key: cord-1035514-z3e411h5
authors: Gómez-Verjan, J.; Gonzalez-Sanchez, I.; Estrella-Parra, E.; Reyes-Chilpa, R.
title: Trends in the chemical and pharmacological research on the tropical trees Calophyllum brasiliense and Calophyllum inophyllum, a global context
date: 2015-09-02
journal: Scientometrics
DOI: 10.1007/s11192-015-1715-2
sha: 05cfa842a87231c5c2871d2194835709b02bc046
doc_id: 1035514
cord_uid: z3e411h5

Tropical trees of Calophyllum genus (Calophyllaceae) have chemical and biological importance as potential source of secondary active metabolites which can lead to the development of new drugs. Research on this species has been rising since 1992 due to the discovering of anti-HIV properties of Calanolide A found in Calophyllum inophyllum leaves. This compound is the most important natural product for potential development of new anti-HIV drugs and phytomedicines. The scientometric analysis (1953–2014) here performed revealed that the most studied species of Calophyllum genus are: C. inophyllum and C. brasiliense, distributed in the Asian, and American continents, respectively. Current research on these species is carried out mainly in India and Brazil, respectively, where these species grow. Research on C. brasiliense is focused mainly on ecological, antiparasitic, cytotoxic properties, and isolation of new compounds. Chemical studies and biodiesel development are the main topics in the case of C. inophyllum. Text mining analysis revealed that coumarins, and xanthones are the main secondary active metabolites responsible for most of the reported pharmacological properties, and are potential compounds for the treatment of leukemia and against intracellular parasites causing American Trypanosomiasis and Leshmaniasis. On the other hand, C. inophyllum represents an important source for the development of 2nd generation biodiesel. Medicinal and industrial applications of these species may impulse sustainable forest plantations. To our knowledge this is the first scientometric and text mining analysis of chemical and biomedical research on Calophyllum genus, C. brasiliense and C. inophyllum.

It is a large tree of the Tropical Rain Forests, and distributed mainly in Central, and South America and the Caribbean region; it can reach 40 m height and 1-3 m diameter. In Brazil is commonly known as ''Guanandi'', and is used in traditional medicine to treat rheumatism, varicose hemorroids, ulcers, inflammation, and pain (Filho et al. 2009 ). In Mexico, its most common name is ''Bari'', and the infusion of the cortex is consumed in the Sierra de Atoyac, Guerrero by women over 9 days for ''cleaning'' the womb after child-birth, while the seeds provide an oil used for lighting and for healing skin afflictions Do Carmo Souza et al. 2009 ). In Colombia, the peasants call this tree ''árbol de aceite'' (oil tree), and the yellow latex exuded from the cortex is applied topically for healing the navels of newborn children (Garcia-Barriga, 1992) . There are several studies about biological activities of this species: antimicrobial, cytotoxic, antineoplastic, antispasmodic, antinociceptive, anti-HIV, and antiulcer properties Huerta-Reyes et al. 2004; Brenzan et al. 2007 Brenzan et al. , 2008 Brenzan et al. , 2012 . Briefly, brasiliensic acid and isobrasiliensic acids have been isolated from stem resin, 1,5dihydroxyxanthone, friedelin, and betulinic acid from the roots; gallic and protocatechuic acid from the fruits (Da Silva et al. 2001) . Protocatechuic acid and epicatechin were isolated from the flowers (Isaias et al. 2004 ). From the trunk bark different xanthones were isolated: brasixanthone A, B, C, D, E, F, G, and toxiloxixanthone A, 6-desoxijacareubin, 3,8-dyhydroxy-1,2-dimethoxyxanthone, 8-desoxygartanin, cudraxanthone F, 4-hydroxyxanthone, 1,2-dimethoxyxanthone, piranojacareubine, garcinin B, and latisxanthone C (Filho et al. 2009 ). Moreover, polyphenols have been isolated from AcOEt fractions of leaves: quercetin, amentoflavone, hyperoside, gallic and proatechuic acid (Da Silva et al. 2001) . Finally, different types of coumarins have been isolated from different polar and non polar extracts of leaves: dipyranocoumarins, such as calanolides A, B, C, D, and E and soulatrolide, and on the other hand 5,7-dyoxycoumarinic coumarins of the mammea type such as mammea type A/BA, A/BB, B/BA, B/BB, C/AO, C/OB, B/BA, B/BA F cycle, and B/BB F cycle among others. It has been proposed the existence of two different chemotypes (chemical phenotypes) of C. brasiliense based on the kind of main compounds that are biosynthesized (Zavaleta-Mancera et al. 2011) .

It is a large tree native from the Tropical Rain Forests of Australasia, and East Africa, and commonly known as Alexandrian laurel. It can reach 22 m of height; the flowers are used in some countries for ornamental purposes. It has many traditional uses in different countries. The fruit oil is indicated to treat rheumatism, gonorrhea and itching; the bark is used to treat hemorrhage, ulcer, and as an expectorant, antiseptic, diuretic and purgative (Potti and Kurup 1970) . This species has been widely studied from a phytochemical perspective. Briefly, from roots it have been isolated: caloxanthone A and B,1,5-dihydroxyxanthone-6-desoxijacarubin, epicatechin, amentoflavone, inophyllum, isoinophyllum, inophyllin A, friedelin and stigmasterol (Jantan et al. 2001 ). In addition, 4-phenylcoumarins inophyllum A, C, D and E, three tricyclic coumarins such as calocoumarin A, B, and C, calofoloid, apetatolide, and phenolic cinnamic acid have also been isolated from the roots. Several xanthones such as inoxanthone, caloxanthone A and B, macluraxanthone, 1,5-dihydroxyxanthone, calophynic acid, brasiliensic acid, inophylloidic acid, calaustralin, calophyllolide, and inophyllum C and E have been isolated the leaves, as well as, friedelin-type triterpenoids, such ascanophyllol, canophyllic acid, friedelin, friedelan-3-one, 3,4-secofriedelane-3,28-dioic acid, 27-(acetyloxy) canophyllic acid, and 27-(acetyloxy)-3-oxofriedelan-28-oic acid (Ito et al. 2006; Laure et al. 2005) .

Nowadays there is an increase in biomedical research providing a rich source of knowledge for pharmaceutical research, most of this knowledge can get lost among the great number of papers produced each year, for example, searching on Scopus Database the word ''Cancer'' retrieved more than 132,736 results only for 2014; clearly it is impossible for one person to read all these publications. Nevertheless, the development of new powerful analytical tools for scientometric analysis, and text mining are now facilitating research by helping to find new knowledge for the development of chemical and biomedical research. For drug and pharmaceutical development (Zhu et al. 2013) in natural products databases could help to reduce hit multiplicity and improve the process of hit to lead identification, or biotechnological approach. In this paper, we perform a scientometric and text mining analysis of chemical and biomedical research on Calophyllum genus focusing mainly on C. brasiliense and C. inophyllum.

During the period 1953-2014 we found 626 published papers indexed in Scopus database referent to Calophyllum spp. most of them (554) are original papers, while the others are errata, notes to editor, conference papers, among others. The main Journals which have published the original contributions are Phytochemistry, Journal of Natural Products, Forest Ecology and Managment, Tetrahedron Letters, and Planta Medica. Concerning to species, 139 papers are on C. brasiliense, and 222 papers on C. inophyllum (Fig. 1 ). This states that most of the research performed on Calophyllum genus has focused on phytochemical studies, biological properties of such compounds, and ecology research.

As depicted in Fig. 1 , there is an increase in the number of publication in the 90s, rising up in 1994, this probably due to the fact that calanolides (a novel class of benzotripyranones) were reported in 1992 to be highly active against HIV-1, since it is a potent inhibitor of the viral enzyme reverse transcriptase (Kashman et al. 1992) . Even so, calanolides A and B were reported to be highly active against HIV-1 replication (Patil et al. 1993) , leading calanolide A to reach the clinical phase II with infected patients (Butler 2005) since it was found in the previous stage to be well tolerated by healthy volunteers showing mild side effects (Creagh et al. 2001) . Until 2005 Calanolide A was considered as a promising candidate to be approved by the FDA as a new drug for HIV-AIDS treatment (Butler 2005) ; however, the development of Calanolide A and related compounds is currently on hold, and its fate will be decided by the Sarawak government who owns the pharmaceutical company (Saklani and Kutty 2008) . It is interesting to note that the first patents that protect the pharmaceutical applications, and synthesis of this group of compounds are about to expire, since the first patents were conferred since 1997. Another peak in research publications occurs in 2004, this might probably be due to the isolation of new tricyclyc coumarins, and the discovering of new pharmacological activities (antimicrobial, antiparasite, antimalarial, and against coronavirus, among others) of the coumarins, chromanones, and xanthones isolated from this genus (Su et al. 2008) . Additionally interest in this genus, arises from the possible development of 2nd generation biodiesel from seeds of C. inophyllum, as it might represent an important source of nonedible oil (Atabani and César 2014) .

As seen in Table 1 , the main bibliometric indicators for the genus are a low PNC and h value, as well as P, indicating an increasing in the interest of research on this genus; nevertheless, there are more P, CPP and PR on C. inophyllum compared to C. brasiliense. This probably due to the fact that research on its biotechnological applications as an non edible oil source for 2nd generation biodiesel production have shown to be quite remarkable and productive, as the most quoted article on C. inophyllum is on this topic (Sanjid et al. 2013 ). On the other hand, for C. brasiliense the most cited articles have been for ecological applications, such as reforestation (Cusack and Montagnini 2004) (Fig. 1) , nevertheless the CPP and PR on this species has been very low compared to C. inophyllum. Table 2 indicates that the main countries that perform research on Calophyllum spp. are India, Brazil, USA, Malaysia and Japan, this is not surprising as most of these countries posses interesting research programs in natural products; moreover, the USA-NIH program for bioprospecting in collaboration with Malaysia government involved the development of calanolide A as a potential compound against HIV-1 that resulted in the creation of Sarawak Medichem Inc. Species of Calophyllum can also be found in the forest of several of the research leader countries, such as India, Brazil, and Malaysia. Brazil is the leader country on C. brasiliense research, and India is the main country for C. inophyllum.

The leader institutions in research on Calophyllum genus, C. brasiliense and C. inophyllum are University of Putra, Malaysia, Universidade Estadual de Maringa, and University of Malaysia, respectively. This is not surprising as the University of Putra Malaysia possess an interesting program for developing new products (PutraInnotech) among them natural products. University of Malaysia is located at Sarawak. Table 2 and Fig. 2 show the main authors and co-authorship (more than five publications) leaders on research on Calophyllum spp. Richomme P. (Universite d'Angers) is the main author and co-author head in research of this genus, since he has the highest number of publications, specially on C. caledonicum and C. dispar. On the other side, Montagini F. (Yale University) is the leader on research on C. brasiliense, she posses several studies on ecological applications for this species; nevertheless, does not possess to many co-authorship relations (Fig. 2) . Finally, Masjuki H.H (U. of Malaya) is the leader on C. inophyllum publications ( Table 2 ) and one of the main coauthors in this topic (Fig. 2) , he has focused mainly on biodiesel applications of this species. As seen in Fig. 3 the main biological research over the last years in C. brasiliense have been focused on its enviromental and ecological applications; for instance, it has been proposed the development of a phytomedicine (a extract from the leaves containing anti-HIV coumarins) as a strategy to impulse sustainable plantations, contributing to stop deforestation (César et al. 2011; Tapia-Tapia and Reyes-Chilpa 2008) . Even so, there is an important amount of papers for anti-parasitic activities, mostly related to mammea type coumarins, antileishmania (Brenzan et al. 2007) ; and trypanocidal , as well as for cytotoxic properties specially against leukemia cell lines such as K562 and HL-60 (Ito et al. 2006; Gomez-Verjan et al. 2014; Kimura et al. 2005) , and antimicrobial properties mostly related to inhibition of Mycobacterium tuberculosis (Pires et al. 2014) and Helicobacter pylori (Su et al. 2008) . This highlight C. brasiliense as a potential source of natural products, particulary mammea type coumarins with potential for the development of new drugs with antiparasite properties, and against leukemia. The indicators used are: number of publications (P); and Hirsch index (h)

Calophyllum inophyllum has a higher number of publications (147) and different categories of research as compared to C. brasiliense (Fig. 4) . The biotechnological applications have been the most studied topic on this species compared to its pharmacological activities, since there are more than 40 papers on the non-edible oil from its seeds. ''Honne oil'' is a 2nd generation source of biodiesel. The annual yield of a mature tree is about 100 kg of seeds, which produce approximately 18 kg of oil (Rizwanul Fattah et al. 2014 ); once, it has been de-gummed and neutralized its capacities as a biofuel are improved (Ong et al. 2014 ). It has been proved that C. inophyllum biodiesel blends can be used effectively in a diesel engine without modification (Rizwanul Fattah et al. 2014 ). There are also an important amount of papers dedicated uniquely to the isolation of new and majoritarian compounds, such as coumarins (tetracyclic, tricyclic, and mammea type) and xanthones, some of them restricted to this species. Interestingly, C. inophyllum coumarins posses interesting activities as chemopreventive agent against Eipstein Barr Virus; while some xanthones have antimicrobial properties. The text mining analysis performed with Arrowsmith software (that uses the MEDLINE database) showed a higher correlation (0.99-0.98) between the topics Calophyllum spp. AND Research with the terms RT-HIV-1, biodiesel production, biohydrogen, biosorption, Rhodobacter sphaeroide, Enterobacter aerogenes, antibacterial, antifungal, antileishmanial, coumarins, and xanthones. The terms: antimicrobial activity, antibacterial activity, antileishmanial, K562, antiproliferative, and Mycobacterium tuberculosis correlated (0.99-0.96) with C. brasiliense and Research. The terms HIV-1 reverse transcriptase inhibitor, biodiesel, biohydrogen correlated (0.99-0.96) with C. inophyllum and Research, since one of the trending topics over the last years on this species is the obtention of nonedible oil from the seeds for the production of 2nd generation biodiesel. Correlation with R. sphaeroide and E. aerogenes is related to the fact that a two-step biodiesel production method has been proposed with these bacteria (Venkanna and Reddy 2009; Arumugam et al. 2014) .

The text mining analysis indicated that the most interesting secondary metabolites isolated from C. brasiliense are coumarins and xanthones, responsible for its activity against RT-HIV-1, antimicrobial and antiparasital properties. For example, calanolide A, and soulatrolide, have been proposed as a dual agents against M. tuberculosis and HIV-1, the former is an opportunistic microorganism associated with AIDS (Pires et al. 2014; Xu et al. 2004; Huerta-Reyes et al. 2004) . The relationship between Calophyllum spp. and the term Cancer showed correlation (0.99-0.96) with the terms HL-60, selective COX-2 inhibitor, coumarins, apoptosis inductor, raw 264 cells, K562 cells. Moreover, there is a Fig. 4 Pharmacological and Biological activities of C. inophyllum. Others: clinical use report, ocular burn healing, analgesic, anti-platelet, anti-hypertension, anti-inflammatory, anxiolytic, inhibitor (PAF, XAO) strong relationship between leukemia cell lines and mammea type coumarins, since these have shown the induction of cell death by apoptosis tested against several types of leukemia cell lines such as K562 and HL-60 (Ito et al. 2006; Gomez-Verjan et al. 2014 ).

Pharmacological and biological research on Calophyllum spp. has been increasing over the last years (1994 to date), due to its potential as an important source of pharmacologically active compounds against HIV-1, intracellular parasites, cancer cell lines, especially leukemia, among others. In addition, C. inophyllum has shown potential as source of oil for 2nd generation biodiesel. Further studies should focus on toxicological research in order to validate if active secondary metabolites (xanthones and coumarins) have real opportunities for the development of new active drugs or that extracts could be developed as phytomedicines. Medicinal and industrial applications of the main species C. brasiliense, and C. inophyllum could also impulse sustainable forest plantations.

We use Scopus database which covers an expanded spectrum of journals and a faster citation analysis (Falagas et al. 2008) . Searches for publications on Calophyllum, C. 

We used bibliometric indicators described in the literature for bibliometric studies (Li and Willett 2010) ; number of publications (P), number of citations (Ó mean number of citations per publication (CPP), percentage of publications not cited (PNC), percentage of reviews (PR) and Hirsch index (h).

Scientometric cluster analysis (more than 5 co-authorship publications), density (number of co-authorship publications) and network (authors related in the co-authorship clusters) were built with freely available software VOSviewer version 1.6.0 (Van Eck and Waltman 2010).

For trending topics on Calophyllum research we performed text mining analysis with free on line software Arrowsmith (Smalheiser et al. 2009 ), which identify meaningful links between two sets of Medline articles, a UIC-based site for searching links between two literatures within Medline, we search for the intersection (B-list) of Calophyllum AND research (Job ID: 

Biohydrogen and polyhydroxyalkanoate co-production by Enterobacter aerogenes and Rhodobacter sphaeroides from Calophyllum inophyllum oil cake

Calophyllum inophyllum L.-A prospective non-edible biodiesel feedstock. study of biodiesel production, properties, fatty acid composition, blending and engine performance

Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis

Antileishmanial activity of crude extract and coumarin from Calophyllum brasiliense leaves against Leishmania amazonensis

Effects of (-) mammea A/BB Isolated from Calophyllum brasiliense leaves and derivatives on mitochondrial membrane of Leishmania amazonensis

Natural products to drugs: natural product derived compounds in clinical trials

Natural product and natural product derived drugs in clinical trials

Inhibition of HIV-1 reverse transcriptase, toxicological and chemical profile of Calophyllum brasiliense extracts from Chiapas

Safety and Pharmacokinetics of Single Doses of (?)-Calanolide A, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects

The role of native species plantations in recovery of understory woody diversity in degraded pasturelands of Costa Rica

Chemical composition and analgesic activity of Calophyllum brasiliense leaves

In vitro and in vivo anti-helicobacter pylori activity of Calophyllum brasiliense Camb

Comparison of PubMed, Scopus, Web of Science, and Google Scholar: Strengths and weaknesses

Chemical and pharmacological aspects of the genus Calophyllum

Flora Medicinal de Colombia

Molecular mechanisms involved in the cytotoxicity induced by coumarins from Calophyllum brasiliense in K562 leukaemia cells

HIV-1 inhibitory compounds from Calophyllum brasiliense leaves

Pharmacological and phytochemical investigations of different parts of Calophyllum brasiliense (Clusiaceae)

Apoptosis inducing activity of 4-substituted coumarins from Calophyllum brasiliense in human leukaemia HL-60 cells

Inhibitory effects of xanthones on platelet activating factor receptor binding in vitro

The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum Lanigerum

Inhibition of Leukemic cell growth by a novel anti-cancer drug (GUT-70) from Calophyllum brasiliense that acts by induction of apoptosis

Structures of new secofriedelane and friedelane acids from Calophyllum inophyllum of French Polynesia

Bibliometric analysis of chinese research on cyclization, MALDI-TOF and antibiotics

Optimization of biodiesel production and engine performance from high free fatty acid Calophyllum inophyllum oil in CI diesel engine

The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn

Anti-mycobacterium tuberculosis activity and cytotoxicity of Calophyllum brasiliense Cambess (Clusiaceae)

Antibacterial principle of the root bark of Calophyllum inophyllum: Isolation and antibacterial activity

Big pharma, little science?

Cytotoxic effects of mammea type coumarins from Calophyllum brasiliense

Trypanocidal constituents in plants: 7. Mammea-type coumarins. Memórias do Instituto Oswaldo Cruz

Experimental investigation of performance and regulated emissions of a diesel engine with Calophyllum inophyllum biodiesel blends accompanied by oxidation inhibitors

Plant-derived compounds in clinical trials

Impact of palm, mustard, waste cooking oil and Calophyllum inophyllum biofuels on performance and emission of CI engine

Arrowsmith two-node search interface: A tutorial on finding meaningful links between two disparate sets of articles in MEDLINE

A revision of the old world species of Calophyllum (Guttiferae)

Chemical constituents of the plants of the genus Calophyllum

Productos Forestales No Maderables En México : Aspectos Económicos Para El Desarrollo Sustentable Mexican non-wood forest products: Economic aspects for sustainable development

Software survey: VOSviewer, a computer program for bibliometric mapping

Biodiesel production and optimization from Calophyllum inophyllum linn oil (honne oil)-A three stage method

Anti-HIV natural product (?)-calanolide A is active against both drug-susceptible and drug-resistant strains of mycobacterium tuberculosis

Leaf structure of two chemotypes of Calophyllum brasiliense from Mexico

Scientific publications in obstetrics and gynecology journals from China

Acknowledgments Juan Carlos Gomez Verjan is grateful with Posgrado en Ciencias Biomédicas-UNAM and CONACyT for providing a scholarship number 220346. This work was submitted in fulfillment of the requirements to obtain PhD degree at Doctorado en Ciencias Biomédicas and Universidad Nacional Autónoma de México. This research was supported by Grant IG200513 from DGAPA-UNAM. I. Gonzalez-Sanchez was supported by a post-doctoral Grant (DGAPA-UNAM).