Biological Activities of Species of the Genus Clusia L (Clusiaceae): A General Approach

Abstract

The genus Clusia L. is highly diverse in Central and South America, comprising about 300 species, including trees and shrubs, hemiepiphytes, epiphytes, and lianas. This genus deserves attention due to its wide range of biological activities. Clusia belongs to the Clusiaceae family, chemically characterized by the presence of xanthones, benzophenones, flavonoids, coumarins, terpenoids, and other substances with bioactive activity already described. This review aims to highlight the biological activity associated to extracts and isolated substances from species of the Clusia genus, including anti-HIV, antimicrobial, antioxidant, antinociceptive, antitumor, leishmanicidal, modulator of inflammatory processes, neutralization of toxic effects caused by snake bites, and others. This review gathered information on biological activities associated with different types of extracts and isolated substances of the genus Clusia, traditional use, chemical profile, and biological properties of plants of the genus, published in the last 23 years (1998 to 2021) and that can provide support for future research. The paper aims to provide an overview of existing knowledge about the biological properties of the genus Clusia plant species.

Key words
Biological activity; Clusia sp

INTRODUCTION

Among plants with therapeutic contribution, a considerable number are known through popular wisdom, but knowledge about the chemical and bioactive constitution is limited. The Clusiaceae Lindl. family (= Guttiferae Juss.) fall into this context and comprises approximately 14 genera and 800 species of wide geographical distribution, with significant occurrence in the tropics (Anholeti et al. 2017). The family is chemically characterized by the presence of xanthones, benzophenones, flavonoids, coumarins, terpenoids, steroids, among other substances of importance in the plant’s biology and in studies of potential biological activity (Sacramento et al. 2007, Wu et al. 2014, Alves et al. 1999, 2000).

Arawakia L. Marinho, Chrysochlamys Poepp., Clusia L., Garcinia L., Lorostemon Ducke, Mammea L., Moronobea Aubl., Platonia Mart., Symphonia L.f., Tovomita Aubl., Tovomitopsis Planch. Triana, Dystovomita (Engl.) D’Arcycom are the genera that occur in regions of Brazil with phylogenetic domains in the Amazon, Caatinga, Cerrado, and Atlantic Forest (Gasparotto Júnior et al. 2005).

The genus Clusia is highly diversified in Central and South America comprising about 300-400 species including trees and shrubs, hemiepiphytes, epiphytes, and lianas (Oliveira et al. 1999). Clusia species have entire, coriaceous and succulent leaves and the fruits are capsules, with five or five to ten persistent stigmas, each corresponding to a store in which the seeds are located. The seeds are oval, with a smooth surface of yellowish or vinaceous color, always coated by an orange membranous aryl. Despite the uniformity observed in the leaves, in other aspects, there is a great diversity among the species of this genus, as well as huge metabolic plasticity (Winter et al. 2008).

These plants are resistant to water scarcity and highly adaptable to adverse conditions. Succulent leaves, latex production, and the ability to change photosynthetic metabolism provide the genus the advantages needed to remain all over the planet (Oliveira et al. 1999, Luttge 2006, Winter et al. 2008). Clusia is the only genus of tree eudicotyledons capable of performing crassulacean acid metabolism (CAM). Most species of this genus can change their C3 metabolism (the photosynthetic mechanism that involves an intermediate formed by three carbons) to CAM under water restriction conditions, while others are constitutive CAM species (Winter et al. 2008, 2009).

The vast majority of Clusia species are dioecious. The production of resins in the stamens and/or pistils of their flowers acts as a reward for female bees who, when seeking for material the construction of their nests, perform pollination (Porto et al. 2000). Research involving the chemical composition of Clusia floral resins revealed that they are mainly composed of polyisoprenylated benzophenones and fatty acids. Some species can also produce staminal oils to reduce the viscosity of floral resins so that their composition can vary considerably among the species that make up the genus. (Oliveira et al. 1999, Porto et al. 2000, Luttge 2006, Winter et al. 2008, 2009, Anholeti et al. 2015b).

The literature data revealed that Clusia species have several biological activities, including anti-HIV, antimicrobial, antioxidant, antinociceptive, antitumor, leishmanicidal, modulating activity of inflammatory processes, and neutralization of toxic effects caused by venomous snake bites. Furthermore, several species of the genus have been used in traditional medicine. Among the species we can highlight: Clusia amazonica, C. coclensis, C. grandifolia, C. insignis, C. lineata, C. opaca, C. palmicida, C. planchoniana and C. purpurea. A summary of their traditional usage is presented in Table I

Table I
Some species of Clusia used in folk medicine.

Clusia species	Local name	Country	Plant Organ	Traditional use	Ref.
C. flava	-	México	Leaves	Carminative, headaches, wounds and to treat syphilis	Barrios et al. 1991
C. salvinii	Orelha de coyote	México	-	Treat gonorrhea and kidney pain	Yasunaka et al. 2005
C. coclensis	Azahar de monte; copey, and copeicillo	Costa Rica	Leaves	Treat hypertension	Gárcia-González et al. 1998
C. insignis	-	Colombia	Floral resins	Relief from toothache	Langenhein 2003
	Apuí; cebola-brava, and guapoí	Brazil	Resin	Treat constipation and healing of fissures in the breasts
	Mê miomio kangô	Brazil	-	Treat infant oral candidiasis
C. lineata	Came	Peru	Barks and stems	Treat rheumatism	Fenner et al. 2006
C. opaca	-	Colombia	Resiniferous barks	Mixed with the oil from the palm tree Oenocarpus bataua to treat twists and sore joints	Sanz-Biset et al. 2009, Fenner et al. 2006
		Brazil	Resin	Applied on wounds to accelerate healing
C. palmicida	Came	Peru	Barks	Treat rheumatism, inguinal hernia, and broken bones	Fenner et al. 2006
C. planchoniana	-	Colombia	Resin	Treat toothaches	Sanz-Biset et al. 2009
C. purpurea	Cebola-brava	Brazil	Inner bark	Antiseptic and wound scarrant	Fenner et al. 2006
Clusia sp.	Came	Peru	Barks	Macerated in rum with Calliandra angustifolia, Monteverdia macrocarpa (=Maytenus macrocarpa), Tovomita foldatsii and Tovomita stylosa used as a tonic	Sanz-Biset et al. 2009
Clusia sp.	Came	Peru	Barks and stems	Treat rheumatism	Sanz-Biset et al. 2009

Natural products’ chemical diversity and biological properties have been the target of studies for many years. Advances in bioassay techniques, phytochemical studies, and high-performance analytical methods increased the possibilities of discovering new natural compounds with therapeutic potential, boosting studies in this sense (Valli et al. 2018). Despite the growing interest in the classes of substances present in the genus Clusia, there is a lack of review articles gathering aspects related to the biological activity of these compounds. Therefore, this review aims to highlight the biological activity of extracts and substances isolated from species of the genus.

MATERIALS AND METHODS

This is a study with data collection carried out from secondary data through a bibliographic survey, search and database analysis. The search used the keywords defined for the object of study and the period ranged from January 1992 to September 2021. This review used the keywords in different scientific literature databases: National Library of Medicine / NLM (PubMed), Science Direct, Web of Science, Scopus, and Scientific Electronic Library Online (SciELO). The keywords were: Biological activity; Extraction; Isolation; Natural products; Clusia L., Clusiaceae. The following pairs were used to refine the search: Clusia L. AND Biological activity. As an exclusion criterion, all articles that did not address the study’s subject and were not written in Portuguese, English, or Spanish were removed from the search. Subsequently, the eligibility of the studies identified in the search was assessed by reading the titles and abstracts. All those that addressed the biological activity of the genus Clusia were read in full. The analysis of scientific publications focused on searching for experimental or observational articles that describe studies with the recognized biological activity of the genus Clusia.

RESULTS

After reading the 243 abstracts, 97 articles were selected, which were read in full and dealt with Clusia L. and biological activity. Of these, 73 articles were selected and discussed. The articles were analyzed, presented, and their descriptive data discussed. The analysis of scientific publications was carried out with a focus on seeking articles with an experimental or observational design that described studies with the recognized biological activity of the genus Clusia.

The Table II describes the biological activities of extracts and substances (Figure 1) isolated from species of the genus Clusia (Clusiaceae).

Figure 1
Substances isolated from species of the genus Clusia (Clusiaceae) with biological activity. (1) I3, II8-Binaringerin (2) Nemorosone II (3) Chamone I (4) 7-epi-nemorosone (5) Oleanolic acid (6) Nemorosone (7) Betulinic acid (8) Clusiparalicoline A (9) Clusiparalicoline B (10) Clusiparalicoline C (11) Guttiferone E (12) Xanthochymol (13) Clusianone (14) 7-epi-Clusianone (15) Zeaxanthin (16) Lanosterol (17) 2,2-dimethyl-3,5-dihydroxy-7-(4-hydroxyphenyl)chromane (18) Lyoniresinol (19) Rhamnopyranosyl kaempferol (20) Gundlachiione A (21) Gundlachiione B (22) Gundlachiione C (23) Clusiaxanthone.

Table II
Biological activities described for extracts and substances isolated from species of the genus Clusia (Clusiaceae).

Species	Extracts/ substances	Plant organ (solvent)	Biological activities	Dose	IC 50	MIC / MBC	Ref.
C. coclensis	Extract	Leaves (H2O)	Hypotensive effect on normotensive and hypertensive rats	40 mg/Kg	ND	ND	Gárcia-González et al. 1998, Gárcia-González et al. 1996
C. columnaris	Extract	Stems (CH3OH:CH2Cl2)	Antimicrobial activity against Enterococcus faecalis (EF) and Pseudomonas aeruginosa (PA)	ND	ND	EF: MIC = 180 μg/mL; MBC = 270 μg/mL PA: MIC = 140 μg/mL; MBC > 200 μg/mL	Suffredini et al. 2006, Bittar et al.2000
	I3, II8-Binaringerin (1)	Leaves (CH3OH)	Antinociceptive effect in mice	ND	IC50 (writhing test)= 22µmol/kg IC50 (formalin test) = 28µmol/kg	ND
C. grandiflora	Resins	Staminate flowers	Antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, and Candida albicans in bioautography assay	ND	ND	ND	Porto et al. 2000, Lokvam et al. 2000, Diaz-Carballo et al. 2012
	Resins	Pistillate flowers	Antimicrobial activity against S. aureus and B. subtilis, in bioautography assay	ND	ND	ND
	Nemorosone II (2)	Trunk latex (C2H5)2O	Antimicrobial activity against Paenibacillus larvae and P. alvei in bioautography assay	ND	ND	ND
	Chamone I (3)	Pistillate flower (C2H5)2 O
	7-epi-nemorosone (4)	Floral resins (C2H5)2O	Anticancer activity in prostate carcinoma	ND	IC50 (LNCaP WT) = 4.12±0.19µM IC50 (LNCaP ETO MDR1+) = 4.81±0.68µM IC50 (PC-3 WT) = 5.01±0.07µM IC50 (PC-3 ETO MDR1+) = 5.1±0.1µM IC50 (DU-145) = 7.3±0.07µM IC50 (DU-145 MDR1+) = 6.8±0.45µM	ND
C. guatemalensis	Extract	Leaves (CH3OH:CH2Cl2)	Inhibition of HIV-1 virus reverse transcriptase	50 µg/mL	IC50 (HIV-1 RT) = 42 µg/ml IC50 (HIV-1 IIIb/LAV) = 124.1 µg/ml	ND	Huerta-Reyes et al. 2004
C. massoniana				50 µg/mL	ND
C. quadrangula				50 µg/mL	ND
C. hilariana	Extract	Staminate flowers (CH3OH)	Antifeedant effect on Rhodnius prolixus larvae, and promotion of ecdise delay.	100μg/mL	ND	ND	Kelecom et al. 2002
	Oleanolic acid (5)		Toxicity on R. prolixus larvae, and promotion of ecdise delay.	1, 10 e 100μg/mL
	Nemorosone (6)		Promotion of ecdise delay on R. prolixus larvae	10μg/mL
C. insignis	Resins	Staminate flowers	Antimicrobial activity against S. aureus and B. subtilis in bioautography assay	ND	ND	ND	Porto et al. 2000
C. lanceolata	Resins	Staminate flowers	Antimicrobial activity against S. aureus, B. subtilis and C. albicans in bioautography assay	ND	ND	ND	Porto et al. 2000
	Extract	Non-galled and galled leaves (CH3OH)	Antioxidant activity in β-carotene/linoleic acid assay	57 μg/mL	ND	ND	Ferreira et al. 2014
C. nemorosa	Resins	Hermaphrodite flowers	Antimicrobial activity against S. aureus and B. subtilis in bioautography assay	ND	ND	ND	Porto et al. 2000
	Extract	Leaves (C6H14)	Anti-inflammatory and antinociceptive effects on male Swiss mice	62 mg/kg	IC50 (writhing test) = 62mg/kg	ND	Ferro et al. 2013
			Inhibition of protein exudation, leukocyte influx and TNFα levels on pleurisy induced by carrageenan on male Swiss mice	100 and 200 mg/kg	ND	ND	Farias et al. 2012
	Betulinic acid (7)	Roots (H2O)	Decrease of body weights, abdominal fat accumulation, blood glucose, plasma triglycerides, and total cholesterol on male Swiss mice	50 mg/L	ND	ND	Melo et al. 2009
C. palmana	Extract	Leaves and flower buds (CH3CH2OH:H2O); Leaves and fruits (CH3CO2C2H5 fraction)	Neutralization of the hemorrhagic effect induced by Bothrops asper venom in rats	1:50 (poison / extract ratio)	ND	ND	Castro et al. 1999
C. paralicola	Clusiparalicoline A (8)	Roots (CH3CH2OH)	Scission-promoting activity on DNA strands; cytotoxicity in KB cells; growth promotion of neuritas in fetal cortical neurons of rats.	neurite outgrowth promoting activity at 1.0 M	ND	ND	Seo et al. 1999, Takaoka et al. 2002
	Clusiparalicoline B (9)		Scission-promoting activity on DNA strands; cytotoxicity in the KB cells			ND
	Clusiparalicoline C (10)		cytotoxicity in the KB cells			ND
	Extract	Unripe fruits (CH3CH2OH)	Antioxidant activity	ND	EC50(DPPH) = 12.7±0.1; EC50(ABTS) = 7.4±0.4;	ND	Oliveira et al. 2012
C. renggerioides	Resins	Staminate flowers	Antimicrobial activity against S. aureus and B. subtilis in bioautography assay	ND	ND	ND	Porto et al. 2000
C. rosea	Guttiferone E (11) and xanthochymol (12)	Leaves (CH2Cl2:CH3OH)	Inhibition of the cytopathic effects of HIV virus in human lymphoblastoid cells	ND	1-10 µg/mL	ND	Gustafson et al. 1992
C. rosea	Nemorosone (6)	Floral resin (CH3CH2OH)	Cytotoxicity against human cancer cell lines	ND	IC50(HELA): 3.3±0.17µM; 1.6±0.08µg/mL IC50(HeP-2): 3.1±0.17µM; 1.5±0.08µg/mL IC50(PC-3): 7.2±1.3µM; 3.6±0.65µg/mL IC50(U251): 3.9±1.4µM; 1.9±0.70µg/mL IC50 (neuroblastoma cells): 3.10±0.15 - 6.3±0.21µM IC50 (MCF-7): 0.03 - 0.1µM	ND	Cuesta-Rubio et al. 2002, Díaz-Carballo et al. 2008, Popolo et al. 2011
	7-epi-nemorosone (4)	Resins of pistillate flowers	Antiestrogenic activity	10, 20 and 40 μg/well	ND	ND	Camargo et al. 2013
C. spiritu-sanctensis	Nemorosone (6)	Resins of staminate flowers	Antimicrobial activity against S. aureus and B. subtilis in bioautography assay	ND	ND	ND	Porto et al. 2000
C. torresii	Extracts	Leaves and flowers (CH3CH2OH:H2O) Leaves and fruits (CH3CO2C2H5 fraction)	Neutralization of the hemorrhagic effect induced by B. asper venom in rats	1:50 (poison / extract ratio)	ND	ND	Castro et al. 1999
	Clusianone (13)	Fruits (C6H14)	Inhibition of HIV-1 virus infection in lymphoblastoid T cells (C8166)	ND	IC50 = 0.020±0.003 µM	ND	Piccinelli et al. 2005
	7-epi-clusianone (14)			ND	IC50 = 2.0±0.07 µM	ND
C. weddelliana	Resins	Staminate flowers	Antimicrobial activity against S. aureus and B. subtilis in bioautography assay	ND	ND	ND	Porto et al. 2000
C. fluminensis	Extract	Stems; Leaves; Fruits (H2O)	Antiophidic				Da Silva et al. 2019
	Zeaxanthin (15)	Fruits (not described)	Antioxidant and macular degeneration protector.				Mazza et al. 2019
	Extract	Staminate flowers (C6H14) Fruits (C6H14)	Significant reduction of the survival of the insect Oncopeltus fasciatus	1.0 mg/mL (1.0µg/ insect)	ND	ND	Duprat et al. 2017
	Clusianone (13)	Floral extract (C6H14)	Reduction on the survival of the insect Dysdercus peruvianus	0.7 mg/mL (0.7µg/ insect)
	Lanosterol (16)	Fruit extract (C6H14)	Significant reduction on both survival and development of the insects O. fasciatus and D. peruvianus
C. fluminensis	Extract	Leaves (C6H14; CH3OH)	Inhibitory effect of on proteolysis caused by B. jararaca venom	venom /extract ratio: 1:5; 1:10; 1:20; and 1:50	IC50(hexane): 567μg/mL IC50(methanol): 447μg/mL	ND	Oliveira et al. 2014
		Stems (CH3OH) ((CH3)2CO)			IC50(methanol): 245μg/mL IC50(acetone): 180μg/mL
		Fruits (C6H14) ((CH3)2CO)			IC50(n-hexane): 736μg/mL IC50(acetone): 90μg/mL
		Staminate flowers (C6H14; CH2Cl2)			IC50(n-hexane): 220μg/mL IC50(dichloromethane): 630μg/mL
	Extract	Staminate flowers (C6H14)	Significant delay on the development of Aedes aegypti	50 mg/L	ND	ND	Anholeti et al. 2015a
	Clusianone (13)	Staminate flowers (C6H14)	Significant inhibition of survival and complete blockage of development Ae. aegypti
C. criuva	Extracts	Leaves (C6H14; CH3OH)	Antioxidant activity in DPPH assay	ND	EC50(n-hexane): 34.66 ± 19.42 g extract/g DPPH EC50(methanol): 12.54 ± 1.43 g extract/g DPPH	ND	Da Silva et al. 2017
		Pericarp (C6H14; CH3OH)			EC50(n-hexane): 10.94 ± 0.36 g extract/g DPPH EC50(methanol): 5.01 ± 0.16g extract/g DPPH
		Seeds (C6H14; CH3OH)			EC50(n-hexane): 8.32 ± 0.30g extract/g DPPH EC50(methanol): 4.06 ± 1.12g extract/g DPPH
C. burlemarxii	Extract	Leaves (CH3CH2OH)	Antimicrobial activity against B. subtilis and S. aureus	ND	ND	MIC (B. subtilis): 31.25μg/mL MIC (S. aureus): 62.50μg/mL	Ribeiro et al. 2011
		Trunk (CH3OH)	Antimicrobial activity against B. subtilis, Streptococcus mutans and Micrococcus luteus			MIC (B. subtilis): 62.50μg/mL MIC (S. mutans): 62.50μg/mL MIC (M. luteus): 31.25μg/mL
	2,2-dimethyl-3,5-dihydroxy-7-(4-hydroxyphenyl)chromane (17)	Trunk (CH3OH)	Antimicrobial activity against B. subtilis, S. aureus, S. mutans and M. luteus	ND	ND	MIC (B. subtilis): 100μg/mL MIC (S. aureus): 50μg/mL MIC (S. mutans): 100μg/mL MIC (M. luteus): 25μg/mL
	Lyoniresinol (18)	Leaves (CH3CH2OH)	Antimicrobial activity against S. aureus			MIC (S. aureus): 25μg/mL
	Rhamnopyranosyl kaempferol (19)		Antimicrobial activity against B. subtilis and S. aureus			MIC (B. subtilis): 50μg/mL MIC (S. aureus): 100μg/mL
C. gundlachii	Gundlachiione A (20)	Fruits (CH3OH)	Leishmanicidal activity against P. falciparum	ND	IC50(promastigote): 11.30μg/mL IC50(amastigote): 0.84μg/mL	ND	Zhang et al. 2018
	Gundlachiione B (21)				IC50(promastigote): 30.12μg/mL IC50(amastigote): 5.92μg/mL
	Gundlachiione C (22)				IC50(promastigote): 9.63μg/mL IC50(amastigote): 2.32μg/mL
C. latipes	Extract	Leaves (C6H14; CH₃CO2C₂H₅; CH3OH)	Cytotoxic activity against human cancer cell lines (PC-3, RKO, D-384 and MCF-7)	50μg/ml	ND	ND	Bailón-Moscoso et al. 2016
Clusia minor	Extract	Leaves (CH2OH)	Antinociceptive effect on mice	150 and 300 mg/kg	ND	ND	Mangas et al. 2019
Clusia flava	Extract	Leaves (CH3OH)	Leishmanicidal activity against P. falciparum	ND	IC50(promastigote): 32μg/mL	ND	Peraza-Sánchez et al. 2007
C. pernanbucensis	Extract	Stem bark (CH₃CO2C₂H₅))	Leishmanicidal activity against P. falciparum	ND	IC50(amastigote): 65μg/mL	ND	Silva et al. 2013
	Clusiaxanthone (23)				IC50(amastigote): 66.9μM
C. amazonica	Extract	Leaves and stems (H2O)	Leishmanicide				Odonne et al. 2009

• Legend: IC₅₀ - Half maximal inhibitory concentration; MIC - Minimum inhibitory concentration; MBC - Minimum bactericidal concentration; ND - Not determined; (H₂O) water; (CH₃CO₂C₂H₅) ethyl acetate; (CH₃OH) methanol; (CH₃)₂CO) acetone; (CH₃CH₂OH) ethanol; (CH₂Cl₂) dichloromethane; (C₆H₆ ) benzene ; (C₆H₁₄ ) n-hexane; (C₂H₅)₂O diethyl ether.

Anti-HIV activity

Acquired Immunodeficiency Syndrome (AIDS), an infectious disease caused by the Human Immunodeficiency Virus (HIV) that drastically reduces the number of CD4 T cells, is still a worldwide concern. Although the replication cycle of HIV is well known and antiretroviral drugs are available, efforts to develop new pharmaceutical alternatives, which started a long time ago, continue to be conducted, and plant sources have aroused the interest of researchers (Salehi et al. 2018, Reutrakul et al. 2007, Márquez et al. 2005, Rukachaisirikul et al. 2003, Spino et al. 1998). The species of Clusia have been described as a promising matrix of bioactive substances for this purpose.

In 1992, studies conducted by Gustafson and collaborators, tracking HIV activity in extracts of plant species, found a series of compounds with potential activity, and phytochemical studies led to the isolation of a series of new polyisoprenylated benzophenone derivatives called guttiferones with the ability to inhibit the cytopathic effects of HIV infection in vitro. The study describes that the organic extract (CHCl₂:MeOH, 1:1) of leaves of Clusia rosea, collected in the Dominican Republic, is mainly composed of guttiferone E and xantochymol. The active compounds inhibited the cytopathic effects of HIV infection in vitro in lymphoblastoid CEM-SS cells, with an EC₅₀ value of 1-10 µg/mL. In comparison, cytotoxicity occurred at higher concentrations of 50 µg/mL. However, it did not inhibit the activity of the reverse transcriptase enzyme (RT) involved in the AIDS infection mechanism.

Huerta-Reyes et al. 2004 tested organic extracts of leaves in dichloromethane and methanol (CHCl₂:MeOH, 1:1, 50 mg/mL) of 10 species of the Clusia genus, abundant in Mexico, to verify the ability to inhibit the reverse transcriptase enzyme (RT) involved in HIV-1 infection, through immuno-radioactive and colorimetric assay. Leaves extracts of Clusia guatemalensis and C. massoniana showed 70.8% and 72.9% of inhibition, respectively, which was considered a high percentage of inhibition (≥ 70%). The species C. quadrangula (leaves extract) presented inhibition of 65.6%, considered as moderately active. However, when submitted to the inhibition test of replication of HIV-1 IIIb / LAV, the C. quadrangula extracts exhibited less than 52% inhibition.

Piccinelli et al. 2005 described potential HIV activity in C. torresii, an endemic species in Costa Rica. The study was conducted with polyisoprenylated benzophenone isolated from the hexanic extract of the fruits, and the results corroborate Huerta-Reyes’ studies presenting promising anti-HIV results. Nemorosone and 7-epi-Clusianone showed moderately potent anti-HIV activity with EC₅₀ 0.80 and 2.0 µM, respectively. A study of the mechanism of action showed that the benzophenone derivatives, Clusianone and 7-epi-Clusianone, inhibited gp120-s CD4 interaction suggesting interference at the onset of HIV infection and potential preventive activity with neutralization of infectivity by more than 99% when incubated with the virus at 0.05 and 10 µM, respectively, for 60 minutes at 37 ºC, suggesting Clusianone and 7-epi-Clusianone as promising candidates for other studies of HIV infection (Piccinelli et al. 2005, Huerta-Reyes et al. 2004).

Studies carried out by Meneses et al., 2015, with extracts and substances isolated from C. fluminensis, showed anti-HIV-1 RT activity. Among the crude extracts, methanolic extracts from leaves and stems showed activity, demonstrating inhibition of about 42 and 20%, respectively, of the HIV-1-RT. In this study, the efavirenz, a reverse transcriptase inhibitor drug used to combat HIV-1 infection, was used as a control, which showed inhibition of about 92%. Two isolated substances were also tested (clusianone and lanosterol) and the triterpenoid lanosterol showed a moderate inhibitory effect (77.31% ± 10.74). The weak inhibition on HIV-1-RT of the benzophenone clusianone (37.6% ± 1.73) complements the study of Piccinelli et al. 2005, indicating that the inhibition of the reverse transcriptase enzyme does not represent the main mechanism of action of this substance.

Antimicrobial activity

The indiscriminate use of antimicrobials added to the transmission of genetic resistance among bacterial strains has led to the emergence of resistant bacteria in the available therapeutic arsenal. Therefore, searching for new alternatives is necessary, and natural sources have been studied (Jayasuriya et al. 1991, Nguemeving et al. 2006, Nkengfack et al. 2002, Pecchio et al. 2006, Yimdjo et al. 2004). The Clusia genus, the target of this review, has shown antimicrobial activity, especially against gram-positive bacteria.

Suffredini et al. 2006 analyzed organic extracts in dichloromethane and methanol (1:1) produced from Clusia columnaris using broth microdilution assay to trace antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis, and the results were significant (MIC or MBC ≤ 200 µg / mL). The extracts were submitted to the determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) using gentamicin and tetracycline as standard drugs (García-González Matamoros 1996). Pseudomonas aeruginosa and E. faecalis are bacteria related to human infectious diseases, and the results suggest the continuity of studies with the species of Clusia and reinforce plants as a source of a new class of antimicrobials.

Studies were conducted to verify the antimicrobial activity of metabolites isolated from resin and latex of Clusia grandiflora. The polyisoprenylated benzophenones chamone I and II were isolated from the latex of the trunk of C. grandiflora, while nemorosone II from the reward resin of the pollinator of pistillate flowers of the same plant. The bioassays were carried out with Paenibacillus larvae and Paenibacillus alvei, pathogens that cause diseases in beekeeping and prevent the formation of hives. The substances tested demonstrated potent antibacterial activity against the aforementioned pathogens. The work also described that the abundance of bioactive benzophenones in the resin compared to latex indicates that these compounds benefit bees (Lokvam et al. 2000).

Porto et al. 2000 researched the bioactivity of floral resins of seven species of Clusia cultivated at the Agronomic Institute of Campinas, Campinas, São Paulo, Brazil: C. grandiflora, C. insignis, C. lanceolata, C. nemorosa, C. spiritu-sanctensis, C. renggerioides, and C. weddelliana. The study was conducted with pistillate and staminate species and considered the influence of methylation of polyisoprenylated benzophenones on antimicrobial potential. Antimicrobial activity was tested using the bioautography test with Aspergillus niger, Bacillus subtilis, Candida albicans, E. Escherichia coli, Rhodococcus equi, and S. Staphylococcus aureus. Chloramphenicol (antibacterial) and nystatin (antifungal) were used for comparison. Bioautography, a trial capable of providing quantitative and qualitative information, revealed that non-methylated polyisoprenylated benzophenones have greater antimicrobial activity. The results indicated in the resin of C. grandiflora pistillate flowers had higher activity than the resin of C. grandiflora staminate flowers and it is due to the higher concentration of active compounds (polyisoprenylated benzophenones) in the resins of the pistillate flowers. The floral resins of most Clusia species tested presented antimicrobial activity, especially in Gram-positive bacteria S. aureus and B. subtilis (Porto et al. 2000, Neves et al. 2007, Almeida et al. 2008).

Clusia burlemarxii, shrub vegetation found in Chapada Diamantina, Bahia, Brazil, was studied by Ribeiro et al. 2011. In addition to phytochemical research, the authors evaluated the antimicrobial activity of extracts and pure compounds against Streptococcus mutans, S. aureus, B. subtilis, Micrococcus luteus, E. coli, Salmonela cholera, Pseudomonas aeruginosa, Aspergillus niger, and Cladosporium cladosporioides. The extracts, as well as the isolated compounds, presented antimicrobial activity against Gram-positive bacteria, corroborating the results of different species of Clusia (Porto et al. 2000, Lokvam et al. 2000, Ribeiro et al. 2011).

The microdilution test on plates determined the MIC of extracts and isolated compounds. Nutrient broth and chloramphenicol were used as a culture medium for bacteria, malt, and olamine ciclopirox for fungi. The MIC was determined by the emergence of turbidity in the wells. Extracts were considered active when there was inhibition in concentration below or equal to 500 μg/mL and substances when there was inhibition below or equal to 100 μg/mL. The ethanolic extract of C. burlemarxii demonstrated a very promising activity against B. subtilis (31.25μg/mL) and S. aureus (62.50 μg/mL) and the methanolic extract from the trunk against B. subtilis (62.50μg/mL), S. mutans (62.50μg/mL) and M. luteus. Four of the nine isolated substances presented strong antimicrobial activity with MIC of 25 μg/mL and moderate activity with MIC of 50 μg/mL (Ribeiro et al. 2011).

Antitumoral activity

Some isolated compounds of different species of Clusia have shown promising results in the search for new substances with antitumoral activity. Nemorosone is one of these compounds and has been the target of studies by different research groups. Cuesta-Rubio et al. 2002 described C. rosea floral resin as a rich source of polyisoprenylated benzophenones, and after selective extraction of benzophenones and confirmation of a large amount of nemorosone, cytotoxic evaluation tests were performed where the compound was active for epithelioid carcinoma, prostate cancer, and central nervous system cancer (Camargo et al. 2015).

The criteria followed the recommendation of the National Cancer Institute of USA, which considers the significant activity of a product when the IC₅₀ is reached with a concentration less than 4 μg/mL. For epithelioid carcinoma, the IC₅₀ was 1.6 μg/mL for nemorosone; for prostate cancer, 3.6 μg/mL and for central nervous system cancer, 1.9 μg/mL (Cordell et al. 1993).

In search of pharmaceutical alternatives derived from natural products, the substance nemorosone was isolated from alcoholic extracts of C. rosea resins collected in Florida. The studies focused on neuroblastoma, a solid tumor common in childhood and characterized by rapid disease progression. The compound exerted intense activity in neuroblastoma cell lines, both in the matrix cell and in its clones selected for resistance to adriamycin, cisplatin, etoposide, or 5-fluorouracil, medicines widely used in the treatment of cancer (Díaz-Carballo et al. 2008). They found that the cytotoxic effect was due to apoptosis, thus not inducing an inflammatory response. This study demonstrated that nemorosone is a modulator or inhibitor of pathways that play roles in the transduction and integration of extracellular and intracellular oncogenic signals, making it a potential candidate for molecular therapy. The study also demonstrated that nemorosone exhibited cytotoxicity on leukemic cells, affecting protein levels, cell cycle progression, and low cytotoxicity on non-tumor cells. In vivo studies have suggested that nemorosone significantly affected hematopoiesis in mice, making further studies even more attractive (Díaz-Carballo et al. 2008). Corroborating with previous studies, Popolo et al. 2011 also isolated nemorosone from C. rosea floral resins in search of therapeutic alternatives for breast cancer. The study reported that the substance could significantly inhibit cell growth at low concentrations, signaling to be a promising estrogen receptor antagonist and act in the prevention and treatment of breast cancer. Considering the potential of nemorosone and the need to test chemotherapy not only for anticancer or antitumor activity but also for potential mutagenicity, Camargo et al. 2013 carried out a study to determine the mutagenic and antimutagenic activity of the substance using the Ames test, using the TA97a, TA98, TA100 and the TA102 strains of Salmonella typhimurium, subjected to four different concentrations of the compound. The results indicated an absence of mutagenic activity.

The tests were carried out by associating nemorosone with direct (NPD and MMC) and indirect (AFL) mutagens in strains TA98, ta102, and TA100. The association of strain TA98 + NPD did not reduce the number of restricted colonies; TA100 + AFL caused a moderate protective effect with 31% inhibition. An expressive result was verified in the association of the strain TA102 + MMC, which presented a strong protective effect with an inhibition of 53%. The results suggest that nemorosone can potentially reduce the mutagenic damage of anticancer drug therapy, but further studies should be carried out to clarify its mechanism of action (Piccinelli et al. 2005). Another polyisoprenylated benzophenone, isolated from C. rosea and C. grandiflora, is 7-epi-nemorosone (4). The substance was described, in 2012, by Díaz-Carballo and collaborators as a potent antitumor agent with action on prostate carcinoma. The study contributed to the search for new substances derived from plants to treat well-known diseases. Prostate cancer is a frequently diagnosed neoplasia and the second leading cause of cancer death in men due to metastases in distant organs due to resistance to available chemotherapy. The authors presented 7-epi-nemorosone (4) as a promising potential candidate to treat prostate cancer, with androgen-dependent cytotoxicity and absence of cross-resistance (Díaz-Carballo et al. 2012, Da Silva et al. 2019, Neves et al. 2007).

Nemorosone, as well as other polyisoprenylated benzophenones with a bicyclo[3.3.1]nonane-2,4,9-trione nucleus, have been the object of studies, demonstrating a great antitumor potential.

Bailón-Moscoso et al. 2016 studied the chemical composition of organic extracts from Clusia latipes leaves collected in Ecuador and evaluated the in vitro cytotoxicity and genotoxicity in human prostate cancer cells, colon cancer cells, astrocytoma cells, and breast cancer cells. The group presented results of purification and identification of friedelin, friedolan-3-ol and hesperidin, cytotoxic compounds active in the hexane extract. The three substances isolated were antiproliferative in selected cancer cells; however, the hexane extract of C. latipes induced a significant increase in DNA damage in exposed lymphocytes. The genotoxicity detected by the comet assay and the damage detected by this method is repairable DNA damage, requiring, according to the authors, further experiments to determine genotoxic effects and provide more consistent results. Clusia paralicola is another species of the genus that shows possible antitumor activity. Seo and coworkers isolated three biphenyl-derived compounds, clusiparalicoline A, B, and C, from the roots extracts by bioassay-guided fractionation using the DNA strand scission and human cancer cell line KB cytotoxicity assays (Seo et al. 1999). The research showed that clusiparalicoline A and B were active in the DNA strand scission assay, while all three compounds exhibited modest cytotoxicity against the KB cell line. Further, in vivo biological studies will be needed to assess the antineoplastic potential of isolated compounds (Seo et al. 1999, Takaoka et al. 2002).

Antioxidant activity

The search for compounds with antioxidant activity is necessary since oxidative stress involves processes that cause imbalances in the human body, such as cancer, aging, and degenerative processes. Studies conducted with Clusia species (C. lanceolata, C. paralicola, C. criuva and C. fluminensis) focused on antioxidant activity have shown promising results. (Ferreira et al. 2014, Mazza et al. 2019, López-Alarcón Denicola 2013, Athanasas et al. 2004, Wolf et al. 2017, Silva Paiva 2012).

Ferreira et al. 2014 verified that extracts of leaves with galls of C. lanceolata presented higher antioxidant activity than those not galled and attributed this difference to the higher content of phenolic compounds and proanthocyanidins.

Seo et al. 1999 demonstrated that the ethanol extract from green fruits of C. paralicola, its fractions, and the isolated biflavonoids have potent antioxidant activity. Moreover, C. criuva also showed antioxidant potential. The methanolic extract of the fruit pericarps presented the highest percentage of maximum antioxidant activity at 250 μg / mL (Zhang et al. 2018). Silva and Paiva investigated the antioxidant potential of crude extracts of Clusia fluminensis through the neutralization of the stable free radical DPPH and the quantification of flavone and flavonoid content (Silva Paiva 2012). The results pointed out a positive correlation between the presence of flavonoids and the antioxidant activity of these extracts, and the researchers concluded that the acetonic extract of fruits of C. fluminensis is an exciting target for the search for substances with antioxidant activity, especially flavonoids (Athanasas et al. 2004, Silva Paiva. 2012).

Although most studies link antioxidant activity to the presence of flavonoids, which is favored by the characteristic of its chemical structure, the study conducted by Silva et al. 2017 demonstrated that the antioxidant activity exhibited by C. criuva did not present a direct correlation with the presence of this type of substance. The authors suggest that the high values of the flavonoid content observed in hexane extracts may represent; in fact, to the presence of benzophenones that could have interacted with the aluminum chloride used in the quantification methodology.

Antinociceptive activity

The search for new substances with analgesic properties has grown in recent years. Antinociceptive activity was also observed in the Clusia species. Bittar et al. 2000 described the antinociceptive effects of I3, II8-binaringerin isolated from the methanol extract of C. columnaris collected in Venezuela. The substance did not increase the latency period of pain induced by thermal stimuli by discarding the relationship of its mechanism of action with opioid systems. However, it exhibited potent and dose-related antinociceptive properties, with ID₅₀ values of 22 μmol / kg in the writhing test and 28 μmol / kg in the second phase of the formalin test, values that suggest that the substance is more potent than some drugs clinically used as analgesics (Cordell et al. 1993).

Ferro et al. 2013 demonstrated the antinociceptive activity of hexane extract from Clusia nemorosa leaves in chemical pain models through mechanisms that suggest the participation of the adrenergic systems pathways. The extract prevented visceral pain induced by acetic acid in mice for at least two hours. The study suggests that the mechanism may be partially linked to the inhibition of cyclooxygenase and lipoxygenase products and other inflammatory mediators in peripheral tissues, thus interfering in the signal transduction mechanism in primary afferent nociceptors.

To corroborate with studies of the antinociceptive activity of Clusia species, Mangas et al. 2019 evaluated the chemical composition and the potential antinociceptive effect of ethanol extract of Clusia minor leaves. Previous studies also demonstrated mechanical hypernociception induced by intraplantar carrageenan, tumor necrosis factor α (TNFα), and prostaglandin E2 (PGE2). The extract proved to be effective in reducing pain in a dose-dependent manner, in addition to inhibiting mechanical hypernociception of the paw, suggesting that the antinociceptive effect of C. minor occurs by the interaction of various mechanisms through central and peripheral pathways, capable of inflammatory and neurogenic pain.

Leishmanicidal activity

Leishmaniasis is an anthropozoonosis caused by approximately 20 species of a protozoa of the Leishmania genus, belonging to the family Trypasonomatidae, and transmitted by a bite of hematophagous female sandflies belonging to the Phlebotominae family. This is considered a neglected disease and one of the significant public health problems in the world, which affects 98 countries, 12 million cases, and 350 million people at risk of developing leishmaniasis, with 1.5 to 2 million new cases per year. Cases of leishmaniasis with the human immunodeficiency virus (HIV) co-infection are increasing and have been described in 35 countries (Wolf et al. 2017, Silva Paiva 2012).

The leishmanicidal activity of methanol extracts from Clusia flava leaves was verified through in vitro bioassay. The extract of C. flava was able to inhibit the growth of promastigotes of L. mexicana with IC₅₀ 32 μg/mL. As known of literature, IC₅₀ values between 3 and 49 μg/mL are considered as a good inhibition of the microorganism (Peraza-Sánchez et al. 2007). Another study selected plant species used by chayahuite to cure cutaneous leishmaniasis. Forty extracts were evaluated, and among them, the aqueous extract of Clusia amazonica was considered with good IC₅₀ values, 32.9 μg/mL (stems) and 34.6 μg/mL (leaves) (Odonne et al. 2009).

Fruits of Clusia gundlachii, collected in Puerto Rico, were studied by Zhang et al. 2018 and, after fractionation, produced five new polycyclic chloroglucine derivatives that presented activity against intracellular amastigotes of macrophages and promastigotes of Leishmania donovani. The activity is comparable to those observed for the standard pentamidine drug.

Clusia pernambucensis, coming from the Brazilian cerrado, was the target of studies conducted by Silva et al. 2013. From the extract in ethyl acetate of the bark of the stem, it was possible to isolate Clusiaxanthone. The substance was able to control macrophage infection with Leishmania amazonensis amastigotes. These results indicate that the species is a potential source of new compounds with leishmanicidal activity (Da Silva et al. 2017, Wolf et al. 2017).

Modulation of inflammatory processes

Clusia nemorosa is a common species in coastal forests of northeastern Brazil. Farias et al. 2012 evaluated the anti-inflammatory effect of this species leaves’ hexane extract using carrageenan-induced mice pleurisy and cotton pellet-induced mice granuloma using the Boyden chamber assay and flow cytometry (Ferro et al. 2013).

The results were promising as they inhibited exudation, total leukocytes and neutrophils influx, and TNFα levels in carrageenan-induced pleurisy. Although the extract did not suppress the granulomatous tissue formation in the cotton pellet-induced granuloma test, the experiments showed that they revealed that the hexane extract of C. nemorosa inhibited neutrophil chemotaxis induced by CXCL1 in a dose-dependent manner, inhibited the chemoattraction of human neutrophils induced by formyl-methionyl-leucyl-phenylalanine (fMLP), leukotriene B4 (LTB4) and platelet activation factor (PAF). Further, in vivo, biological studies will be needed to assess the antineoplastic potential of isolated compounds (Seo et al. 1999, Takaoka et al. 2002).

Neutralization of toxic effects caused by Bothrops snake accidents

Researches related to neglected diseases are urgent and, as with malaria, dengue, tuberculosis and many other diseases, the risk of snakebite is always present, mainly in poorer areas, being an occupational and environmental risk added to poverty. Serum therapy, recommended in cases of snakebite accidents, acts on the systemic effects caused by the venom. However, the local effects, responsible for example for the amputations, draw attention to the need to search for antivenom support therapies. Extracts from different species of Clusia, such as C. torressi, C. palmana and C. fluminensis demonstrated positive effects in neutralizing the effects caused by snake venoms, exhibiting, for example, proteolytic, hemolytic and anti-hemorrhagic activity (Castro et al., 1999, Da Silva et al. 2019).

Da Silva et al. 2019 showed promising results in inhibiting the activities of Bothrops jararaca and B. jararacussu venoms, regardless of the experimental protocol used or the route of administration of the extracts. The presence of tannins, flavonoids, saponins, steroids, and terpenoids was described. These results suggest that C. fluminensis extracts can be effective against some toxic effects of B. jararaca or B. jararacussu venom, a promising tool for treating accidents caused by such snakes. Thus, anti-venom properties of C. fluminensis extracts deserve further investigation (Da Silva et al. 2019).

Other activities

The hypotensive effect of Clusia coclensis aqueous extract was tested in normotensive and hypertensive animals, and a significant reduction in venous return was found in both rat strains. The extract caused a peripheral vasoconstrictor effect so the hypotensive and antihypertensive effect was attributed to a direct effect on the myocardium by a decrease in the strength of cardiac contraction (García-González Matamoros 1998, 1996).

Mazza et al. 2019 described the presence of potentially bioactive compounds in aril extracts from Clusia fluminensis fruits, including the carotenoid zeaxanthin, described as an important macular protector and regenerator. The concentration of zeaxanthin (0,823 mg/g), higher than that found in other plant matrices, indicates that the species may be a potential source of bioactive substances. Other studies with Clusia fluminensis identified biopesticide activity in hexane extracts of fruits and flowers, and the Clusianone was isolated from the species. The study measured the larvicidal potential of extracts and substances, contributing to the search for less toxic natural insecticides for humans and the environment as alternatives to traditional control of the culicid (Duprat et al. 2017).

Anholeti et al. 2015a also evaluated the effects of the hexane extracts of the fruits and flowers of Clusia fluminensis and the main component of flower extract, a purified benzophenone Clusianone, against Aedes aegypti. Although the treatment of larvae with fruit and flower extracts of C. fluminensis did not affect the survival of A. aegypti (50 mg / L), it significantly delayed the development of the mosquito. The Clusianone isolated (50 mg / L) of flower extract killed 93.3% of larvae and completely blocked the development of A. aegypti. The results reinforce the importance of developing Clusianone as a biopesticide to control vectors of insects of tropical diseases (Duprat et al. 2017).

Clusia hilariana was the target of studies conducted by Kelecom et al. 2002. The methanolic extracts of staminate flowers promoted food inhibition in 4th stage larvae of Rhodnius prolixus (one of the vectors of Chagas Disease) in addition to the delay of ecdysis. Isolated oleanolic acid promoted toxicity over larvae of the 4th stage of R. prolixus and was also able to delay ecdysis. The mixture of benzophenones isolated from the species also promoted the delay in the ecdysis of larvae of the 4th stage of

R. prolixus. Corroborating the biological potential of Clusia paralicola, previously reported with antitumor activity (Seo et al. 1999), the species was also studied by Takaoka et al. 2002 who found that clusiparalicoline A, a prenylated and geranylated biphenyl compound isolated from the roots of C. paralicola through sequential Stille reactions and palladium-catalyzed Suzuki-Miyaura reactions, exhibited potent activity for promoting neurite outgrowth in a primary culture of fetal rat cortical neurons. The results presented encourage further studies on the structure-activity relationship of compounds isolated from the species to elucidate mechanisms of action and the biological activity of therapeutic prototypes of plant origin.

CONCLUSION

The value of plant species as a source of molecules with therapeutic potential is historically known. The challenges associated with the process capable of transforming the plant into medicine are numerous and can only be overcome with interdisciplinary knowledge. In this review, we seek to provide information about some approaches of the research of the genus Clusia, focusing on biological activities. The genus was found to have bioactive properties, including antibacterial, antitumor, antivenom, insecticide, anti-inflammatory, antioxidant, smooth muscle relaxant, neuroprotective and antiprotozoal.

The studies demonstrated were conducted with extracts and compounds isolated from different parts of the Clusia species, and the promising results deserve further investigation. A summary of the information related to the therapeutic potential of Clusia will undoubtedly add value to research on the genus.

ACKNOWLEDGMENTS

The authors thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance code 001 and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ.

REFERENCES

• ALMEIDA LS, MURATA RM, YATSUDA R, DOS SANTOS MH, NAGEM TJ, ALENCAR SM, KOO H ROSALEN PL. 2008. Antimicrobial activity of Rheedia brasiliensis and 7-epiClusianone against Streptococcus mutans. Phytomedicine 15(10): 886-891.
• ALVES TM, ALVES R, ROMANHA AJ, ZANI CL, SANTOS MH NAGEM TJ. 1999. Biological activities of 7-epiClusianone. J Nat Prod 62(2): 369-371.
• ALVES TMA, SILVA AF, BRANDÃO M, GRANDI TSM, SMÂNIA EFA, SMÂNIA JÚNIOR A ZANI CL. 2000. Biological screening of Brazilian medicinal plants. Mem Inst Oswaldo Cruz 95 (3): 367-373.
• ANHOLETI MC, DUPRAT RC, FIGUEIREDO MR, KAPLAN MA, SANTOS MG, GONZALEZ MS, RATCLIFFE NA, FEDER D, PAIVA SR MELLO C. B. 2015a. Biocontrol evaluation of extracts and a major component, Clusianone, from Clusia fluminensis Planch. Triana against Aedes aegypti. Mem Inst Oswaldo Cruz 110(5): 629-635.
• ANHOLETI MC, PAIVA SR, FIGUEIREDO MR KAPLAN MA. 2015b. Chemosystematic aspects of polyisoprenylated benzophenones from the genus Clusia. An Acad Bras Cienc 87: 289-301.
• ANHOLETI MC, SILVA KMM, MORAES MG, SANTOS MG, FIGUEIREDO MR, KAPLAN MAC, JOFFILY A PAIVA SR. 2017. Leaf anatomy and epicuticular waxes composition of Clusia fluminensis Planch. Triana (Clusiaceae). Arab J Med Aromat 3: 68-86.
• ATHANASAS K, MAGIATIS P, FOKIALAKIS N, SKALTSOUNIS AL, PRATSINIS H KLETSAS D. 2004. Hyperjovinols A and B: Two new phloroglucinol derivatives from Hypericum jovis with antioxidant activity in cell cultures. J Nat Prod 67(6): 973-977.
• BAILÓN-MOSCOSO N, ROMERO-BENAVIDES JC, SORDO M, VILLACÍS J, SILVA R, CELI L, MARTÍNEZ-VÁZQUEZ M OSTROSKY-WEGMAN P. 2016. Phytochemical study and evaluation of cytotoxic and genotoxic properties of extracts from Clusia latipes leaves. Rev Bras Farmacogn 26(1): 44-49.
• BARRIOS M, CALVO M, ARGUEDAS E CASTRO O. 1991. Epicatequina en Clusia stenophylla y Clusia flava. Ing Cienc Quim 13: 27-28.
• BITTAR M, SOUZA MM, YUNES RA, LENTO R, DELLE MONACHE F CECHINEL FILHO V. 2000. Antinociceptive activity of I3, II8-binaringenin, a biflavonoid present in plants of the guttiferae. Planta Med 66(1): 84-86.
• CAMARGO MS, OLIVEIRA MT, SANTONI MM, RESENDE FA, OLIVEIRA-HOHNE AP, ESPANHAM LG, NOGUEIRA CH, CUESTA-RUBIO O, VILEGAS W VARANDA E. 2015. Effects of nemorosone, isolated from the plant Clusia rosea, on the cell cycle and gene expression in MCF-7 BUS breast cancer cell lines. Phytomedicine 22(1): 153-157.
• CAMARGO MS ET AL. 2013. Evaluation of estrogenic, antiestrogenic and genotoxic activity of nemorosone, the major compound found in brown Cuban propolis. BMC Complement Med 13: 201.
• CASTRO O, GUTIERREZ JM, BARRIOS M, CASTRO I, ROMERO M UMANA E. 1999. Neutralization of the hemorrhagic effect induced by Bothrops asper (Serpentes: Viperidae) venom with tropical plant extracts. Rev Biol Trop 47(3): 605-616.
• CORDELL GA, KINGHORN AD PEZZUTO JM. 1993. Separation, structure elucidation and bioassay of cytotoxic natural products, In: Bioactive Natural Products: Detection, Isolation and Structure Determination Colegate SM and Molyneux RJ Eds. CRC Press Boca Raton 199-200.
• CUESTA-RUBIO O, FRONTANA-URIBE BA, RAMÍREZ-APAN T CÁRDENAS J. 2002. Polyisoprenylated benzophenones in cuban propolis; biological activity of nemorosone. J Biosci 57(3-4): 372-378.
• DA SILVA AR, ANHOLETI MC, PIETROLUONGO M, SANCHEZ EF, VALVERDE AL, DE PAIVA SR, FIGUEIREDO MR, KAPLAN MAC FULY AL. 2019. Utilization of the Plant Clusia fluminensis Planch Triana Against Some Toxic Activities of the Venom of Bothrops jararaca and B. jararacussu Snake Venom Toxic Activities. Curr Top Med Chem 19(22): 1990-2002.
• DA SILVA KMM, NÓBREGA AB, LESSA B, ANHOLETI MC, LOBÃO AQ, VALVERDE AL, PAIVA SR JOFFILY A. 2017. Clusia criuva Cambess. (Clusiaceae): anatomical characterization, chemical prospecting and antioxidant activity. An Acad Bras Cienc 89: 1565-1578.
• DÍAZ-CARBALLO D, GUSTMANN S, ACIKELLI AH, BARDENHEUER W, BUEHLER H, JASTROW H, ERGUN S STRUMBER D. 2012. 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. Phytomedicine 19(14): 1298-1306.
• DÍAZ-CARBALLO D, MALAK S, BARDENHEUER W, FREISTUEHLER M REUSCH HP. 2008. Cytotoxic activity of nemorosone in neuroblastoma cells. J Cell Mol Med 12(6B): 2598-2608.
• DUPRAT RC ET AL. 2017. Laboratory evaluation of Clusia fluminensis extracts and their isolated compounds against Dysdercus peruvianus and Oncopeltus fasciatus. Rev Bras Farmacogn 27: 59-66.
• FARIAS JA ET AL. 2012. Modulation of inflammatory processes by leaves extract from Clusia nemorosa both in vitro and in vivo animal models. Inflammation 35(2): 764-771.
• FENNER R, BETTI AH, MENTZ LA RATES SMK. 2006. Plantas utilizadas na medicina popular brasileira com potencial atividade antifúngica. Rev Bras Ciênc farm 42(3): 369-394.
• FERREIRA RO, JUNIOR ARC, SILVA TMG, CASTRO RN, SILVA TMS CARVALHO MG. 2014. Distribution of metabolites in galled and non-galled leaves of Clusia lanceolata and its antioxidant activity. Rev Bras Farmacogn 24(6): 617-625.
• FERRO JNS, SILVA JP, CONSERVA LM BARRETO E. 2013. Leaf extract from Clusia nemorosa induces an antinociceptive effect in mice via a mechanism that is adrenergic systems dependent. Chin J Nat Med 11(4): 385-390.
• GARCÍA-GONZÁLEZ M MATAMOROS OM. 1996. Cardiovascular effects of aqueous extracts of the leaves of Clusia coclensis (Guttiferae). Rev Biol Trop 44(1): 87-91.
• GARCÍA-GONZÁLEZ M MATAMOROS OM. 1998. Acción vaso-periférica del extracto acuoso de las hojas de Clusia coclensis (Clusiaceae). Rev Biol Trop 46(3): 575-578.
• GASPAROTTO JÚNIOR A, BRENZAN MA, PILOTO IC, CORTEZ, DAG, NAKAMURA CV, DIAS FILHO BP, RODRIGUES FE FERREIRA AG. 2005. Estudo fitoquímico e avaliação da atividade moluscicida do Calophyllum brasiliense Camb (Clusiaceae). Quim Nova 28(4): 575-578.
• GUSTAFSON K, BLUNT J, MUNRO M, FULLER R, MCKEE T, CARDELLINA J, MCMAHON J, CRAGG G BOYD M. 1992. The guttiferones, HIV-inhibitory benzophenones from Symphonia globulifera, Garcinia livingstonei, Garcinia ovalifolia and Clusia rosea. Tetrahedron 48: 10093-10102.
• HUERTA-REYES M, BASUALDO MDEL C, LOZADA L, JIMENEZ-ESTRADA M, SOLER C REYES-CHILPA R. 2004. HIV-1 inhibition by extracts of Clusiaceae species from Mexico. Biol Pharm Bull 27(6): 916-920.
• JAYASURIYA H, CLARK AM MCCHESNEY JD. 1991. New antimicrobial filicinic acid derivatives from Hypericum drummondii. J Nat Prod 54(5): 1314-1320.
• KELECOM A, REIS GL, FEVEREIRO PC, SILVA JG, SANTOS MG, MELLO NETO CB, GONZALEZ MS, GOUVEA RC ALMEIDA GS. 2002. A multidisciplinary approach to the study of the fluminense vegetation. An Acad Bras Cienc 74: 171-181.
• LANGENHEIN JH. 2003. Plant resins: chemistry, evolution, ecology and ethnobotany. Hong Kong: Timber Press, 586 p.
• LOKVAM J, BRADDOCK JF, REICHARDT PB CLAUSEN TP. 2000. Two polyisoprenylated benzophenones from the trunk latex of Clusia grandiflora (Clusiaceae). Phytochemistry 55(1): 29-34.
• LÓPEZ-ALARCÓN C DENICOLA A. 2013. Evaluating the antioxidant capacity of natural products: a review on chemical and cellular-based assays. Anal Chim Acta 763: 1-10.
• LUTTGE U. 2006. Photosynthetic flexibility and ecophysiological plasticity: questions and lessons from Clusia, the only CAM tree, in the neotropics. New Phytologist 171: 7-25.
• MANGAS R, REYNALDO G, VECCHIA MT, AVER K, PIOVESAN LG, BELLO A, RODEIRO I, MALHEIROS A, SOUZA MM MENENDEZ R. 2019. Gas Chromatography/Mass Spectrometry characterization and antinociceptive effects of the ethanolic extract of the leaves from Clusia minor L. J Pharm Pharmacogn Res 7: 21-30.
• MÁRQUEZ N, SANCHO R, BEDOYA LM, ALCAMÍ J, LÓPEZ-PÉREZ JL, FELICIANO AS, FIEBICH BL MUÑOZ E. 2005. Mesuol, a natural occurring 4-phenylcoumarin, inhibits HIV-1 replication by targeting the NF-kappaB pathway. Antiviral Res 66(2-3): 137-145.
• MAZZA KEL, SANTIAGO MCPA, PACHECO S, NASCIMENTO LSM, BRAGA ECO, MARTINS VC, CUNHA CP, GODOY RLO BORGUINI RG. 2019. Determinação de Substâncias Bioativas em Arilos dos Frutos de Clusia fluminensis Planch. Triana. Rev Virtual Quim 11(1): 3-17.
• MELO CL ET AL. 2009. Betulinic acid, a natural pentacyclic triterpenoid, prevents abdominal fat accumulation in mice fed a high-fat diet. J Agric Food Chem 57(19): 8776-8781.
• MENESES LC, RIBEIRO MS, ANHOLETI MC, FIGUEIREDO MR, KAPLAN MAC, SANTOS MG, PEREIRA HS PAIVA SR PAIXÃO ICNP. 2015. Cytotoxicity and antiviral activity of extracts and compounds isolated from Clusia fluminensis. DST - J Bras Doenças Sex Transm 27: 73-78.
• NEVES JS, COELHO LP, CORDEIRO RS, VELOSO MP, RODRIGUES E SILVA PM, DOS SANTOS MH MARTINS MA. 2007. Antianaphylactic properties of 7-epiClusianone, a tetraprenylated benzophenone isolated from Garcinia brasiliensis. Planta Medic 73(7): 644-649.
• NGUEMEVING JR, AZEBAZE AGB, KUETE V, ERIC CARLY NN, BENG VP, MEYER M, BLOND A, BODO B NKENGFACK AE. 2006. Laurentixanthones A and B, antimicrobial xanthones from Vismia laurentii. Phytochemistry 67(13): 1341-1346.
• NKENGFACK AE, MKOUNGA P, MEYER M, FOMUM ZT BODO B. 2002. Globulixanthones C, D and E: three prenylated xanthones with antimicrobial properties from the root bark of Symphonia globulifera. Phytochemistry 61(2): 181-187.
• ODONNE G, BOURDY G, CASTILLO D, ESTEVEZ Y, LANCHA-TANGOA A, ALBAN-CASTILLO J, DEHARO E, ROJAS R, STIEN D SAUVAIN M. 2009. Ta’ta’, Huayani: perception of leishmaniasis and evaluation of medicinal plants used by the Chayahuita in Peru. Part II. J Ethnopharmacol 126(1): 149-1458.
• OLIVEIRA CMA, PORTO ALM, BITTRICH V MARSAIOLI AJ. 1999. Two polyisoprenylated benzophenones from the floral resins of three Clusia species. Phytochemistry 50(6): 1073-1079.
• OLIVEIRA EC, ANHOLETI MC, DOMINGOS TF, FAIOLI CN, SANCHEZ EF, DE PAIVA SR FULY AL. 2014. Inhibitory effect of the plant Clusia fluminensis against biological activities of Bothrops jararaca snake venom. Nat Prod Commun (1): 21-25.
• OLIVEIRA RF, CAMARA CA , AGRAB MF SARMENTO TMS. 2012. Biflavonoids from the Unripe Fruits of Clusia paralicola and their Antioxidant Activity. Nat Prod Commun 7(12): 1597-1600
• PECCHIO M, SOLÍS PN, LÓPEZ-PÉREZ JL, VASQUEZ Y, RODRÍGUEZ N, OLMEDO D, CORREA M, SAN FELICIANO A GUPTA MP. 2006. Cytotoxic and antimicrobial benzophenones from the leaves of Tovomita longifolia. J Nat Prod 6(3): 410-413.
• PERAZA-SÁNCHEZ SR, CEN-PACHECO F, NOH-CHIMAL A, MAY-PAT F, SIMÁ-POLANCO P, DUMONTEIL E, GARCÍA-MISS MR MUT-MARTÍN M. 2007. Leishmanicidal evaluation of extracts from native plants of the Yucatan peninsula. Fitoterapia 78(4): 315-318.
• PICCINELLI AL, CUESTA-RUBIO O, CHICA MB, MAHMOOD N, PAGANO B, PAVONE M, BARONE V RASTRELLI L. 2005. Structural revision of Clusianone and 7-epi-Clusianone and anti-HIV activity of polyisoprenylated benzophenones. Tetrahedron 61(34): 8206-8211.
• POPOLO A, PICCINELLI AL, MORELLO S, SORRENTINO R, OSMANY CR, RASTRELLI L PINTO A. 2011. Cytotoxic activity of nemorosone in human MCF-7 breast cancer cells. Can J Physiol Pharmacol 89(1): 50-57.
• PORTO AL, MACHADO SM, OLIVEIRA CM, BITTRICH V, AMARAL MC MARSAIOLI AJ. 2000. Polyisoprenylated benzophenones from Clusia floral resins. Phytochemistry 55(7): 755-768.
• REUTRAKUL V, ANANTACHOKE N, POHMAKOTR M, JAIPETCH T, SOPHASAN S, YOOSOOK C, KASISIT J, NAPASWAT C, SANTISUK T TUCHINDA P. 2007. Cytotoxic and anti-HIV-1 caged xanthones from the resin and fruits of Garcinia hanburyi. Planta Medic 73(1): 33-40.
• RIBEIRO PR, FERRAZ CG, GUEDES ML, MARTINS D CRUZ FG. 2011. A new biphenyl and antimicrobial activity of extracts and compounds from Clusia burlemarxii. Fitoterapia 82 (8): 1237-1240.
• RUKACHAISIRIKUL V, PAILEE P, HIRANRAT A, TUCHINDA P, YOOSOOK C, KASISIT J, TAYLOR WC REUTRAKUL V. 2003. Anti-HIV-1 protostane triterpenes and digeranylbenzophenone from trunk bark and stems of Garcinia speciosa. Planta Med 69(12): 1141-1146.
• SACRAMENTO CK, COELHO JE, CARVALHO JEU, MÜLLER CH NASCIMENTO WMO. 2007. Cultivo do mangostão no Brasil. Rev Bras Fruticultura 29(1): 195-203.
• SALEHI B ET AL. 2018. Medicinal Plants Used in the Treatment of Human Immunodeficiency Virus. Int J Mol Sci 19(5): 1459.
• SANZ-BISET J, CAMPOS-DE-LA-CRUZ J, EPIQUIEN-RIVERA MA CAÑIGUERAL SA. 2009. A first survey on the medicinal plants of the Chazuta valley (Peruvian Amazon). J Ethnopharmacol 122(2): 333-362.
• SEO EK, HUANG L, WALL ME, WANI MC, NAVARRO H, MUKHERJEE R, FARNSWORTH NR KINGHORN AD. 1999. New biphenyl compounds with DNA strand-scission activity from Clusia paralicola. J Nat Prod 62(11): 1484-1487.
• SILVA EA, FILHA RF, SILVEIRA L, LOPES ED, PAULA N, BRAZ-FILHO J LAILA RE. 2013. Clusiaxanthone and Tocotrienol Series from Clusia pernambucensis and their Antileishmanial Activity. J Braz Chem Soc 24: 1314-1324.
• SILVA KMM, NÓBREGA AB, LESSA B, ANHOLETI MCA, LOBÃO AQ, VALVERDE AL, PAIVA SR JOFFILY A. 2017. Clusia criuva Cambess. (Clusiaceae): anatomical characterization, chemical prospecting and antioxidant activity. An Acad Bras Cienc 89: 1565-1578.
• SILVA MC PAIVA SR. 2012. Antioxidant activity and flavonoid content of Clusia fluminensis Planch. Triana. An Acad Bras Cienc 84: 609-616.
• SPINO C, DODIER M SOTHEESWARAN S. 1998. Anti-HIV coumarins from Calophyllum seed oil. Bioorg Med Chem Lett (24): 3475-3478.
• SUFFREDINI IB, PACIENCIA ML, NEPOMUCENO DC, YOUNES RN VARELLA AD. 2006. Antibacterial and cytotoxic activity of Brazilian plant extracts of Clusiaceae. Mem Inst Oswaldo Cruz 101(3): 287-290.
• TAKAOKA S, NAKADE K FUKUYAMA Y. 2002. The first total synthesis and neurotrophic activity of clusiparalicoline A, a prenylated and geranylated biaryl from Clusia paralicola. Tetrahedron Lett 43(39): 6919-6923.
• VALLI M, RUSSO HM BOLZANI VS. 2018. The potential contribution of the natural products from Brazilian biodiversity to bioeconomy. An Acad Bras Cienc 90: 763-778.
• WINTER K, GARCIA M HOLTUM JA. 2008. On the nature of facultative and constitutive CAM: environmental and developmental control of CAM expression during early growth of Clusia, Kalanchoe, and Opuntia. J Exp Bot 59(7): 1829-1840.
• WINTER K, GARCIA M HOLTUM JA. 2009. Canopy CO2 exchange of two neotropical tree species exhibiting constitutive and facultative CAM photosynthesis, Clusia rosea and Clusia cylindrica. J Exp Bot 60(11): 3167-3177.
• WOLF NP, DE MELLO TFP, NAVASCONI TR, MOTA CA, DEMARCHI IG, ARISTIDES SMA, LONARDONI MVC, TEIXEIRA JJV SILVEIRA TGV. 2017. Safety and efficacy of current alternatives in the topical treatment of cutaneous leishmaniasis: a systematic review. Parasitology 144(8): 995-1004.
• WU SB, LONG C KENNELLY EJ. 2014. Structural diversity and bioactivities of natural benzophenones. Nat Prod Rep 31(9): 1158-1174.
• YASUNAKA K, ABE F, NAGAYAMA A, OKABE H, LOZADA-PÉREZ L, LÓPEZ-VILLAFRANCO E, MUÑIZ EE, AGUILAR A REYES-CHILPA R. 2005. Antibacterial activity of crude extracts from Mexican medicinal plants and purified coumarins and xanthones. J Ethnopharmacol 97(2): 293-299.
• YIMDJO MC, AZEBAZE AG, NKENGFACK AE, MEYER AM, BODO B FOMUM ZT. 2004. Antimicrobial and cytotoxic agents from Calophyllum inophyllum. Phytochemistry 65(20): 2789-2795.
• ZHANG J, ZHAO J, SAMOYLENKO V, JAIN S, TEKWANI BL, MUHAMMAD I. 2018. New Polyisoprenylated Polycyclic Phloroglucines from Clusia gundlachii. Nat Prod Commun 13(3): 361-365.

Publication Dates

• Publication in this collection
  15 July 2024
• Date of issue
  2024

History

• Received
  27 July 2022
• Accepted
  23 Nov 2023