Natural Products from Marine Invertebrates and Microorganisms in Brazil between 2004 and 2017 : Still the Challenges , More Rewards

The Brazilian marine biodiversity represents a unique, yet underexplored resource of biologically active compounds. This review provides an analysis of the development of marine natural products chemistry in Brazil within the period comprised between 2004 and 2017. Emphasis is directed towards marine invertebrate and marine microorganisms metabolites, including isolation, structure analysis, biosynthesis, bioactivities and total synthesis. An overview of the research on marine natural products by Brazilian researchers is also discussed, as well as perspectives for the development of the chemistry of marine natural products in Brazil.


Introduction
The chemistry of natural products is a science well established in Brazil, spanned over 60 years and all over the country.Most of Brazilian natural product researchers devote efforts to the investigation of plant metabolites.From the beginning of the 21 st century there has been a substantial growth of research on microbial natural products by Brazilian researchers, 1 and on marine natural products as well.The interest of Brazilian natural product chemists to investigate other sources than plants for the isolation of secondary metabolites are consequential to the chemical diversity of marine and microbial organisms.Clearly distinctive biosynthetic pathways arose from unrelated biological groups or from their respective associated microorganisms.Increasing evidences demonstrate that bacteria, cyanobacteria and fungi are now considered as the actual producers of many natural products first isolated from macroorganisms, both terrestrial 2,3 and marine. 4hile the knowledge on the secondary metabolism interplay between micro-and macroorganisms is only starting to be deciphered, it seems clear that the approximate number of 300,000 secondary metabolites so far identified from all biological sources may represent only a tiny fraction of genes regulating the biosynthesis of natural products. 5Unexpressed genes coding the biosynthesis of natural products appear to be the largest fraction of genomes encoding the biochemistry of natural products pathways.Thus, if the sciences of investigating natural products have expanded to unexpected boundaries in a very impressive rate since the advent of genomic tools, there is no need to say that much more remains to be done, particularly exploring new biological sources for the discovery of secondary metabolites.Among poorly known sources of natural products, Gram-negative bacteria are now under a more intense scrutiny, since these bacteria are capable of survive in many habitats and produce a series of antimicrobial molecules. 6Additionally, the exciting discovery of a new marine biome at the mouth of the Amazon river provided a series of yet uninvestigated species of marine sponges and other marine invertebrates. 7he move of natural products chemistry in Brazil towards contemporary approaches to discover novel natural products has been slow, for various reasons.First, the lack of expertise on the use of genomic tools for the investigation of secondary metabolism is critical.This is a severe gap that must be faced in the current education of graduate students involved in natural products chemistry projects.Second, the need of closer collaborative efforts between chemists, pharmacologists and biologists, including microbiologists, is evident.There are still very few collaborative research efforts in Brazil involving bioassay-guided isolation, as well as the chemical synthesis and medicinal chemistry of bioactive or chemically unique natural products.However, the most difficult challenge to address is the need to develop a truly innovative natural products science in Brazil.A new vision in the way of natural product chemistry has been performed is very much in need of consideration, since the country is still one with the highest biodiversity in the planet-remaining largely unexplored towards the identification of novel, biologically active natural products. 8he Brazilian marine environment is now under a more intense investigation by Brazilian natural product chemists, as shown by the exponential growth of research in this field.This review covers the literature on natural products chemistry of marine invertebrates and marine microorganisms published between 2004 and August 2017 by Brazilian researchers as corresponding authors.
Research on algae natural products in Brazil has been the subject of two special issues of the Brazilian Journal of Pharmacognosy, 9 and therefore will not be herein discussed.A special issue of the same journal on marine natural products has been published in 2015. 10Publications dealing with crude extracts or with only partially identified, bioactive or not, chemical entities or even primary metabolites, are not included as well.

Marine Microorganisms
As predicted in a previous review, 11 the investigation of marine-derived fungi and bacteria metabolites by Brazilian researchers has grown impressively during over the last decade.Collaborative efforts between microbiologists and chemists led to the discovery of a number of bioactive metabolites produced by marine-derived microbes.Investigation on the biosynthesis of marine-derived microbial metabolites during this period is also noteworthy.The large majority of bacteria metabolites isolated by Brazilian researchers are derived from amino acids, while polyketides corresponds to up 50% for fungi secondary metabolites.

Bacteria
A sponge-associated strain of Pseudomonas fluorescens produced the known diketopiperazine cyclo-(L-Leu-L-Pro) (1, Figure 1). 12Assignment of the absolute configuration was based on comparison with literature data, with no mention to a value of specific rotation.Cultures of Streptomyces sp.provided the known diketopiperazines (Figure 1) cyclo-(L-Phe-trans-4-OH-L-Pro) (2), cyclo-(L-Phe-L-Pro) (3) and cyclo-(L-Trp-L-Pro) (4).No mention to the experimental assignment of absolute configuration was provided. 13Well-known prodigiosin (5), deoxycholic acid (6) and cholic acid (7) were isolated from cultures of Pseudoalteromonas sp.(Figure 1). 14Since the production of sterols by bacteria is very unlikely, 15 growth media used in this investigation, namely starch casein agar, may contain sterols, thus compounds 6 and 7 may be media components.
The new 2(1H)-pyrazinones giovaninones A-D (8-11, Figure 1) were produced by a strain of Streptomyces sp.isolated from marine sediments. 16Compounds were identified by analysis of spectroscopic data, using HPLC-SPE-NMR (high performance liquid chromatography-solid phase extraction-nuclear magnetic resonance) with a cryoprobe.No bioactivity data was reported for compounds 8-11.
Bromotyrosine-derived verongidoic acid (12), 11-hydroxyaerothionin (13) and fistularin-3 (14) have been isolated from cultures of Pseudovibrio denitrificans  obtained from the sponge Arenosclera brasiliensis (Figure 2), and identified by analysis of spectroscopic data, including the assignment of absolute configuration by circular dichroism analysis. 17The production of bromotyrosine-derived metabolites by a marine bacterium provided strong evidence that such metabolites are likely not produced by sponges, as it has been repeteadly assumed in the past. 18,19The isolation of 12-14 from cultures of a Pseudovibrio Gram-negative bacterial strain illustrates the potential metabolic diversity of this particular group of marine bacteria, first described only ten years ago. 20ponges harbor a high density of cyanobacteria and bacteria which may exceed those of surrounding seawater by up to three orders of magnitude. 18The microbiome composition of Aplysina sponges, the main source of bromotyrosine-derived metabolites, is rather homogeneous within the genus, [21][22][23] but distinct to the environmental microbiome to which the sponges are exposed. 24One of the unique characteristics of the microbiome of Aplysina sponges is the high diversity and abundance of bacteria belonging to "Poribacteria" and Chloroflexi clades, 19,21,22,25 bacterial groups which are considered true sponge symbionts 26 and that present the enzymatic machinery for the biosynthesis of secondary metabolites. 27,28Based on evidences that marine sponges share microbiomes with similar composition, it is possible that horizontal gene transfer between marine sponge symbionts is common. 29However, there is still no definitive evidences of exchange of genomic material between sponge-associated bacteria. 29,30On the other hand, colonization of sponges by bacteria found in surrounding seawater has been repeteadly observed, indicating that a bacterial interchange between species is a real possibility. 26uch evidences are supported by solid exprimental data indicating both vertically and horizontally bacterial transmission within and between sponge species. 21,22,26,31he importance of developing strategies for culturing marine bacteria, in particular sponge symbionts, must be stressed, 21,22,26,32 since the large majority of sponge-associated microbial strains are considered to be resistant to cultivation 26 or the secondary metabolism is difficult to be trigger.This is not only particularly relevant for the correct assignment of a microbial production of secondary metabolites, 30 along to the knowledge of microbial physiology and ecology of sponge symbionts 22,26,31 but also for the detailed investigation of unique biosynthetic pathways which are not found elsewhere in nature but in sponges.

Marine Invertebrates
Marine invertebrates collected along the Brazilian coastline for chemical and pharmacological investigation have a large extension of redundancy with invertebrates collected in the past in the Caribbean region.Such redundancy led to the isolation of several known compounds, 70% of which are aminoacid-derived.

Mollusks
Very often shell-less marine mollusks accumulate metabolites captured from preys, which can be invertebrates such as sponges, ascidians, bryozoans, soft-corals and other mollusks.Such metabolites are considered as chemical defenses of the soft-bodied, frequently beautifully colored nudibranchs.

Ascidians
Colonial ascidians are members of Tunicata phylum which are the most often investigated towards the discovery of bioactive secondary metabolites.A large number of ascidians natural products are alkaloids and NRPS-derived peptides, some of which are produced by the associated microflora such as Prochloron. 92,93rom the ascidian Clavelina oblonga the new aminoalcohol (2S,3R)-2-aminododecan-3-ol (230, Figure 28) has been isolated together with the known bis-oxazolidinone 144, previously reported only from Verongid sponges.The absolute stereochemistry of 230 was determined after derivatization and circular dichroism analysis.Compound 230 displayed antifungal activity against Candida albicans and C. glabrata with MIC at 0.7 and 30.0 µg mL -1 , respectively. 94The new polyunsaturated alcohol 3Z,6Z,9Z-dodecatrien-1-ol (231, Figure 28) have been obtained from Botrylloides giganteum. 58nvestigation of the extract from Didemnum ligulum yielded asterubin (232, Figure 28) and N,N-dimethyl-O-methylethanolamine (233, Figure 28). 69Extracts of the ascidian Didemnum sp.provided the highly modified diketopiperazines (Figure 28) rodriguesine A (224) and B (225).Rodriguesines N-acetyl derivatives 234 and 235, respectively, have been obtained from another sample of the same ascidian collected at the same location. 95Structure of compounds 224, 225, 234 and 235 has been established by analysis of spectroscopic data, while absolute configuration has been established by Marfey's method.
Investigation of an aqueous MeOH extract of the ascidian Eudistoma vannamei yielded two new staurosporine derivatives, 2-hydroxy-7-oxostaurosporine (236, Figure 29) and 3-hydroxy-7-oxostaurosporine (237, Figure 29).The mixture of 236 and 237 displayed cytotoxic activity across a panel of tumor cell lines with IC 50 values in the range of 10.3-144.47nM and was 14 times more cytotoxic than staurosporine (238). 96The occurrence of such alkaloids in E. vannamei may be correlated to the presence of associated biota, such as Streptomyces bacteria.In the light of to this hypothesis, marine microorganisms associated with E. vannamei were recovered and cultured.One strain of Streptomyces sp. was able to generate staurosporine (238), detected by LC-MS/MS analysis, while none of the hydroxy-7-oxo derivatives were detected. 97

Total Synthesis of Marine Natural Products in Brazil
In the first and sole review on the synthesis of marine metabolites by Brazilian organic synthesis chemists, Prof Alphonse Kelecom reviewed the synthesis of twenty-three metabolites, the large majority being terpenes. 98Synthesis of alkaloids and polyketides have also been included.The present coverage attempts to comprehensively update Prof Kelecom's review, organized by biological source and biogenetic grounds.Only total syntheses of natural products have been herein considered, including syntheses that enabled structural re-assignments of natural products.Partial syntheses, formal syntheses, syntheses of "unnatural" natural products and of natural product derivatives are explicitly omitted.

Total synthesis of marine microbe metabolites
The antibiotic pentabromopseudilin ( 239) is considered the first secondary metabolite isolated from cultures of a marine bacterium, namely Pseudomonas bromoutilis 99 and Chromobacterium sp. 100 Schwalm et al. 101 synthesis of 239 (Scheme 4) proceeded from the orthomethoxy benzenediazonium salt 240 converted into the 2-arylpyrroline 241 in 78% yield after optimization.The product 241 was converted into the 2-substituted protected pyrrole 242 by oxidation with DDQ in almost quantitative yield.Deprotection of both pyrrole and phenol groups to give 243 was accomplished in excellent yields, followed by bromination with pyridine/HBr to give the natural product 239 in 28% overall yield.
Enhygrolide A (244) was isolated from cultures of the marine myxobacterium Enhygromyxa salina, and displayed antibiotic activity against Arthrobacter crystallopoietes. 102he synthesis of 244 (Scheme 5) 103 was accomplished from the condensation of tetronic acid 245 with paramethoxybenzaldehyde (246) using Hantzch ester 247 as hydride source and L-proline as catalyst.Esterification of the product 248 with pivaloyl chloride under basic conditions provided 249 which underwent alkylation with isobutyl magnesium bromide to give 250.Condensation with benzaldehyde followed by phenol deprotection gave enhygrolide A (244) in 54% overall yield.
The total synthesis of coibacins A (251) and B (252) have been completed and allowed the revision of the stereochemistry (Scheme 6). 104Coibacins were first isolated from the cyanobacterium Oscillatoria sp. and displayed cytotoxic and anti-Leishmanial activity. 105The highly convergent strategy involved the preparation of four  Scheme 5. Total synthesis of enhygrolide A (244). 102termediates, 257, 263, 265 and 269.The preparation of ketal 257 started by protection of the epoxyalcohol 253, followed by esterification of alcohol 254 and metatesis reaction with Grubbs I catalyst, to afford the lactone 255 in 58% yield over four steps.Reduction with DIBALH and formation of the ketal group was followed by the alcohol deprotection and oxidation to give the chiral ketal 257 in 72% over four additional steps.The synthesis of phosphonium salt 263 was achieved from the diol 258 via two tandem oxidation/Wittig olefinations, followed by the diester 260 reduction and monoprotection.The phosphonium salt 263 was then prepared by usual interconversions.The overall yield for the preparation of 263 from 258 was 32%.Coupling of 257 with 263, followed by the alcohol deprotection and oxidation to the corresponding aldehyde gave 265 in 60% over two steps.Next, preparation of the cyclopropane moiety involved a Charette asymmetric cyclopropanation of trans-crotyl alcohol (266) using a borolane-based ligand.The product 267 was reacted with 2-mercaptobenzothiazole in the presence of diisopropyl azodicarboxylate to give 268 in a Mitsunobu-type reaction.Oxidation of the mercaptane 268 with ammonium molybdate and oxygen peroxide yielded the suitable sulfone 269 in 39% over three steps.Coupling aldehyde 265 with the sulfone 269 was achieved in the presence of sodium hexamethyldisilazide.The product 270 was subjected to oxidation with pyridinium chlorocromate to afford a mixture of geometric isomers resulting from the Wittig reactions, which could be efficiently separated by HPLC.Analysis of the products obtained indicated that (5S,16R,18R)-251 was the enantiomer of natural coibacin A, which had, then, its stereochemistry redefined.The synthetic strategy developed for the synthesis of coibacin A enabled the preparation of all its stereoisomers.Coibacin B (252) was prepared by a very similar approach to that of coibacin A (251).
The preparation of 5,5-dichlorohexanal (284) involved the conversion of hex-5-en-2-one (281) to its corresponding hydrazone followed by oxidation in the presence of copper chloride to give 282.Hydroboration-oxidation followed by oxidation of the alcohol 283 gave 284.Reaction of 284 with Scheme 7. Total synthesis of lyngbyabellin M (271). 106e chiral propionate ester 285 provided the ester 286 which was hydrolysed to 287.The absolute configuration of 287 was confirmed by its conversion to the corresponding diol (by reduction of the acid with LiAlH 4 ), followed by conversion to the corresponding acetonide with 2,2-dimethoxypropane with concomitant Mosher ester analysis.After the alcohol protection of 287, the product was coupled with 280 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and DMAP, followed by ethyl ester hydrolysis with hydroxymethyltin to provide 289.Intermediate 289 was coupled with 274 also using EDC and DMAP, followed by the alcohol deprotection, to give lyngbyabellin M (271).The brominated alkaloids 3-bromoverongiaquinol (290) and 5-monobromocavernicolin (291), previously isolated from the sponge Aplysina cavernicola, 108 have been synthezised (Scheme 8).109 Starting from para-benzoquinone (292), which reacted with the lithium enolate of N,O-bistrimethylsilylacetamide (293) to give the mixture of protected and unprotected amides 294 and 295.The mixture of 294 and 295 were first brominated then treated with 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in MeCN to provide 290 and 291 in 47 and 20% yield, respectively.

Aromatic derivatives
A convergent synthesis of metachromin A (309), previously isolated from the sponge Hippospongia metachromia, 112 has been completed (Scheme 11). 113ynthesis of the non-aromatic fragment 310 started by alkylation of the trimethylsilylenol ether derived from 2,6-dimethylcyclohexanone (311) with methyl vinyl ketone (312).The product (313) was protected with 2,2-dimethyl-1,3-propanediol (314) before a Wittig olefination followed by the ketone deprotection, to give 310.The synthesis of the aromatic moiety 316 started with the transformation of the chloride 317 into the carboxylic acid 318, which was then reduced and protected to give 319.The protected alcohol 319 was then oxidized and acetoxylated to yield 320 before transformation of the protected alcohol in the phosphonate 316.Both 310 and 316 were then coupled via a Horner-Wadsworth-Emmons reaction, to yield the precursor of the natural product 309, which was obtained after the reduction of esters and oxidation of the hydroquinone.

Polyketides
A synthesis of callystatin A (327), a potently cytotoxic complex polyketide isolated from the sponge Callyspongia truncata in minute amounts (1 mg from 100 kg of sponge), 115 has been developed (Scheme 13) 116 in preparing three fragments, 328, 329 and 330, for subsequent coupling.Fragment 328 was synthezised from the chiral diol ester 331 by tert-butylsilyl (TBS)-protection, followed by ester reduction to the corresponding aldehyde, which was condensed with ethyl 2-((bis(o-tolyloxy))phosphoryl) acetate to give the unsaturated ester 332 in a 94:6 Z/E selectivity.The ester was converted to the chiral lactone by treatment with DIBALH for the ester reduction, a Dowex resin for the alcohols deprotection, followed by a MnO 2 oxidation to provide the lactone 333.Protection of the primary alcohol with TBS, then reduction of the lactone carbonyl group and treatment of the lactol with i-PrOH and catalytic PPTS provided the desired ketal 328.The second fragment was the phosphonium salt 329, synthezised from methyl (R)-3-hydroxy-2-methylpropanoate (334), first by alcohol protection, then ester reduction followed by a Swern oxidation to provide the aldehyde 335.This aldehyde was coupled with the β-ketophosphonate 336 to yield the unsaturated ester 337.Ester reduction with DIBALH, followed by alcohol substitution by bromine and subsequent substitution by tributylphosphine provided the suitable phosphonium salt 329.Coupling of 328 and 329 in the presence of ((methylsulfinyl)methyl)lithium gave the conjugated diene 339 in excellent yield (82%) and with a 95:5 E/Z stereoselectivity.Primary alcohol deprotection followed by functional group interconversions (FGI) to its corresponding iodide 340 was accomplished in 90% yield in two steps.The third fragment 330 was synthezised through the longer sequence, starting by coupling 341 and 342 in 89% yield and 95:5 diastereoselectivity. Conversion of the oxazolidinone 343 to its corresponding Weinreb's amide and alcohol protection led to 344, which was then converted to the alcohol 345 by amide reduction to its corresponding aldehyde before condensation with methyl 2-(diethoxyphosphoryl)acetate and reduction of the ester formed.The allylic alcohol 345 was converted to its epoxide before alkylation with Me 2 CuCNLi 2 to give the diol 346.Oxidation of the primary alcohol followed by coupling with EtO 2 C−C(=PPh 3 )Me gave the unsaturated ester 347 which was reduced and oxidized to the aldehyde 348.Protection of the alcohol, conversion of the aldehyde to its corresponding vinyl iodide and alcohol deprotection provided the third fragment 330 for the synthesis of callystatin in 21% overall yield from 341.Coupling of 340 with 330 (the TBS protected 330) in the presence of t-BuLi and MeO-9-BBN to provide a boronate intermediate in order to be subjected to a palladium-catalyzed crosscoupling led to the formation of the pentaene 350 in 38% yield.Final FGIs followed by alcohol deprotection gave callystatin A (327) in 3.5% overall yield.

Corals
A synthesis of racemic pathylactone A (352), isolated from the soft coral Paralemnalia thyrsoides, 117 was developed (Scheme 14) 118 from 2-methylcyclohex-2-en-1-one (353) by Scheme 11.Total synthesis of synthesis of metachromin A (309). 113heme 12.Total synthesis of esculetin-4-carboxylic acid ethyl ester (322). 114cheme 13.Total synthesis of callystatin A (327). 116lkylation with the Gilman reagent then with allyl bromide, to give a 1:4 mixture of stereoisomers 354 and 355.Intermediate 355 was further alkylated with 1-((3-iodopropoxy)methyl)-4-methoxybenzene to give the mixture of alcohols 356 and 357 which was transformed into the alkene 358 with POCl 3 and DBU.Double dond epoxidation followed by cyclization provided a mixture of tetrahydrofurans 360 and 361.Alcohol protection and double bond cleavage on the stereoisomer 361 gave the ketone 363 which was transformed into the natural product 352 after oxidation of the tetrahydrofuran ring into its respective lactone followed by alcohol deprotection.Careful analysis of the NMR data obtained by the authors for synthetic 352 indicated that the original report on its isolation presented some misassignments, particularly for the carbinolic group.

Mollusks
A synthesis of racemic spisulosine (364), previously isolated from the clam Spisula polynyma, was achieved (Scheme 15). 119Palmitaldehyde (365) was subjected to a Morita-Baylis-Hillman reaction with methyl acrylate and 1,4-diazabicyclo[2.2.2]octane (DABCO), to provide the corresponding alcohol-conjugated ester, which was protected and hydrolysed to give 366.The acid 366 was subjected to a Curtius rearrangement to give the acyloin 367 in 40% in a four-step reaction sequence.Condensation of 367 with benzylamine and mild reduction with NaBH 3 CN gave the protected amine 368.Deprotection of both benzyl and sylil groups led to the natural product 364 in 10% overall yield.

Ascidians
Polycitrin A (369), isolated previously from the ascidian Polycitor africanus, 120 has been synthezised using a Heck arylation as the key step (Scheme 16). 121Palladiummediated Heck arylation between maleic anhydride with the tetrafluoroborate salt of diazonium 371 gave anhydride 372 in 46% yield after the deprotection of phenol groups.Scheme 17.Total synthesis of synthesis of rubrolide B (377). 124omination of 372 followed by coupling of product 373 with tyramine (374) provided the natural product 369 in 12% overall yield.A related and improved synthesis for polycitrin A (369), as well as for prepolycitrin (375) and polycitrin B (376), has been subsequently developed. 122brolides are butenolides which have been first isolated from the ascidian Ritterella rubra. 123Recently a unified synthesis of rubrolides B, I, K and O has been developed (the synthesis of rubrolide B, 377, is illustrated in Scheme 17). 124Suzuki coupling of the lactone 378 with the boronic aromatic derivative 379 gave the product 380 in very good yield (73%) after deprotection.The aromatic lactone 380 was then coupled with para-methoxybenzaldehyde (381) to afford intermediate 382.Deprotection of the phenol group followed by perbromination of both benzene moieties led to the natural product 377 in 42% overall yield from 378.
These remarkable total syntheses by Brazilian organic synthetic chemists represent major achievements, during a period of limited financial support for research by Brazilian Federal funding agencies.Sadly, the real challenge of total synthesis of natural products in Brazil is currently being pursued by only very few research groups of organic chemists, most of which are senior researchers.Therefore, we expect a diminishing number of total syntheses of marine natural products achievements by Brazilian chemists in the forthcoming years.

Marine Natural Products in Brazil: Present and Future
The current interest by Brazilian natural product scientists to investigate marine natural products is justified by the fact that secondary metabolites isolated from marine organisms present a chemical diversity which is very distinct of terrestrial plants.Such interest is evident when we consider the number of isolated compounds, both known and new, and in the number of articles published within the period covered in the present review (Figures 30  and 31).This change of perspective by Brazilian natural product scientists towards marine natural products is considered very positive.Nature is virtually an infinite source of structurally exquisite compounds, most of which are biologically active.Biological sources are very abundant in Brazil, both terrestrial and marine.New strategies and bioassays, the use of modern and sensitive tools for dereplication and prioritization, searching for minor metabolites, are approaches that should be envisaged for the discovery of new natural compounds, from any biological source.
As previously predicted, 11 research on marine microbial secondary metabolites expanded significantly during the 2004-2017 period (Figure 31).This is certainly also associated to the chemical novelty of secondary metabolites produced by marine-derived strains, the relatively easy access to marine microbes when compared to marine invertebrate collections and the possibility to obtain large amounts of material for investigation by microbial culturing.Marine-derived fungi have been explored more extensively than marine-derived bacteria by Brazilian natural product chemists.It seems that fungi are more friendly to manipulate, to grow and to produce secondary metabolites of interest.6][127][128][129][130][131][132][133][134][135][136][137][138][139] Marine sponges are prolific in providing unique bioactive chemicals, many of which appear to be produced by associated microorganisms.As shown in Figure 32, alkaloids comprise the main group of marine secondary metabolites isolated by Brazilian researchers, followed by metabolites of mixed biosynthetic origin, polyketides and terpenes.Peptides are the least group of metabolites isolated, even including common diketopiperazines in this class of compounds.The distribution of metabolites of distinct biosynthetic pathways follow the usual distribution of marine natural products from the organisms of origin.6][127][128][129][130][131][132][133][134][135][136][137][138][139] Although an analysis of bioactivities has not been herein included, it sounds as illogical to correlate bioactivities to certain classes of metabolites or organisms.This is because the reported bioactivities are the author's choice rather than a comprehensive assessment of a bioactivity for each particular compound.
Perspectives for the development of marine natural products in Brazil indicate it as a promising venue.
Challenges include the access to minor and water-soluble metabolites, which are difficult to handle.Difficulties related to complex structure determination of novel minor metabolites are also evident.Additional problems to be circumvented include the re-isolation of known compounds and the chemical isolation of culture media components when dealing with marine microbes.Much expertise should be developed aiming to overcome such issues and promote a sounding capacity building and science of utmost quality, as marine natural products has shown to be since its origins in the 1950's.As for microbial natural products, 1 the chemistry of marine natural products in Brazil is still in its infancy.It is expected to grow to its maturity in the forthcoming years, resulting from the development of multidisciplinary projects.Marine natural products chemistry in Brazil should be well developed in order to deserve its current designation-marine bioproducts from the blue Amazon.

Figure 30 .
Figure 30.Articles on marine natural products published by Brazilian researchers as corresponding authors between January 2004 and August 2017.

Figure 31 .
Figure 31.Number of marine natural products per biological group isolated by Brazilian researchers as corresponding authors.

Figure 32 .
Figure 32.Biogenetic origin of marine natural products isolated by Brazilian researchers as corresponding authors.