleton alterations induced by Geodia corticostylifera depsipeptides in breast cancer cells. Peptides 2006; 27: 2047-2057
  • 47 Freitas VM, Rangel M, Bisson LF, Jaeger RG, Machado-Santelli GM. The geodiamolide H, derived from Brazilian sponge Geodia corticostylifera, regulates actin cytoskeleton, migration and invasion of breast cancer cells cultured in three-dimensional environment. J Cell Physiol 2008; 216: 583-594
  • 48 Esteves EL, Paula TSD, Lerner C, Lôbo-Hajdu G, Hajdu E. Morphological and molecular systematics of the Monanchora arbuscula complex (Poecilosclerida: Crambeidae), with the description of five new species and a biogeographic discussion of the genus in the Tropical Western Atlantic. Invertebr Syst 2018; 32: 457-503
  • 49 Kossuga MH, Nascimento AM, Reimão JQ, Tempone AG, Taniwaki NN, Veloso K, Ferreira AG, Cavalcanti BC, Pessoa C, Moraes MO, Mayer AMS, Hajdu E, Berlinck RGS. Antiparasitic, antineuroinflammatory, and cytotoxic polyketides from the marine sponge Plakortis angulospiculatus collected in Brazil. J Nat Prod 2008; 71: 334-339
  • 50 Ferreira EG, Wilke DV, Jimenez PC, De Oliveira JR, Pessoa ODL, Silveira ER, Viana FA, Pessoa C, De Moraes MO, Hajdu E, Costa-Lotufo LV. Guanidine alkaloids from Monanchora arbuscula: chemistry and antitumor potential. Chem Biodivers 2011; 8: 1433-1445
  • 51 Pinheiro US, Berlinck RGS, Hajdu E. Shallow-water Niphatidae (Haplosclerina, Haplosclerida, Demospongiae) from the São Sebastião Channel and its environs (tropical southwestern Atlantic), with the description of a new species. Contrib Zool 2006; 74: 271-278
  • 52 De Oliveira JHHL, Grube A, Köck M, Berlinck RGS, Macedo ML, Ferreira AG, Hajdu E. Ingenamine G and cyclostellettamines G–I, K, and L from the New Brazilian species of marine sponge Pachychalina sp. J Nat Prod 2004; 67: 1685-1689
  • 53 De Oliveira JHHL, Nascimento AM, Kossuga MH, Cavalcanti BC, Pessoa CO, Moraes MO, Macedo ML, Ferreira AG, Hajdu E, Pinheiro US, Berlinck RGS. Cytotoxic alkylpiperidine alkaloids from the Brazilian marine sponge Pachychalina alcaloidifera . J Nat Prod 2007; 70: 538-543
  • 54 Cavalcanti BC, Sombra CML, de Oliveira JHHL, Berlinck RGS, de Moraes MO, Pessoa C. Cytotoxicity and genotoxicity of ingenamine G isolated from the Brazilian marine sponge Pachychalina alcaloidifera . Comp Biochem Physiol C Toxicol Pharmacol 2008; 147: 409-415
  • 55 Muricy G, Moraes FC. Marine sponges of Pernambuco State, NE Brazil. Rev Bras Oceanogr 1998; 46: 213-217
  • 56 Santos EA, Quintela AL, Ferreira EG, Sousa TS, Pinto FDCL, Hajdu E, Carvalho MS, Salani S, Rocha DD, Wilke DV, Torres MDCM, Jimenez PC, Silveira ER, La Clair JJ, Pessoa ODL, Costa-Lotufo LV. Cytotoxic plakortides from the Brazilian marine sponge Plakortis angulospiculatus . J Nat Prod 2015; 78: 996-1004
  • 57 Trindade-Silva AE, Rua C, Silva GGZ, Dutilh BE, Moreira APB, Edwards RA, Hajdu E, Lobo-Hajdu G, Vasconcelos AT, Berlinck RGS, Thompson FL. Taxonomic and functional microbial signatures of the endemic marine sponge Arenosclera brasiliensis . PLoS One 2012; 7: e39905
  • 58 Rua CPJ, Trindade-Silva AE, Appolinario LR, Venas TM, Garcia GD, Carvalho LS, Lima A, Kruger R, Pereira RC, Berlinck RGS, Valle RAB, Thompson CC, Thompson F. Diversity and antimicrobial potential of culturable heterotrophic bacteria associated with the endemic marine sponge Arenosclera brasiliensis . PeerJ 2014; 2014: e419
  • 59 Nicacio KJ, Ióca LP, Fróes AM, Leomil L, Appolinario LR, Thompson CC, Thompson FL, Ferreira AG, Williams DE, Andersen RJ, Eustaquio AS, Berlinck RGS. Cultures of the marine bacterium Pseudovibrio denitrificans Ab134 produce bromotyrosine-derived alkaloids previously only isolated from marine sponges. J Nat Prod 2017; 80: 235-240
  • 60 Ióca LP, Romminger S, Santos MFC, Bandeira KF, Rodrigues FT, Kossuga MH, Nicacio KJ, Ferreira ELF, Morais-Urano RP, Passos MS, Kohn LK, Arns CW, Sette LD, Berlinck RGS, Ióca LP, Romminger S, Santos MFC, Bandeira KF, Rodrigues FT, Kossuga MH, Nicacio KJ, Ferreira ELF, Morais-Urano RP, Passos MS, Kohn LK, Arns CW, Sette LD, Berlinck RGS. A strategy for the rapid identification of fungal metabolites and the discovery of the antiviral activity of pyrenocine a and harzianopyridone. Quim Nova 2016; 39: 720-731
  • 61 Toledo TR, Dejani NN, Monnazzi LGS, Kossuga MH, Berlinck RGS, Sette LD, Medeiros AI. Potent Anti-inflammatory activity of pyrenocine A isolated from the marine-derived fungus Penicillium paxilli Ma(G)K. Mediators Inflamm 2014; 2014: 767061
  • 62 Scopel M, dos Santos O, Frasson AP, Abraham WR, Tasca T, Henriques AT, Macedo AJ. Anti-Trichomonas vaginalis activity of marine-associated fungi from the South Brazilian Coast. Exp Parasitol 2013; 133: 211-216
  • 63 Santos OCS, Soares AR, Machado FLS, Romanos MTV, Muricy G, Giambiagi-deMarval M, Laport MS. Investigation of biotechnological potential of sponge-associated bacteria collected in Brazilian coast. Lett Appl Microbiol 2015; 60: 140-147
  • 64 Zilberberg C, Abrantes DP, Marques JA, Machado LF, Marangoni LFB. Conhecendo os Recifes Brasileiros: Rede de Pesquisas Coral Vivo. Rio de Janeiro, RJ: Museu Nacional, Universidade Federal do Rio de Janeiro (Brasil); 2016
  • 65 Kossuga MH, De Lira SP, Nascimento AM, Gambardella MTP, Berlinck RGS, Torres YR, Nascimento GGF, Pimenta EF, Silva M, Thiemann OH, Oliva G, Tempone AG, Melhem MSC, De Souza AO, Galetti FCS, Silva CL, Cavalcanti B, Pessoa CO, Moraes MO, Hajdu E, Peixinho S, Rocha RM. Isolamento e atividades biológicas de produtos naturais das esponjas Monanchora arbuscula, Aplysina sp., Petromica ciocalyptoides e Topsentia ophiraphidites, da ascídia Didemnum ligulum e do octocoral Carijoa riisei . Quim Nova 2007; 30: 1194-1202
  • 66 Sousa TS, Nuzzo G, Torres MCM, Lopes NP, Cutignano A, Jimenez PC, Santos EA, Gomes BA, Sardo A, Pessoa ODL, Costa-Lotufo LV, Fontana A. Amphidinolide P from the Brazilian octocoral Stragulum bicolor . Brazilian J Pharmacogn 2015; 25: 600-604
  • 67 Moritz MIG, Marostica LL, Bianco ÉM, Almeida MTR, Carraro JL, Cabrera GM, Palermo JA, Simões CMO, Schenkel EP. Polyoxygenated steroids from the octocoral leptogorgia punicea and in vitro evaluation of their cytotoxic activity. Mar Drugs 2014; 12: 5864-5880
  • 68 Soletti RC, De Faria GP, Vernal J, Terenzi H, Anderluh G, Borges HL, Moura-Neto V, Gabilan NH. Potentiation of anticancer-drug cytotoxicity by sea anemone pore-forming proteins in human glioblastoma cells. Anticancer Drugs 2008; 19: 517-525
  • 69 Parker MW, Feil SC. Pore-forming protein toxins: from structure to function. Prog Biophys Mol Biol 2005; 88: 91-142
  • 70 Costa-Lotufo LV, Carnevale-Neto F, Trindade-Silva AEE, Silva RR, Silva GGZ, Wilke DV, Pinto FCL, Sahm BDB, Jimenez PCC, Mendonça JN, Lotufo TMC, Pessoa ODL, Lopes NPP. Chemical profiling of two congeneric sea mat corals along the Brazilian coast: adaptive and functional patterns. Chem Commun 2018; 54: 1952-1955
  • 71 Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, Nguyen DD, Watrous J, Kapono CA, Luzzatto-Knaan T, Porto C, Bouslimani A, Melnik AV, Meehan MJ, Liu WT, Crüsemann M, Boudreau PD, Esquenazi E, Sandoval-Calderón M, Kersten RD, Pace LA, Quinn RA, Duncan KR, Hsu CC, Floros DJ, Gavilan RG, Kleigrewe K, Northen T, Dutton RJ, Parrot D, Carlson EE, Aigle B, Michelsen CF, Jelsbak L, Sohlenkamp C, Pevzner P, Edlund A, McLean J, Piel J, Murphy BT, Gerwick L, Liaw CC, Yang YL, Humpf HU, Maansson M, Keyzers RA, Sims AC, Johnson AR, Sidebottom AM, Sedio BE, Klitgaard A, Larson CB, Boya CAP, Torres-Mendoza D, Gonzalez DJ, Silva DB, Marques LM, Demarque DP, Pociute E, OʼNeill EC, Briand E, Helfrich EJN, Granatosky EA, Glukhov E, Ryffel F, Houson H, Mohimani H, Kharbush JJ, Zeng Y, Vorholt JA, Kurita KL, Charusanti P, McPhail KL, Nielsen KF, Vuong L, Elfeki M, Traxler MF, Engene N, Koyama N, Vining OB, Baric R, Silva RR, Mascuch SJ, Tomasi S, Jenkins S, Macherla V, Hoffman T, Agarwal V, Williams PG, Dai J, Neupane R, Gurr J, Rodríguez AMC, Lamsa A, Zhang C, Dorrestein K, Duggan BM, Almaliti J, Allard PM, Phapale P, Nothias LF, Alexandrov T, Litaudon M, Wolfender JL, Kyle JE, Metz TO, Peryea T, Nguyen DT, VanLeer D, Shinn P, Jadhav A, Müller R, Waters KM, Shi W, Liu X, Zhang L, Knight R, Jensen PR, Palsson B, Pogliano K, Linington RG, Gutiérrez M, Lopes NP, Gerwick WH, Moore BS, Dorrestein PC, Bandeira N. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 2016; 34: 828-837
  • 72 Almeida JG, Maia AI, Wilke DV, Silveira ER, Braz-Filho R, La Clair JJ, Costa-Lotufo LV, Pessoa OD. Palyosulfonoceramides A and B: unique sulfonylated ceramides from the Brazilian zoanthids Palythoa caribaeorum and Protopalythoa variabilis . Mar Drugs 2012; 10: 2846-2860
  • 73 Pinto FCL, Almeida JGL, Silveira ER, Costa AM, Guimarães LA, Wilke DV, Costa-Lotufo LV, Torres MDCM, Pessoa ODL. Steroids from the Brazilian Zoanthids Palythoa caribaeorum and Palythoa variabilis . J Braz Chem Soc 2017; 28: 485-491
  • 74 Kelecom A, Solé-Cava AM. Comparative study of zoanthid sterols the genus Palythoa (hexacorallia, zoanthidea). Comp Biochem Physiol B Biochem 1982; 72: 677-682
  • 75 Wilke DV, Jimenez PC, Pessoa C, de Moraes MO, Araújo RM, da Silva WMB, Silveira ER, Pessoa ODL, Braz-Filho R, Lopes NP, Costa-Lotufo LV. Cytotoxic lipidic α-amino acids from the zoanthid Protopalythoa variabilis from the Northeastern Coast of Brazil. J Braz Chem Soc 2009; 20: 1455-1459
  • 76 Pinto FCL, Silveira ER, Vasconcelos ACL, Florêncio KGD, Oliveira FAS, Sahm BB, Costa-Lotufo LV, Bauermeister A, Lopes NP, Wilke DV, Pessoa ODL. Dextrorotatory chromomycins from the marine Streptomyces sp. associated to Palythoa caribaeorum . J Braz Chem Soc 2020; 31: 143-152
  • 77 Wilke DV, Jimenez PC, Araujo RM, da Silva WM, Pessoa OD, Silveira ER, Pessoa C, de Moraes MO, Skwarczynski M, Simerska P, Toth I, Costa-Lotufo LV. Pro-apoptotic activity of lipidic alpha-amino acids isolated from Protopalythoa variabilis . Bioorg Med Chem 2010; 18: 7997-8004
  • 78 Sahm BDB, Peres J, Rezende-Teixeira P, Santos EA, Branco PC, Bauermeister A, Kimani S, Moreira EA, Bisi-Alves R, Bellis C, Mlaza M, Jimenez PC, Lopes NP, Machado-Santelli GM, Prince S, Costa-Lotufo LV. Targeting the oncogenic TBX2 transcription factor with chromomycins. Front Chem 2020; 8: e110
  • 79 Shenkar N, Swalla BJ. Global diversity of Ascidiacea. PLoS One 2011; 6: e20657
  • 80 Schmidt EW, Donia MS. Life in cellulose houses: symbiotic bacterial biosynthesis of ascidian drugs and drug leads. Curr Opin Biotechnol 2010; 21: 827-833
  • 81 Bauermeister A, Branco PC, Furtado LC, Jimenez PC, Costa-Lotufo LV, Lotufo TMC. Tunicates: a model organism to investigate the effects of associated-microbiota on the production of pharmaceuticals. Drug Discov Today Dis Model 2019; 28: 13-20
  • 82 Cuevas C, Francesch A. Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat Prod Rep 2009; 26: 322-337
  • 83 DʼIncalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 2010; 9: 2157-2163
  • 84 Trigo J, Subbiah V, Besse B, Moreno V, López R, Sala MA, Peters S, Ponce S, Fernández C, Alfaro V, Gómez J, Kahatt C, Zeaiter A, Zaman K, Boni V, Arrondeau J, Martínez M, Delord JP, Awada A, Kristeleit R, Olmedo ME, Wannesson L, Valdivia J, Rubio MJ, Anton A, Sarantopoulos J, Chawla SP, Mosquera-Martinez J, DʼArcangelo M, Santoro A, Villalobos VM, Sands J, Paz-Ares L. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 2020; 21: 645-654
  • 85 Losada A, Muñoz-Alonso MJ, García C, Sánchez-Murcia PA, Martínez-Leal JF, Domínguez JM, Lillo MP, Gago F, Galmarini CM. Translation elongation factor eEF1A2 is a novel anticancer target for the marine natural product plitidepsin. Sci Rep 2016; 6: e35100
  • 86 Alonso-Álvarez S, Pardal E, Sánchez-Nieto D, Navarro M, Caballero MD, Mateos MV, Martín A. Plitidepsin: design, development, and potential place in therapy. Drug Des Devel Ther 2017; 11: 253-264
  • 87 Rodrigues SA, Rocha RM, Lotufo TMC. Guia ilustrado para identificação das ascídias do estado de São Paulo. São Paulo: FAPESP; 1998
  • 88 Lotufo T, Silva A. Ascidiacea do litoral cearense. In: Matthews-Cascon H, Lotufo T. eds. Biota marinha da costa oeste do Ceará. Brasília: Ministério do Meio Ambiente; 2006: 221-247
  • 89 da Rocha RM, Dias GM, Lotufo TMC. Checklist das ascídias (Tunicata, Ascidiacea) do Estado de São Paulo, Brasil. Biota Neotrop 2011; 11: 749-759
  • 90 Dias GM, Rocha RM, Lotufo TMC, Kremer LP. Fifty years of ascidian biodiversity research in São Sebastião, Brazil. J Mar Biol Assoc United Kingdom 2013; 93: 273-282
  • 91 Paiva SV, De Oliveira Filho RR, Lotufo TMC. Ascidians from Rocas Atoll, northeast Brazil. Front Mar Sci 2015; 2: e39
  • 92 Moreno TR, de Faria SB, Rocha RM. Biogeography of Atlantic and Mediterranean ascidians. Mar Biol 2014; 161: 2023-2033
  • 93 Seleghim MHR, De Lira SP, Campana PT, Berlinck RGS, Custódio MR. Localization of granulatimide alkaloids in the tissues of the ascidian Didemnum granulatum . Mar Biol 2007; 150: 967-975
  • 94 Torres YR, Bugni TS, Berlinck RGS, Ireland CM, Magalhães A, Ferreira AG, Da Rocha RM. Sebastianines A and B, novel biologically active pyridoacridine alkaloids from the Brazilian ascidian Cystodytes dellechiajei . J Org Chem 2002; 67: 5429-5432
  • 95 Berlinck RGS, Britton R, Piers E, Lim L, Roberge M, Da Rocha RM, Andersen RJ. Granulatimide and isogranulatimide, aromatic alkaloids with G2 checkpoint inhibition activity isolated from the Brazilian ascidian Didemnum granulatum: structure elucidation and synthesis. J Org Chem 1998; 63: 9850-9856
  • 96 Roberge M, Berlinck RGS, Xu L, Anderson HJ, Lim LY, Curman D, Stringer CM, Friend SH, Davies P, Vincent I, Haggarty SJ, Kelly MT, Britton R, Piers E, Andersen RJ. High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide. Cancer Res 1998; 58: 5701-5706
  • 97 Seleghim MHR, Lira SP, Kossuga MH, Batista T, Berlinck RGS, Hajdu E, Muricy G, Da Rocha RM, Do Nascimento GGF, Silva M, Pimenta EF, Thiemann OH, Oliva G, Cavalcanti BC, Pessoa C, De Morues MO, Galetti FCS, Silva CL, De Souza AO, Peixinho S. Antibiotic, cytotoxic and enzyme inhibitory activity of crude extracts from Brazilian marine invertebrates. Brazilian J Pharmacogn 2007; 17: 287-318
  • 98 Britton R, De Oliveira JHHL, Andersen RJ, Berlinck RGS. Granulatimide and 6-bromogranulatimide, minor alkaloids of the Brazilian ascidian Didemnum granulatum . J Nat Prod 2001; 64: 254-255
  • 99 Jimenez PC, Fortier SC, Lotufo TMC, Pessoa C, Moraes MEA, De Moraes MO, Costa-Lotufo LV. Biological activity in extracts of ascidians (Tunicata, Ascidiacea) from the northeastern Brazilian coast. J Exp Mar Bio Ecol 2003; 287: 93-101
  • 100 Takeara R, Jimenez PC, Costa-Lotufo LV, Lopes JLC, Lopes NP. Sample optimization for rapid identification of nucleosides and bases from ascidian extracts using ESI-MS/MS. J Braz Chem Soc 2007; 18: 1054-1060
  • 101 Takeara R, Basso TO, Jimenez PC, Costa-Lotufo LV, Lopes NP, Lopes JLC. Pyrimidine alkaloids from Eudistoma vannamei . Brazilian J Pharmacogn 2015; 25: 698-700
  • 102 Pimenta ATA, Jimenez PC, Costa-Lotufo LV, Braz-Filho R, Lima MAS. New unusual alkaloids from the ascidian Eudistoma vannamei . Nat Prod Commun 2014; 9: 1713-1715
  • 103 Jimenez PC, Wilke DV, Ferreira EG, Takeara R, De Moraes MO, Silveira ER, Lotufo TMDC, Lopes NP, Costa-Lotufo LV. Structure elucidation and anticancer activity of 7-oxostaurosporine derivatives from the Brazilian endemic tunicate Eudistoma vannamei . Mar Drugs 2012; 10: 1092-1102
  • 104 Schupp P, Eder C, Proksch P, Wray V, Schneider B, Herderich M, Paul V. Staurosporine derivatives from the ascidian Eudistoma toealensis and its predatory flatworm Pseudoceros sp. J Nat Prod 1999; 62: 959-962
  • 105 Schupp P, Proksch P, Wray V. Further new staurosporine derivatives from the ascidian Eudistoma toealensis and its predatory flatworm Pseudoceros sp. J Nat Prod 2002; 65: 295-298
  • 106 Schupp P, Steube K, Meyer C, Proksch P. Antiproliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm. Cancer Lett 2001; 174: 165-172
  • 107 Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R. A new alkaloid Am-2282 of Streptomyces origin taxonomy, fermentation, isolation and preliminary characterization. J Antibiot (Tokyo) 1977; 30: 275-282
  • 108 Montenegro TGC, Rodrigues FAR, Jimenez PC, Angelim AL, Melo VMM, Filho ER, De Oliveira MCF, Costa-Lotufo LV. Cytotoxic activity of fungal strains isolated from the ascidian Eudistoma vannamei . Chem Biodivers 2012; 9: 2203-2209
  • 109 Jimenez PC, Ferreira EG, Araújo LA, Guimarães LA, Sousa TS, Pessoa ODL, Lotufo TMC, Costa-Lotufo LV. Citotoxicidad de actinomicetos asociada a la ascidia Eudistoma vannamei (millar, 1977), endémica de la costa noreste de brasil. Lat Am J Aquat Res 2013; 41: 335-343
  • 110 Andréo MA, Jimenez PC, Siebra JBCN, Costa-Lotufo LV, Vessecchi R, Niehues M, Lopes JLC, Lopes NP. Systematic UPLC-ESI-MS/MS study on the occurrence of staurosporine and derivatives in associated marine microorganisms from Eudistoma vannamei . J Braz Chem Soc 2012; 23: 335-343
  • 111 Sousa TS, Jimenez PC, Ferreira EG, Silveira ER, Braz-Filho R, Pessoa OD, Costa-Lotufo LV. Anthracyclinones from Micromonospora sp. J Nat Prod 2012; 75: 489-493
  • 112 Abreu PA, Sousa TS, Jimenez PC, Wilke DV, Rocha DD, Freitas HPS, Pessoa ODL, La Clair JJ, Costa-Lotufo LV. Identification of pyrroloformamide as a cytokinesis modulator. Chembiochem 2014; 15: 501-506
  • 113 Takeara R, Jimenez PC, Wilke DV, Odorico de Moraes M, Pessoa C, Peporine Lopes N, Lopes JLC, Monteiro da Cruz Lotufo T, Costa-Lotufo LV. Antileukemic effects of Didemnum psammatodes (Tunicata: Ascidiacea) constituents. Comp Biochem Physiol A Mol Integr Physiol 2008; 151: 363-369
  • 114 Vervoort H, Fenical W, Epifanio RDA. Tamandarins A and B: new cytotoxic depsipeptides from a Brazilian ascidian of the family Didemnidae. J Org Chem 2000; 65: 782-792
  • 115 Kozlowski EO, Pavao MSG. Effect of sulfated glycosaminoglycans on tumor invasion and metastasis. Front Biosci (Schol Ed) 2011; 3: 1541-1551
  • 116 Pavão MSG, Mourão PAS, Mulloy B, Tollefsen DM. A unique dermatan sulfate-like glycosaminoglycan from ascidian: its structure and the effect of its unusual sulfation pattern on anticoagulant activity. J Biol Chem 1995; 270: 31027-31036
  • 117 Pavão MSG, Aiello KRM, Werneck CC, Silva LCF, Valente AP, Mulloy B, Colwell NS, Tollefsen DM, Mourão PAS. Highly sulfated dermatan sulfates from ascidians. Structure versus anticoagulant activity of these glycosaminoglycans. J Biol Chem 1998; 273: 27848-27857
  • 118 Kozlowski EO, Pavao MSG, Borsig L. Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P-selectin. J Thromb Haemost 2011; 9: 1807-1815
  • 119 Abreu WS, Soares PAG, Motta JM, Kozlowski EO, Teixeira FCOB, Soares MA, Borsig L, Mourão PAS, Pavão MSG. Tunicate heparan sulfate enriched in 2-sulfated β-glucuronic acid: structure, anticoagulant activity, and inhibitory effect on the binding of human colon adenocarcinoma cells to immobilized P-selectin. Mar Drugs 2019; 17: e351
  • 120 Velasco-Alzate KY, Bauermeister A, Tangerina MMP, Lotufo TMC, Ferreira MJP, Jimenez PC, Padilla G, Lopes NP, Costa-Lotufo LV. Marine bacteria from Rocas Atoll as a rich source of pharmacologically active compounds. Mar Drugs 2019; 17: e671
  • 121 Mohimani H, Gurevich A, Mikheenko A, Garg N, Nothias LF, Ninomiya A, Takada K, Dorrestein PC, Pevzner PA. Dereplication of peptidic natural products through database search of mass spectra. Nat Chem Biol 2017; 13: 30-37
  • 122 Rodrigues BSF, Sahm BDB, Jimenez PC, Pinto FCL, Mafezoli J, Mattos MC, Rodrigues-Filho E, Pfenning LH, Abreu LM, Costa-Lotufo LV, Oliveira MCF. Bioprospection of cytotoxic compounds in fungal strains recovered from sediments of the Brazilian coast. Chem Biodivers 2015; 12: 432-442
  • 123 Chen J, Wang C, Lan W, Huang C, Lin M, Wang Z, Liang W, Iwamoto A, Yang X, Liu H, Long P. Gliotoxin inhibits proliferation and induces apoptosis in colorectal cancer cells. Mar Drugs 2015; 13: 6259-6273
  • 124 Nguyen VT, Lee JS, Qian ZJ, Li YX, Kim KN, Heo SJ, Jeon YJ, Park WS, Choi IW, Je JY, Jung WK. Gliotoxin isolated from marine fungus Aspergillus sp. induces apoptosis of human cervical cancer and chondrosarcoma cells. Mar Drugs 2014; 12: 69-87
  • 125 Hubmann R, Hilgarth M, Schnabl S, Ponath E, Reiter M, Demirtas D, Sieghart W, Valent P, Zielinski C, Jäger U, Shehata M. Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. Br J Haematol 2013; 160: 618-629
  • 126 Vigushin DM, Mirsaidi N, Brooke G, Sun C, Pace P, Inman L, Moody CJ, Coombes RC. Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo . Med Oncol 2004; 21: 21-30
  • 127 Hubmann R, Sieghart W, Schnabl S, Araghi M, Hilgarth M, Reiter M, Demirtas D, Valent P, Zielinski C, Jäger U, Shehata M. Gliotoxin targets nuclear NOTCH2 in human solid tumor derived cell lines in vitro and inhibits melanoma growth in xenograft mouse model. Front Pharmacol 2017; 8: e319
  • 128 Haun F, Neumann S, Peintner L, Wieland K, Habicht J, Schwan C, Østevold K, Koczorowska MM, Biniossek M, Kist M, Busch H, Boerries M, Davis RJ, Maurer U, Schilling O, Aktories K, Borner C. Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin. Nat Commun 2018; 9: e3524
  • 129 Reece KM, Richardson ED, Cook KM, Campbell TJ, Pisle ST, Holly AJ, Venzon DJ, Liewehr DJ, Chau CH, Price DK, Figg WD. Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p 300 complex in a preclinical model of prostate cancer. Mol Cancer 2014; 13: e91
  • 130 Uchoa PKS, Pimenta ATA, Braz-Filho R, de Oliveira MCF, Saraiva NN, Rodrigues BSF, Pfenning LH, Abreu LM, Wilke DV, Florêncio KGD, Lima MAS. New cytotoxic furan from the marine sediment-derived fungi Aspergillus niger . Nat Prod Res 2017; 31: 2599-2603
  • 131 Park SY, Oh HH, Park YL, Yu HM, Myung DS, Cho SB, Lee WS, Park D, Joo YE. Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway. Int J Oncol 2017; 51: 959-966
  • 132 Wang J, Jiang Z, Lam W, Gullen EA, Yu Z, Wei Y, Wang L, Zeiss C, Beck A, Cheng EC, Wu C, Cheng YC, Zhang Y. Study of malformin C, a fungal source cyclic pentapeptide, as an anticancer drug. PLoS One 2015; 10 (11) e0140069
  • 133 Liu Y, Wang M, Wang D, Li X, Wang W, Lou H, Yuan H. Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells. Cancer Chemother Pharmacol 2016; 77: 63-75
  • 134 Saraiva NN, Rodrigues BSF, Jimenez PC, Guimarães LA, Torres MCM, Rodrigues-Filho E, Pfenning LH, Abreu LM, Mafezoli J, De Mattos MC, Costa-Lotufo LV, De Oliveira MDCF. Cytotoxic compounds from the marine-derived fungus Aspergillus sp. recovered from the sediments of the Brazilian coast. Nat Prod Res 2015; 29: 1545-1550
  • 135 Ambjørner SEB, Wiese M, Köhler SC, Svindt J, Lund XL, Gajhede M, Saaby L, Brodin B, Rump S, Weigt H, Brünner N, Stenvang J. The pyrazolo[3,4-d]pyrimidine derivative, SCO-201, reverses multidrug resistancm Mediated by ABCG2/BCRP. Cells 2020; 9: e613
  • 136 Rabindran SK, He H, Singh M, Brown E, Collins KI, Annable T, Greenberger LM. Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C. Cancer Res 1998; 58: 5850-5858
  • 137 Rabindran SK, Ross DD, Doyle LA, Yang W, Greenberger LM. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res 2000; 60: 47-50
  • 138 Guimarães LA, Jimenez PC, Sousa TDS, Freitas HPS, Rocha DD, Wilke DV, Martín J, Reyes F, Pessoa ODL, Costa-Lotufo LV. Chromomycin A2 induces autophagy in melanoma cells. Mar Drugs 2014; 12: 5839-5855
  • 139 Arthaud IDB, Rodrigues FAR, Jimenez PC, Montenegro RC, Angelim AL, MacIel VMM, Silveira ER, Freitas HPS, Sousa TS, Pessoa ODL, Lotufo TMC, Costa-Lotufo LV. Studies on the secondary metabolites of a Pseudoalteromonas sp. isolated from sediments collected at the northeastern coast of Brazil. Chem Biodivers 2012; 9: 418-427
  • 140 Soto-Cerrato V, Viñals F, Lambert JR, Kelly JA, Pérez-Tomás R. Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells. Mol Cancer Ther 2007; 6: 362-369
  • 141 Lu CH, Lin SC, Yang SY, Pan MY, Lin YW, Hsu CY, Wei YH, Chang JS, Chang CC. Prodigiosin-induced cytotoxicity involves RAD51 down-regulation through the JNK and p 38 MAPK pathways in human breast carcinoma cell lines. Toxicol Lett 2012; 212: 83-89
  • 142 Li D, Liu J, Wang X, Kong D, Du W, Li H, Hse CY, Shupe T, Zhou D, Zhao K. Biological potential and mechanism of prodigiosin from Serratia marcescens subsp. Lawsoniana in human choriocarcinoma and prostate cancer cell lines. Int J Mol Sci 2018; 19: e3465
  • 143 Pérez-Tomás R, Montaner B, Llagostera E, Soto-Cerrato V. The prodigiosins, proapoptotic drugs with anticancer properties. Biochem Pharmacol 2003; 66: 1447-1452
  • 144 Cheng SY, Chen NF, Kuo HM, Yang SN, Sung CS, Sung PJ, Wen ZH, Chen WF. Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells. Apoptosis 2018; 23: 314-328
  • 145 Silva AET, Guimarães LA, Ferreira EG, Torres MDCM, Da Silva AB, Branco PC, Oliveira FAS, Silva GGZ, Wilke DV, Silveira ER, Pessoa ODL, Jimenez PC, Costa-Lotufo LV. Bioprospecting anticancer compounds from the marine-derived actinobacteria Actinomadura sp. collected at the Saint Peter and Saint Paul Archipelago (Brazil). J Braz Chem Soc 2017; 28: 465-474
  • 146 Gerber NN. Prodigiosin-like pigments from Actinomadura (Nocardia) pelletieri and Actinomadura madurae . Appl Microbiol 1969; 18: 1-3
  • 147 Gerber NN. A novel, cyclic, tripyrrole pigment from Actinomadura (Nocardia) madurae . Tetrahedron Lett 1970; 11: 809-812
  • 148 Hosseini A, Espona-Fiedler M, Soto-Cerrato V, Quesada R, Pérez-Tomás R, Guallar V. Molecular interactions of prodiginines with the BH3 domain of anti-apoptotic Bcl-2 family members. PLoS One 2013; 8: e57562
  • 149 Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, Bornmann W, Kantarjian H, Viallet J, Samudio I, Andreeff M. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (Obatoclax). Cancer Res 2008; 68: 3413-3420
  • 150 Ferreira EGG, Torres MCMD, da Silva ABB, Colares LLFL, Pires K, Lotufo TMCM, Silveira ERR, Pessoa ODLD, Costa-Lotufo LV, Jimenez PCC. Prospecting anticancer compounds in actinomycetes recovered from the sediments of Saint Peter and Saint Paulʼs Archipelago, Brazil. Chem Biodivers 2016; 13: 1149-1157
  • 151 Jensen PR, Moore BS, Fenical W. The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. Nat Prod Rep 2015; 32: 738-751
  • 152 Bauermeister A, Velasco-Alzate K, Dias T, Macedo H, Ferreira EG, Jimenez PC, Lotufo TMC, Lopes NP, Gaudêncio SP, Costa-Lotufo LV. Metabolomic fingerprinting of Salinispora from Atlantic oceanic islands. Front Microbiol 2018; 9: e3021
  • 153 Zhou X, Fenical W. The unique chemistry and biology of the piericidins. J Antibiot (Tokyo) 2016; 69: 582-593
  • 154 Zhou X, Liang Z, Li K, Fang W, Tian Y, Luo X, Chen Y, Zhan Z, Zhang T, Liao S, Liu S, Liu Y, Fenical W, Tang L. Exploring the natural piericidins as antirenal cell carcinoma agents targeting peroxiredoxin 1. J Med Chem 2019; 62: 7058-7069
  • 155 Ma YM, Liang XA, Kong Y, Jia B. Structural diversity and biological activities of indole diketopiperazine alkaloids from fungi. J Agric Food Chem 2016; 64: 6659-6671
  • 156 Minelli A, Bellezza I, Grottelli S, Galli F. Focus on cyclo(His-Pro): history and perspectives as antioxidant peptide. Amino Acids 2008; 35: 283-289
  • 157 Gomez DR, Tang C, Zhang J, Blumenschein GR, Hernandez M, Lee JJ, Ye R, Palma DA, Louie AV, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Welsh JW, Gibbons DL, Karam JA, Kavanagh BD, Tsao AS, Sepesi B, Swisher SG, Heymach JV. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019; 37: 1558-1565
  • 158 Ding Z, Ma M, Zhong C, Wang S, Fu Z, Hou Y, Liu Y, Zhong L, Chu Y, Li F, Song C, Wang Y, Yang J, Li W. Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure. Bioorganic Med Chem 2020; 28: 115186
  • 159 Munro MH, Blunt JW, Dumdei EJ, Hickford SJ, Lill RE, Li S, Battershill CN, Duckworth AR. The discovery and development of marine compounds with pharmaceutical potential. J Biotechnol 1999; 70: 15-25
  • 160 Lallier LE, McMeel O, Greiber T, Vanagt T, Dobson ADW, Jaspars M. Access to and use of marine genetic resources: understanding the legal framework. Nat Prod Rep 2014; 31: 612-616
  • 161 Alves RJV, Weksler M, Oliveira JA, Buckup PA, Pombal JP, Santana HRG, Peracchi AL, Kellner AWA, Aleixo A, Bonino ARL, De Almeida AMP, Albernaz AL, Ribas CC, Zilberberg C, Grelle CEV, Da Rocha CFD, Lamas CJE, Haddad CFB, Bonvicino CR, Prado CPA, De Lima DO, Rossaferes DC, Dos Santos FR, Salimena FRG, Perini FA, Bockmann FA, Franco FL, Del Giudice GML, Colli GR, Vieira ICG, Marinho-Filho J, Werneck JMCF, Dos Santos JAD, Do Nascimento JL, Nessimian JL, Cordeiro JLP, Del Claro K, Salles LO, Casatti L, Py-Danie LHR, Silveira LF, Toledo LF, De Oliveira LF, Malabarba LR, Da Silva MD, Couri MS, Martins MRC, Tavares MDS, Sobral MEG, Vieira MV, Oliveira MDLA, De Pinna MCC, Hopkins MJG, Solé M, Menezes NA, Passos P, Dʼandrea PS, Pinto PCEA, Viana PL, Toledo PM, Dos Reis RE, Vilela R, Bastos RP, Collevatti RG, Silva RC, Fisher SC, Caramaschi U. Brazilian legislation on genetic heritage harms biodiversity convention goals and threatens basic biology research and education. An Acad Bras Cienc 2018; 90: 1279-1284
  • 162 Cragg GM, Grothaus PG, Newman DJ. New horizons for old drugs and drug leads. J Nat Prod 2014; 77: 703-723
  • 163 Falkson G, Sandison AG, Falkson HC, Fichardt T. Chromomycin A 3 (Toyomycin) and radiotherapy in the treatment of advanced malignancy. South African Med J 1966; 4: 38-39
  • 164 DʼIncalci M, Badri N, Galmarini CM, Allavena P. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer 2014; 111: 646-650
  • 165 Marco E, Gago F. DNA structural similarity in the 2: 1 complexes of the antitumor drugs trabectedin (Yondelis) and chromomycin A3 with an oligonucleotide sequence containing two adjacent TGG binding sites on opposing strands. Mol Pharmacol 2005; 68: 1559-1567