Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl.

1): 763-778
(Annals of the Brazilian Academy of Sciences)
Printed version ISSN 0001-3765 / Online version ISSN 1678-2690
http://dx.doi.org/10.1590/0001-3765201820170653
www.scielo.br/aabc | www.fb.com/aabcjournal

The potential contribution of the natural products from

Brazilian biodiversity to bioeconomy

MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Departamento

de Química Orgânica, Instituto de Química, Universidade Estadual Paulista ‘Júlio de Mesquita
Filho’, Av. Prof. Francisco Degni, 55, 14801-970 Araraquara, SP, Brazil

Manuscript received on August 22, 2017; accepted for publication on September 20, 2017

ABSTRACT
The development of our society has been based on the use of biodiversity, especially for medicines and
nutrition. Brazil is the nation with the largest biodiversity in the world accounting for more than 15% of
all living species. The devastation of biodiversity in Brazil is critical and may not only cause the loss of
species and genes that encode enzymes involved in the complex metabolism of organisms, but also the loss
of a rich chemical diversity, which is a potential source for bioeconomy based on natural products and new
synthetic derivatives. Bioeconomy focus on the use of bio-based products, instead of fossil-based ones and
could address some of the important challenges faced by society. Considering the chemical and biological
diversity of Brazil, this review highlights the Brazilian natural products that were successfully used to
develop new products and the value of secondary metabolites from Brazilian biodiversity with potential
application for new products and technologies. Additionally, we would like to address the importance of
new technologies and scientific programs to support preservation policies, bioeconomy and strategies for
the sustainable use of biodiversity.
Key words: Brazilian biodiversity, natural products, medicinal chemistry, database.

INTRODUCTION World Health Organization, the use of traditional

medicine is growing in developed countries as a
The development and growth of our society has
complimentary use and reaches 80% in Africa, that
been based on the use of biodiversity. Plant
depends essentially on plants for primary health
species, particularly those identified as having
care (WHO 2017a). Pharmaceutical companies
nutrition and medicinal uses, were essential for
are interested in investigating plants as source for
human survival. Ancient populations around the
new lead structures and also for the development
planet established a set of useful plant species by
a long experienced selection. According to the of standardized herbal agents with proved efficacy,
safety and quality (Calixto 2000). The medicinal
Correspondence to: Vanderlan da Silva Bolzani
E-mail: [email protected] properties of plants have been the focus of scientific
* Contribution to the centenary of the Brazilian Academy of researches in the field of natural products, and great
Sciences. advances were achieved in the last century (Valli

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764 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

et al. 2012). Given the number of plant species diversity caused by urbanization, agriculture and
on Earth and the several biosynthetic pathways livestock. These areas contain several species that
capable of producing extraordinary chemical can be threatened with extinction in the near future,
diversity, biodiversity in tropical and equatorial and the biological knowledge would also be lost
environments offers a particularly rich potential in since they contain only 0.5% of the approximately
biologically active compounds that can be used as 300,000 species of plants cataloged and known in
models for medicinal chemistry and drug discovery the world as endemic to these environments (MMA
(Bolzani et al. 2012). 2017, Myers et al. 2000).
The term biodiversity can be defined The rate of Brazilian natural resources
as the variety and complexity among living devastation is alarming and many species are at risk
organisms, encompassing species, DNA, genes, of extinction. Furthermore, considering the loss of
proteome, metabolome and their interaction knowledge of traditional population on the uses of
with their ecological systems (Wilson 1999, these species, countless natural products of distinct
Noss 1990). Associated with biodiversity, there classes and completely unknown structural types
is a rich diversity of natural compounds with can be lost, many of them of inestimable scientific
peculiar structures that are still one of the most and technological value. To reverse this situation,
sophisticated sources of new molecular models for it is important to create interdisciplinary research
medicinal chemistry, development of new drugs, programs involving biologists, chemists, botanists
agrochemicals, fragrances, cosmetics, and food and pharmacologists dedicated to the rational use
supplements. Among the 1211 new low molecular and conservation of the remaining forest areas.
weight prototypes (known as New Chemical The devastation of biodiversity in Brazil may
Entities - NCE) introduced on the world market as not only cause the loss of rich chemical diversity,
pharmaceuticals during the period 1981-2014, 60% essential for prospecting hits and leads of effective
are derived from natural products, mimetics or drugs, but also the loss of genes that encode
designed from natural product structures (Newman enzymes involved in the complex metabolism of
and Cragg 2016). plants (Silva et al. 2010).
Brazil is the country with the largest The economical interest in the natural resources
biodiversity in the world and has been taking of “Terra Brasilis” dates from the colonization
actions to preserve it, being the first nation to period. The first Brazilian exploration based
sign the Convention on Biological Diversity in on extractive of the country was the exploration
1992. It stands out for having a mega biodiversity, of Caesalpinia echinata (Fabaceae), known as
accounting for more than 15% of all living species paubrasilia, used in Europe as source of natural
in the planet (MMA 2017). Brazil has an area of dye (Silva et al. 2010). As a result, the occupation
8,511,996 km² in which six terrestrial biomes are of the coastal area of Brazil began in this period and
distributed (the Amazon rainforest, the Caatinga, currently about 60% of the Brazilian population
the savana-like Cerrado, the Atlantic Forest, the lives in this region (SOS Mata Atlântica 2017).
swamp known as the Pantanal and the Pampas) This predatory occupation almost caused the
and a sea coast of 7,491 km hosting three marine extinction of a whole Brazilian biome, the Atlantic
ecosystems and twelve major hydrographic regions forest, of which only about 7% remains. Therefore,
(MMA 2017). Two of these ecosystems, the Atlantic the combination of social, political and economic
Forest and the Cerrado, are considered hotspots of welfare with the rational use of natural resources
biodiversity due to the accelerated loss of biological is of extreme importance. Despite the devastation

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 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 765

process of some biomes, Brazil has shown commodities and electricity, instead of fossil-based
commitment in the conservation and sustainable ones. Bioeconomy is the key element that could
use of biodiversity, being the key negotiator of the address some of the important challenges faced
Nagoya protocol (Pavarini et al. 2012). by society, especially regarding energy generation
Apart from the indiscriminate predation by replacing non-green fossil fuels with cleaner
of biodiversity, the world population is facing alternatives (Philp 2015). It comes to assist the
serious problems such as maintaining quality of replacing and changing the world’s economical
life, improving quality in sub-developed countries systematic in order to prevent collapse. We could
and making a sustainable use of Earth resources take metabolic engineering as an example of new
(Brugge et al. 2016). Population random growth technologies that had considerably broadened the
is the main cause of these problems. Statistics variety and amount of compounds now accessible
indicate that there will be more than nine billion that were once restricted to naturally occurring
people in the world by 2050, and with a higher metabolites (Murphy 2011).
proportion increasing their quality of life (which Brazil could be a leader in this economic
could be excellent), it can become unsustainable transition since it is granted with all the
since resources are finite. The current economic conditions to be a sustainable model. It has the
model can no longer be sustained by the world, largest biodiversity of the globe, suitable climate
and an economy based in bio-products is not only condition, abundant land, relative small population
attractive as a gain in quality of life, but also a and plenty of natural resources. Infrastructure has
mandatory commitment to the Earth (Philp 2015). to be improved and greener technologies must be
There are two aspects that could work together to incorporated to industry and agriculture. Brazilian
achieve this important task: public policies and economic success heavily relied on commodity
implement of new technologies. New technologies exports. This commodity success deviated
bring “greener”, safer, renewable, waste-free attention from important actions that should have
methods to replace old processes and public been done in structural (infrastructure, political
policies are essential to apply them in an organized reforms) and institutional (education, research,
and evenly manner. These two aspects are the core institutes) investments. Brazil failed in converting
of the new world sustainability strategy called its economic boom into knowledge, as can be seen
bioeconomy (El Chichakli et al. 2016). by the global share of high added value export that
scarcely changed in the last 20 years (Gallagher
BIOECONOMY
and Porzecanski 2010). Brazil should now “run
Bioeconomy is not a business segment or a specific after the lost time” and heavily invest in turning
scientific innovation, but includes “all economic commodities to high added value products. That
activity derived from bio-based products and means investing evenly in education, science and
processes which contribute to sustainable and innovative industry. Maybe more important than
resource-efficient solutions to the challenges we investment, Brazil should focus on improving
face regarding food, chemicals, materials, energy public management and supporting innovation
production, health and environmental protection” by reducing bureaucracy. As an example, patent
(RSB 2017). Bioeconomy is now part of the application in Brazil expects to wait 11 years to be
strategic actions of more than 40 countries (El approved, but this has started to be addressed (INPI
Chichakli et al. 2016). It uses bio-based products, 2017).

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766 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

Considering the chemical and biological the 1950s to the 1970s, who contributed greatly to
diversity present in Brazil, there is a universe of the formation of a new generation of researchers
opportunities for bio-based innovation. In the next in Brazil. Otto R. Gottlieb was initially interested
section we would like to point a few examples of in the immense biological diversity of the Amazon
Brazilian natural products that were successfully biome by studying arylpyrones, chromenes and
used (some by foreign countries) to develop benzophenones in species of the Myristicaceae
new products and give evidence of the country and Lauraceae families (Silva et al. 2010, Gottlieb
biodiversity potential. and Mors 1980). These natural products are
known due to their effects on the central nervous
THE POTENTIAL OF BRAZILIAN system, and therefore are important for the sedative
NATURAL PRODUCTS
pharmacological effect (Gottlieb and Mors 1980).
Neolignans are also well studied natural
Secondary metabolites play a key role in plants
products from Amazonian plants, mainly isolated
by regulating, balancing, adapting to habitats,
from Aniba spp. Gottlieb, Yoshida research
physical and climatic factors and protecting against
groups and also several Brazilian researchers
pathogens and predators. In view of the large
published a series of works on phytochemistry,
territorial extension of Brazil and the different
chemosystematic and biological activities of this
habitats in which the plants had to adapt during their
class of C6-C3 dimers, which classification was
evolution, it is well known that the Brazilian flora
designated by Gottlieb himself. Neolignans,
has an extraordinary, but underexplored chemical
as well as lignans, are well known due to the
diversity that could be used for the development
many pharmacological properties, especially
of bio-based products, including pharmaceuticals,
antitumor, anti-inflammatory, antileishmanial, and
cosmetics, food supplements and agricultural
antichagasic (Gottlieb and Mors 1980). Lignans
pesticides.
and neolignans of Brazilian species are chemically
The flora and fauna of the Brazilian Biomes and biologically well studied, particularly those
reveal a diversity of compound classes and isolated from Myristicaceae and Lauraceae
structural types of secondary metabolites. Plants, families. Approximately 350 neolignans and 270
fungi, insects, marine organisms and bacteria are lignans have been described in the literature from
sources of biologically active substances, being a plant species of the Brazilian flora (Silva et al. 2010)
rich natural library of hits and drug leads (Barreiro and about 75% of these were described by Gottlieb,
and Bolzani 2009). Natural product chemistry collaborators and other Brazilian researchers,
is a traditional research field in Brazil, and until which main focus were phenolic derivatives.
recently, most of the studies have been focused Natural products from plants of the Brazilian
on the fractionation, isolation and structural biodiversity are comprehensively reviewed from
elucidation of secondary plant metabolites. The the pharmaceutical, cosmetic and nutraceutical
study of microorganisms and marine organisms is point of view. Despite the immense chemical and
becoming more common in the national scientific biological resources, few examples of natural
projects, adding a new feature to the chemistry of products from the Brazilian biodiversity have
natural products in Brazil. reached the world market of drugs, and were
The modern phytochemistry in Brazil was developed outside of Brazil. The discovery of
introduced by the researchers Dr. Walter B. Mors, bradykinin (1) (Figure 1), isolated from the venom
Dr. Otto R. Gottlieb and Benjamin Gilbert from of Bothrops jararaca, is one of these examples

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 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 767

Figure 1 - Structure of bradykinin (1), a peptide extracted from Bothrops jararaca and the drug captopril (2, Captoten®) an ACE
inhibitor used for the treatment of hypertension designed from molecular simplification of 1.

(Ferreira et al. 1970). This peptide is an inhibitor of

the angiotensin-converting enzyme (ACE), which
is responsible for the conversion of angiotensin I
to angiotensin II during the passage through the
pulmonary circulation, and an important target for
hypertension treatment. Further investigations and
structural simplification led to the development of a Figure 2 - Pilocarpine (3), imidazole alkaloid active ingredient
new class of peptidomimetics, the ACE inhibitors, of Salagen® (Novartis).
classically represented by captopril (2), (Captoten®)
(Figure 1; Buss and Waigh 1995).
The alkaloid pilocarpine (3) (Figure 2) isolated
from Pilocarpus sp (Rutaceae) is another successful (Borraginaceae) was launched a few years ago
example of drug development from a natural on the pharmaceutical market as Acheflan ®
product isolated from a Brazilian biodiversity plant (Achē). This topical anti-inflammatory drug was
species. Pharmacological studies have shown that completely developed in Brazil, and consists of
pilocarpine is a muscarinic-type cholinergic agonist. a mixture of sesquiterpenes of the essential oil
Salagen® (Novartis) was launched as a medicine
of C. verbenaceae (Passos et al. 2007, Fernandes
to alleviate xerostomia due to the abnormality of
et al. 2007). The pharmaceutical industry Achē
the salivary glands that are affected by radiation in
also launched the anxiolytic standardized herbal
patients with head and neck cancer in the course of
medicine Sintocalmy® prepared with the extract of
radiotherapy treatment (Horiot et al. 2000).
Passiflora incarnata (Passifloraceae) containing
Concerning drug development, there are no
the flavonoid vitexin (apigenin-8-C-glucoside)
examples of pure drug compounds developed as
drugs in Brazil, however, there are some herbal (4) (Figure 3) as one of the active compounds.
medicines developed completely in Brazil. Natural Besides that, Stryphnodendron adstringens (Mart.)
products from the Brazilian biodiversity have been is traditionally used in wound healing, and the
extensively studied in research groups in Brazil, pharmaceutical company Apsen Farmacêutica
but the great number of isolated compounds is not have developed Fitoscar®, an ointment based on
consistent with the very few examples of drugs this species that contain a mixture of phenolic
developed. The first drug based on a chemically derivatives, mainly condensed tannins (Souza et al.
standardized extract of Cordia verbenaceae 2007, Minatel et al. 2010).

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768 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

for citrus growth and is the largest producer of

orange in the world, accounting for approximately
40% of the world production. Limonene is an
innovative green chemical and is being applied for
a wide variety of environmentally friendly uses
such as a bio-based solvent (replacing petroleum-
based ones), cleaning agent (conveniently in a
formulation with other surfactants) and pesticide
ingredient. Limonene has several more properties
as anticancer, chemopreventive, detoxifier and
anti-asthmatic. It can also be used as a chemical
Figure 3 -The flavonoid vitexin (4), from the Passiflora
incarnata extract, and one of the compounds present in the platform to produce higher added valued products.
herbal medicine Sintocalmy®. Nevertheless, much of the limonene comprised in
the citrus peels are not extracted as a by-product,
but are simply wasted (Ciriminna et al. 2014).

SCIENTIFIC PROGRAMS AND PUBLIC POLICIES

Within the scenario of need for economical

changes turning to a more sustainable world,
preservation research programs and public policies
are of extreme importance. In the research area,
in 1999 the ‘Fundação de Amparo à pesquisa
Figure 4 - Limonene (5), a natural product from citrus species.
do Estado de São Paulo’/FAPESP approved the
BIOTA/FAPESP Program and one of its objectives
The few examples of medicines or herbal is the search for bioactive compounds from São
medicines from species or chemicals from Brazilian Paulo State biodiversity, aiming at to find new
biodiversity makes evident that many plant species lead molecules from the main biomes Cerrado
has no refined study to validate medicinal plants, and Atlantic Forest. This program is a successful
representing a huge economic potential to be example that organized information about Brazilian
explored. biodiversity can assist the sustainable use of natural
Biodiversity provides extravagant molecular resources, launch of environmental laws and social
structures, but not only complex structures are and economic development (Joly et al. 2010).
medicinally or economically useful. In fact, Some examples of the advances and important
simplicity is usually much more useful, and we can information obtained from Brazilian biodiversity
get to the concept that less is more. A simple example in this collaborative program will be presented to
of a versatile bioeconomy chemical is limonene (5, highlight its importance.
Figure 4). This natural product abundantly found in The Amazonian forest region is a very rich
citrus fruits (it is a by-product of the citrus industry), Brazilian biome, and among all the variety of
is a renewable chemical in several applications such plants it encompasses, several hallucinogen and
as perfume, flavoring and, more recently, as a green toxic species can be found. Since pre-Colombian
solvent. Brazil is granted with good conditions times, the tea obtained from the decoction of these

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 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 769

plants, including species from Banisteriopsis and 12 and 14 can also be found in toads from the
Psychotria genera (McKenna et al. 1998), have been Bufo genus, and these compounds are considered
used in indigenous rituals, even so nowadays it can as prohibited drugs in United States, Australia
also be consumed in rituals of syncretic religions and United Kingdom (Queiroz et al. 2015). These
in Brazil, such as “Santo Daime” and “União do results contributed to a better understanding of the
Vegetal” (Labate and Feeney 2012). The Ayahuasca Ayahuasca, which consumption in Brazil is legal,
is a tea obtained from B. caapi (Malpighiaceae) and to emphasize the need of a stricter control in
and is consumed by these religions. However, the identification of these species in order to avoid
Tetrapterys mucronata (Malpighiaceae) can the risk of intoxication.
occasionally be used in this preparation due to the In the Brazilian territory, there are many
morphological similarity of these two species. It is tropical fruits that are important for the discovery
known that Banisteriopsis caapi has alkaloids in its of bioactive compounds, and its consumption is
chemical composition (Samoylenko et al. 2010), increasing due to the recognition of their nutritional
however, there were no studies in T. mucronata and therapeutic effects (Zeraik et al. 2011). In the
genus until recently. Northeast region, there are several species adapted
A phytochemical study performed by to the extremophile biome Caatinga. Many fruits
Queiroz et al. (2014) resulted in the isolation from these species play an important role in this
of 22 compounds from the ethanol extract of T. region’s economy, especially Spondias tuberosa
mucronata, of which six are new natural products, (Anacardiaceae), since it blooms and bear fruits
including two dimeric indole alkaloids (6 and over the dry season. Phytochemical investigations
7), one glycosylated lignin (8) and three new on S. tuberosa fruit pulp methanolic extract led to
phenanthrene derivatives (9, 10 and 11). Since this the identification of eight compounds, in which one
plant is known for acting in the central nervous is a new phenylethanol derivative, 16, and another
system, all compounds isolated were evaluated for one is a new benzoic acid derivative, 17, (Figure
the inhibition of acetylcholinesterase activity, and 6). Compounds 18 and 19 (Figure 6) presented
compounds 9 and 10, bufotenine (12), 5-methoxy- high antioxidant activity by DPPH (2,2-diphenyl-
N-methyltryptamine (13) and 5-methoxy- 1-picrylhydrazyl), ABTS (2,2’-azino-bis(3-
bufotenine (14) were active in concentrations ethylbenzothiazoline-6-sulphonic acid)) and
below 15 μM (Figure 5, Queiroz et al. 2014). ORAC (Oxygen Radical Absorbance Capacity)
In addition, compounds 12, 13, 14 and (EC50 3.51 ± 0.33 µM,1.13 ± 0.80 µM and 2.9 ±
15 (2-methyl-6- methoxy-1,2,3,4-tetrahydro- 0.2 µM for 18 and EC50 9.65 ± 0.21 µM, 7.55 ±
β-carboline) had not been reported yet as 0.40 µM and 3.4 ± 0.2 µM for 19 respectively),
possible constituents of Ayahuasca, therefore, a very similar values to the positive control quercetin
quantification of these substances by LC-ESI/MS/ (EC50 3.49 ± 0.23 µM, 2.97 ± 0.40 µM and 4.1
MS was performed. It was determined that in the ± 0.1 µM), and an acetylcholinesterase activity
water decoction of T. mucronata, compounds 12, inhibition of IC50 11.53 ± 0.59 µM and 12.65 ±
13, 14 and 15 were present in concentrations of 0.65 µM, respectively, comparable to the positive
2.32 ± 0.14, 0.50 ± 0.04, 1.53 ± 0.09 and 0.10 ± control galantamine (IC50 2.40 ± 0.25 µM) (Zeraik
0.01 mg.g -1, respectively. These amounts can et al. 2016).
increase with an optimum extraction method, Besides that, the dichloromethane extract
which can be achieved by the longer decoction time obtained from S. tuberosa pulp was evaluated for
required to Ayahuasca tea preparation. Compounds induction of quinone reductase activity, a cancer

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770 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

Considering that Jatropha genus is a rich

source of bioactive compounds, Pinto et al.
(2015) selected aerial parts of Jatropha ribifolia
(Euphorbiaceae) for a study. A new orbitide,
ribifolin (20, Figure 7), was obtained from the ethyl
acetate fraction of the hydro alcoholic extract and,
in order to characterize its structure, HRESIMS
analysis was initially employed. Knowing the exact
mass, a MS/MS analysis was performed, in which
a loss of water could be observed initially (due to
the ring opening), followed by the losses of amino
Figure 5 - Compounds isolated from T. mucronata (6-15). acid residues. Detailed information of 1D and 2D
NMR spectroscopy were necessary to determine
its stereochemistry, such as quantitative amino acid
chemopreventive activity assay (Cuendet et al. analysis, molecular dynamics/simulated annealing
2006). This extract presented an induction ratio and Raman optical activity calculations and
of 2.8 at 20 µg mL-1 in Hepa1c1c7 cells, and the measurements (Pinto et al. 2015).
cell viability was 78.6%, indicating a low toxicity After isolation and elucidation of compound
of this extract at this determined concentration 20, this peptide was synthesized using the solid-
(Zeraik et al. 2016). Therefore, according to phase technique (SPPS) in order to confirm the
these results, it was possible to identify and to proposed sequence and to obtain the amounts
highlight the biological potential in antioxidant needed to perform bioassays. In this process, a
and chemopreventive assays of this important linear sequence of ribifolin (21) was obtained in
functional fruit present in Brazilian Caatinga. addition to the cyclic one. These two substances
A relatively new research field in our research were evaluated for antiplasmodial activity, being
group is the study of species containing peptides chloroquine the positive control (IC50= 0.3 µM).
in its chemical composition, especially orbitides, The cyclic ribifolin presented a moderate activity
which are peptides cyclized by N-to-C and do of IC50 = 42 μM against P. falciparum 3D7 strain,
not present disulfides linkages. There are several while the linear derivative presented a much weaker
species from Jatropha genus that present this class effect on inhibiting the survival of the parasites
of compounds and they are known to exhibit a (IC50 = 519 μM). This was a very interesting result
great variety of biological activities (Sabandar et since it provided evidence that the cyclization step
al. 2013) (possibly due to its specificity, metabolic is important to improve the biological activity,
stability and similarity to protein structural mainly due to the minimization of conformational
patterns), including activity against Plasmodium freedom of the molecule, making it more specific.
falciparum, a protozoan responsible for the most Besides that, a cytotoxicity evaluation was
severe form of malaria, a neglected disease that performed, and it was observed that none of the
affect more than 200,000,000 people each year compounds were toxic to kidney cells (HEK293T)
(WHO 2017b). There are few available drugs for at the concentration range tested (0.001−100
malaria disease treatment, however, the parasites μM) (Pinto et al. 2015). These results are very
have been gaining resistance and the search for stimulating for further orbitides research from
new drugs to fight malaria has increased. species of Euphorbiaceae family.

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 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 771

Figure 6 - New compounds (16 and 17) and bioactive compounds (18 and 19) isolated from S.
tuberosa.

Figure 7 - Ribifolin (20), orbitide isolated from Jatropha ribifolia, and its linear derivative (21).

Figure 8 - the natural alkaloid (–)-3-O-acetylspectaline (22) isolated from S. spectabilis and its
derivative (23).

The ornamental species of Senna results obtained on pyridine compound (23, Figure
(Leguminoseae) are known for several applications, 8) suggested an efficacy for treating schizophrenia
and our group has studied Senna spectabilis due positive symptoms and an antidepressant-like
to the piperidine alkaloids it produces (Bolzani et effect (Valli et al. 2015). This compound can be
al. 1995, Viegas et al. 2004, 2005, Pivatto et al. synthesized with good yielding (96%) and its
2005). A series of pyridine anticholinesterasic chemical structure could be further investigated to
compounds were designed using molecular design new lead compounds. These results reinforce
hybridization technique between tacrine and the the use of rational approaches for increasing natural
natural alkaloid (–)-3-O-acetylspectaline (22) products biological activity and prospecting new
isolated from S. spectabilis (Valli et al. 2011). activities for known compounds.
The cholinergic system plays an important role An interesting study, also focused on S.
in the treatment of schizophrenia and depression, spectablis species, was performed with an endophytic
thus the pharmacological profile of three pyridine fungus that can be found on its leaves, named
compounds was evaluated aiming at potential Phaeoacremonium sp. Three new isoaigialones
adjuvants for the treatment of CNS disorders. The (A, B and C) and aigialone (compounds 24, 25,

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772 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

26 and 27, respectively, Figure 9), were isolated observed that bacteria can became resistant to these
from the ethyl acetate extract of this fungus. These substances and researches aiming new compounds
compounds were evaluated against Cladosporium with similar activity are being developed around
cladosporioides and C. sphaerospermum using bio- the world.
autography and compounds 25 and 27 presented Kielmeyera variabilis (Clusiaceae) is used in
antifungal activity with a detection limit of 5 μg Brazilian folk medicine to treat several tropical
(using Nystatin as a positive control at a detection diseases and bacterial infections. A bioactivity-
limit of 1 μg), that could be related to a defensive guided fractionation of the ethanolic extract
role of these compounds in S. spectablis leaves of K. variabilis branches was performed in
against microbial pathogens. Compounds 24-27
our research group and led to the isolation of
were also evaluated for cytotoxicity performed by
a new acylphoroglucinol (28, Figure 10), which
MTT assay against HeLa (human cervical tumor
the complex structure was elucidated by 1D
cell line) using camptothecin as a positive control
and 2D NMR spectroscopic analysis, mass
(IC50 = 0.12 μM). Compound 27 resulted in an IC50
spectrometry and its absolute configuration was
of 50 μM while 25 presented an IC50 value of 100
determined by electronic circular dichroism. This
μM, and compounds 24 and 26 were inactive (Silva
compound activity was evaluated against several
et al. 2017).
One of the most important discoveries Staphylococcus aureus (MRSA) strains and the
of human kind was the penicillin, the first in vitro antibacterial activity (MIC) observed for
antibiotic described in history. It is produced by EMRSA-16 was 0.5 mg L-1, a higher activity when
the Penicillium chrysogenum fungus and this compared to the control antibiotic (norfloxacin,
substance made a remarkable improvement in MIC = 128 mg L-1) (Coqueiro et al. 2016). This
human life expectancy after its discovery due to activity corroborated to the uses of this species in
the possibility to treat several bacterial infections folk medicine in Brazil and has opened a possibility
that used lead to death. Several other antibiotics for further evaluation of the anti-MRSA mechanism
were developed after penicillin, however, it was of action.

Figure 9 - New isoaigialones (24, 25 and 26) and aigialone (27) isolated from Phaeoacremonium sp.

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 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 773

to bring benefits both to science and to strengthen

the national bioeconomy. Countries like Germany
and England have a robust bioeconomy although
they do not have a great biodiversity in their
territories. In this sense, the objective of NuBBEDB
is to assist in the development of different fields of
Brazilian science, technological development of
biodiversity products with high added value and
public policies.
Figure 10 - New acylphoroglucinol (28) isolated from The NuBBEDB is being used by the scientific
Kielmeyera variabilis. community (Villoutreix et al. 2013, Harvey et
al. 2015, Kuenemann et al. 2016, Neves et al.
Another recent program for biodiversity is the 2015, Mohamed et al. 2016), and a work recently
NuBBE database: the database of natural products completed by our group described a synthetic
from Brazilian biodiversity. The chemical diversity analogue of the natural product piperlongumine as
of the Brazilian species is being catalogued by an inhibitor of breast cancer cell line migration.
this project created in 2013, initially with 640 Piperlongumine (29, Figure 12) is an amide
compounds isolated and identified by the Research alkaloid isolated from species of Piper having
Group Nucleus of Bioassay, Biosynthesis and a selective cytotoxic activity for some cancer
Ecophysiology of Natural Products (Valli et al. cell lines (Raj et al. 2011). Piperlongumine was
2013). NuBBEDB currently provides data of more selected for studies from NuBBE Database in a cell
than 2000 compounds of plants, marine organisms, migration-based screening with MDA-MB-231
fungi, etc, and contains chemical (metabolic class, breast cancer cells (EC50 of 3.0 ± 1.0 μM). A series
chemical structure, physicochemical properties, of analogues of piperlongumine were designed,
common and IUPAC name and molecular and the molecular simplified analogue (30, Figure
mass), biological (occurrence, habitat, biological 12) was the most active of the series, surpassing the
activities), pharmacological and spectroscopic data activity of piperlongumine (EC50 of 1.5 ± 1 μM)
(Pilon et al. 2017). This database is freely accessible and remaining selective with a selectivity index of
online, where it is possible to search for properties, 4.4 (Valli et al. 2017).
chemical structure, class of natural products or a
NEW TECHNOLOGIES
combination of molecular or biological criteria
(Figure 11, NUBBEDB 2017). The development of new technologies together
The scientific information published in more with preservation policies is a key strategy
than 50 years of studies on Brazilian biodiversity for the sustainable use of biodiversity. New
becomes easier to access when standardized, analytical approaches have been widely used
certified and organized in a database. The access for understanding the chemical metabolism of
and mapping of the molecular heritage of Brazilian biodiversity. The focus has been to understand in
biodiversity significantly reduces the time spent in a holistic way the relationships and interactions of
understanding and increases feasibility of applying a living system and its environment, to detect the
processes that involve technological research. This role of the natural products in these interactions
information center is freely available online in order and to identify all molecular components in a

An Acad Bras Cienc (2018) 90 (1 Suppl. 1)

774 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

Figure 11 - Layout of the search platform on NuBBEDB website.

complex sample. This objective is possible with the metabolites of a given biological origin matrix)
development of more sensitive mass spectrometry is a strategy widely used in European and Asian
(MS), nuclear magnetic resonance (NMR) and high countries to validate plants for human use. This
performance liquid chromatography (HPLC), used kind of study consists in comparative analysis on
for the identification of pure secondary metabolites metabolites from different samples, therefore, a
or in complex mixtures, reducing the amount of metabolomics study should approach analytical
sample for research and the time required for methods considering all inherent chemical
analysis. characteristics from the natural product classes
Metabolomics (which consist in a set of studied. This information should contain all
qualitative and quantitative data on the secondary secondary metabolites present in the studied sample.

An Acad Bras Cienc (2018) 90 (1 Suppl. 1)

 NATURAL PRODUCTS FROM BRAZILIAN BIODIVERSITY 775

Figure 12 - Piperlongumine (29), an amide alkaloid isolated from Piper species and its biologically
active simplified analogue (30).

It has become a robust tool to answer questions about and provides outstanding selectivity, avoiding
how organisms of our great biodiversity interact several protection and deprotection steps in
with the environment, and can be a very useful chemical reactions. Therefore, biocatalysis can be
tool for the rapid validation of herbal medicines, cheap, simplify processes, require milder reaction
nutraceuticals and drugs in Brazil. The Brazilian conditions, can be used with water as solvent and
Ministry of Health produced a list of medicinal reduce waste. The production process of the top-
useful plants of interest for the health care system selling drug Atorvastatin uses biotransformation
(SUS) and the use of new analytical methodologies to improve production by synthesizing two chiral
is an excellent experimental approach to Brazilian centers of the side chain (Murphy 2011).
scientific and technological research of plants, and This is an opportunity for a development
an opportunity for the national and global drug based on knowledge and innovation, increase
market (Funari et al. 2013). exports of high added value products with, clean
The very important areas that could boost production and lessen environmental impact. In 30
bioeconomy are metabolic engineering and years Brazil has tripled the scientific contribution
biotechnology. Biotechnology is one of the worldwide, and has trained professionals. In spite
most important technological tools today and of the great competitiveness and growing exports of
has contributed to improve economic and social agroindustry and commodities, a modest scientific
systems. It has contributed enormously to the success has been converted in technological products
treatment of diseases, the preparation of new and processes. There are more than 1700 research
medicines for human and animal application, the groups developing biotechnology research activity
improved reproduction of plant and animal species, with a potential to interact with companies. There
the development and improvement of food, the are also some sectors of the economy that already
sustainable use of biodiversity and the recovery rely on biotechnological processes and products in
and treatment of waste (Decreto 2017). their activities. Considering the chemical, genetic
Biocatalysis, for example, is being used to and biochemical diversity present in Brazilian
lower fossil-based products use, and improve biodiversity, Brazil has a universe of opportunities
sustainability, efficiency and cost of chemical for biotechnological innovation. In addition, the
production and could be used in the production regional distribution of this biodiversity creates
of biofuels, surfactants and plastics. It can be opportunities for local economic development, and
developed using cellular extracts, cells or enzymes, leverage of social development (Decreto 2017).

An Acad Bras Cienc (2018) 90 (1 Suppl. 1)

776 MARILIA VALLI, HELENA M. RUSSO and VANDERLAN S. BOLZANI

CONCLUSIONS de Pessoal de Nível Superior (CAPES), and

Conselho Nacional de Desenvolvimento Científico
Brazilian biodiversity is undoubtedly vast.
e Tecnológico (CNPq) for grant support and research
Nevertheless, few products have emerged from this
fellowships. MV acknowledges scholarship
rich chemical universe. This rich biodiversity could
#167874/2014-4 and #152243/2016-0 from CNPq;
be in-between the main sources for discoveries
HMR acknowledges scholarship #152341/2015-2
in natural products which could be applied to
from CNPq.
improve the quality of life of the world population.
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