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Marine Natural Products in Medicinal Chemistry Carlos Jiménez*
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Departamento de Química, Facultade de Ciencias e Centro de Investigacións Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain ABSTRACT: An overview of the marine natural products (MNPs) field is shown, including an update of FDA-approved drugs and those in clinical trials that can be considered derivatives of MNPs. The importance of marine microorganisms in present studies and the application of emerging techniques and technologies to this field are highlighted.
KEYWORDS: Marine natural products, drug discovery, medicinal chemistry
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explored, many still unknown scaffolds are likely yet to be discovered.4 Material supply is the main drawback for drug development of MNPs because they are obtained from natural sources, usually in only very small amounts. Total chemical synthesis or semisynthesis is the most useful technique to solve this supply problem. Alternatively, biotechnological techniques can be employed in some cases, such as large-scale fermentation of the producer microorganism or the cultivation of invertebrates, although this has proven more difficult. To date, there are six structural types of approved therapeutic agents that can be considered derivatives of MNPs.5 Two nucleosides, the anticancer cytarabine (ara-C) and the antiviral vidarabine (ara-A), were the first US Food and Drug Administration (FDA)-approved drugs (1969 and 1976, respectively) derived from two natural arabino-nucleosides. Cytarabine is still in use today, but vidarabine has been discontinued in the US and in Europe. Moreover, these MNPs can be considered as templates for other commercially available antiviral drugs.7 The peptide toxin, ω-conotoxin MVIIA ziconotide (Prialt), indicated for pain control, was the first FDA-approved drug (2004) directly derived from a MNP. The first anticancer FDA-approved drug (2015) isolated directly from a marine natural source, the tunicate Ecteinascidia turbinata, was ecteinascidin 743 (trabectedin, Yondelis). In Europe, it was approved in 2007 for treatment of advanced soft tissue sarcoma and in 2009 for treatment of recurrent platinum-sensitive ovarian cancer when coupled to liposomal doxorubicin by the European Medicines Agency (EMA). Another anticancer agent, eribulin mesylate, is a synthetic truncated derivative of the polyketide MNP halichondrin B. It
he importance of natural products (NPs) in drug discovery has been extensively documented, including their contribution to the development of present drugs.1,2 The NP chemical diversity is more closely aligned with drugs than synthetic libraries, thus making them ideal candidates for drug discovery projects. Marine organisms can be considered the most recent source of bioactive natural products in relation to terrestrial plants and nonmarine microorganisms. Their exploitation was dependent on the development of techniques for collecting samples and improving spectrometric, mainly NMR, and separation methods. Approximately 28,500 marine natural products (MNPs) had been identified by the end of 2016.3 Cytotoxic and anticancer properties account for the majority of biological activity reported for MNPs. This is not surprising considering the ecological role of MNPs as chemical defense. The fact that the main source of funds for MNP drug discovery research in the US was the NIH/NCI has been suggested by some authors as the main reason for the greater emphasis on antitumor activity.4 Oceans cover more than 70% of the Earth’s surface and host a huge species diversity. Of the 35 animal phyla identified taxonomically, 34 are found in the marine environment, and many of these are found only in marine media.5 The first living organisms appeared in the sea more than 3500 million years ago, and as a result, these organisms have undergone the longest evolutionary period. Over time, harsh marine conditions favored the production of a great variety of molecules bearing unique structures in terms of diversity, structural, and functional features and also in higher incidence of significant bioactivity in relation to NPs from terrestrial life forms.6 This explains the sheer structural diversity of MNPs, and considering that less than 5% of the deep sea has been © XXXX American Chemical Society
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DOI: 10.1021/acsmedchemlett.8b00368 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Figure 1. Examples of marine natural products and derivatives that are in advanced clinical trials.
neutropenia. The synthetic tetrahydroisoquinoline alkaloid, structurally related to trabectedin, lurbinectedin (PM01183) is a highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. Lurbinectedin was granted by the EMA orphan drug designation for the treatment of ovarian cancer in 2012. Lurbinectedin is currently undergoing late-stage (Phase II/III) clinical evaluation by Pharmamar as Zepsyre in platinum-resistant ovarian, BRCA1/ 2-mutated breast, and small-cell lung cancer. There are two ADCs of auristatins, depatuxizumab mafodotin (depatux-m, ABT-414) and polatuzumab vedotin (DCDS-4501A). The former is a conjugate between the depatux antibody and monomethyl auristatin F (MMAF) that targets the epidermal growth factor receptor (EGFR) gene involved in the development of many human cancers. The latter contains a humanized immunoglobulin-G1 (IgG1) mAb targeting the human B-cell surface antigen CD79b and monomethyl auristatin E, which inhibits cell division and promotes apoptosis by binding to tubulin and disrupting the microtubule network. In April 2018, orphan designation was granted by the EMA for polatuzumab vedotin for the treatment of diffuse large B-cell lymphoma. The alkaloid tetrodotoxin (Tectin), extracted from puffer fish livers, is in Phase III clinical trials for the treatment of severe pain due to its analgesic effects related to the inhibition of the initiation and conduction of impulses in the peripheral nervous system. Two Phase III clinical trials of CaPre, an extract of ω-3 fatty acids from krill rather than fish where the EPA and DHA are either free fatty acids or bound to phospholipid esters, are carried out by Canadian Acasti Pharma in collaboration with the US CordenPharma.9 A Phase III trial of salinosporamide A (NPI-0052, Marizomib) in combination with standard Temozolomide-based radiochemotherapy versus standard Temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma was initiated. Salinosporamide A is a halogenated MNP isolated from the marine bacterium Salinispora tropica, which
was approved by the FDA in 2010 and is marketed by Eisai Pharmaceuticals under the name of Halaven. The last approved anticancer drug related to MNP is the antibody− drug conjugate (ADC), brentuximab vedotin. It is marketed by Seattle Genetics under the name of Adcetris. It is composed of a tumor-specific antibody and the pentapeptide monomethyl auristatin E, which is a derivative of dolastatin 10. This drug was approved by the FDA in 2011 and in Europe in 2015. The FDA granted regular approval in November of 2017 for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy. Additionally, it was approved by the FDA to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy in March of 2018. Lovaza is a mixture of two ethyl esters of fish-derived ω-3 polyunsaturated fatty acids, eicosapentanaenoic acid (EPA), and docosahexaenoic acid (DHA). It was approved by the FDA in 2004 as a therapeutic agent for reducing serum triglycerides, and it is marketed by GlaxoSmithKline. Vascepa, sold by Amarin, is a pure EPA ethyl ester ω-3 polyunsaturated fatty acid, while Epanova, sold by AstraZeneca, is a mixture of three free ω-3 polyunsaturated fatty acids. They were approved by the FDA in 2013 and 2014, respectively, to treat also hypertriglyceridemia. Moreover, 23 compounds constitute the global marine pharmaceutical clinical pipeline, which are in Phase III, II, or I of drug development.8 Compounds in phase III include plinabulin (see Figure 1), which was developed from the fungal diketopiperazine halimide, isolated from a marine fungus Aspergillus sp. and from phenylahistin (the 6S stereoisomer of halimide) isolated from the terrestrial fungus Aspergillus ustus. This antimicrotubule agent inhibits tubulin polymerization. Currently, the combination therapy of plinabulin and docetaxel is in Phase III clinical trials for the treatment of nonsmall cell lung cancer and for the prevention of chemotherapy-induced B
DOI: 10.1021/acsmedchemlett.8b00368 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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in clinical trials is very promising. The design of new ADCs and the combination with other anticancer agents represent an interesting opportunity to explore the extraordinary potential of MNPs in the anticancer field where the majority of the marketed and candidate drugs fall. With the aim of ensuring the widest development of their structural diversity and bioactivity, the MNPs are best tested in the broadest range of biological assays, which is increasingly facilitated by emerging technologies.5
showed to be a potent anticancer drug by inhibiting the proteasome. The cyclic depsipetide plitidepsin (dehydrodidemnin B), commercialized as Aplydin by Pharmamar, which was in Phase III for the treatment of multiple myeloma in combination with dexamethasone, failed to approve the marketing authorization by the EMA in March 2018. The FDA and EMA both granted breakthrough therapy designation to enfortumab vedotin in 2018, another ADC of auristatin E but using an anti-Nectin-4-monoclonal antibody, for patients with locally advanced or metastatic urothelial cancer. Although marine invertebrates have been the source of the majority of bioactive MNPs, with Porifera (sponges) and Cnidaria phyla being the most prolific, the true origin of most marine natural products appears to be the microorganisms living in concert with them. Most invertebrates are sessile and soft bodied and thus are subject to potential parasite predation and detrimental microbial colonization. As a result, they require a complex arsenal of metabolites produced by symbiotic microorganisms for facilitating their natural defenses. This is likely the reason why almost all of the MNPs approved as drugs or currently in clinical trials come from bacterial and cyanobacterial biosynthetic sources.10 The Ascomycota (kingdom Fungi) and Actinobacteria have been among the four most widely collected phyla, along with Porifera and Cnidaria, during the last years.3 Microbial derived compounds will almost certainly dominate the MNP field in the coming years due to the diversity of microbial metabolites, the relative ease of their collection, and the advanced technologies for extraction of their genomic material and its manipulation in heterologous systems. In fact, marine actinomycete strains, both free living as those associated with marine invertebrates have been found to produce a high capacity for novel bioactive production with unique structural features when compared to terrestrial actinomycete isolates.11 The future of this field depends on the application of emerging advanced techniques and technologies to solve two main problems: microorganisms that cannot be cultured with current fermentation techniques and the activation of hidden microbial gene clusters responsible for the production of desired secondary metabolites. Some examples of emerging techniques are the metagenomic approach in which the total DNA extracted directly from environment samples is studied; genome mining, which involves systematic analysis of genome sequences with bioinformatics tools, and heterologue biosynthesis methods, which involve transfer of the genetic pathway for a desired NP to a surrogate host.12 The development of automated extraction, prefractionation, and dereplication methodologies has enhanced the quality of the extract analysis. Rapid dereplication processes using MS based or NMR based hyphenated analytical techniques coupled with the informative databases of NP (MarinLit, AntiMarine, SciFinder, etc.) have reduced the time consumed in repeatedly discovering known structures. In order to find new hits, a fusion approach has been proposed, combining biofractionation (activity-driven isolation) of bioactive extracts and the search for unique chemical constituents by NMR and LC/MS followed by their isolation and a broad evaluation in diverse biological assays.10 Taking into account the extremely rich biodiversity of the marine environment, the potential of MNPs in drug discovery is inestimable. The success ratio between approved drugs to date and the total of MNPs reported (ca. 28,500) is still very high in comparison to synthetic compounds, and the pipeline
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AUTHOR INFORMATION
Corresponding Author
*Tel: +34 881 01 2170. Fax: +34 981 67 065. E-mail: carlos.
[email protected]. ORCID
Carlos Jiménez: 0000-0003-2628-303X Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author declares no competing financial interest.
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ACKNOWLEDGMENTS C.J. is thankful to Ministry of Economy and Competitiveness (MINECO) (Grant AGL2015-63740-C2-2-R) of Spain, cofounded by the FEDER Programme from the European Union, for funding.
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REFERENCES
(1) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629−661. (2) Patridge, E.; Gareiss, P.; Kinch, M. S.; Hoyer, D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov. Today 2016, 21, 204−207. (3) Blunt, J. W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R. A.; Prinsep, M. R. Marine natural products. Nat. Prod. Rep. 2018, 35, 8−53 and the former articles of this series. (4) Newman, D. J.; Cragg, G. M. Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”. Planta Med. 2016, 82, 775−789. (5) Altmann, K.-H. Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery. Chimia 2017, 71, 646−652. (6) Romano, G.; Costantini, M.; Sansone, C.; Lauritano, C.; Ruocco, N.; Ianora, A. Marine microorganisms as a promising and sustainable source of bioactive molecules. Mar. Environ. Res. 2017, 128, 58−69. (7) Abdelmohsen, U. R.; Balasubramanian, S.; Oelschlaeger, T. A.; Grkovic, T.; Pham, N. B.; Quinn, R. J.; Hentschel, U. Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections. Lancet Infect. Dis. 2017, 17, e30−e41. (8) According to the following websites: http:// marinepharmacology.midwestern.edu; http://www.fda.gov/; http:// www.ema.europa.eu/ema; http://clinicaltrials.gov/ (accessed on August 6, 2018). (9) McCoy, M. Out of the sea and into the factory. Chem. & Eng. News. June 25, 2018, 34−35. (10) Gerwick, W. H.; Moore, B. S. Lessons from the Past and Charting the Future of Marine Natural Products Drug Discovery and Chemical Biology. Chem. Biol. 2012, 19, 85−98. (11) Seghal Kiran, G.; Ramasamy, P.; Sekar, S.; Ramu, M.; Hassan, S.; Ninawe, A. S.; Selvin, J. Synthetic biology approaches: Towards sustainable exploitation of marine bioactive molecules. Int. J. Biol. Macromol. 2018, 112, 1278−1288. (12) Zhang, G.; Li, J.; Zhu, T.; Gu, Q.; Li, D. Advanced tools in marine natural drug discovery. Curr. Opin. Biotechnol. 2016, 42, 13− 23.
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DOI: 10.1021/acsmedchemlett.8b00368 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
