Natural Products from the Yucatecan Flora: Structural Diversity and

Review Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

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Natural Products from the Yucatecan Flora: Structural Diversity and Biological Activity Gloria I. Hernań dez-Bolio,† Javier A. Ruiz-Vargas,‡ and Luis M. Peña-Rodríguez*,‡ †

J. Nat. Prod. Downloaded from pubs.acs.org by UNIV OF TEXAS AT DALLAS on 03/12/19. For personal use only.

Departamento de Recursos del Mar, Centro de Investigaciones y Estudios Avanzados del Instituto Politécnico Nacional - Unidad Mérida, Mérida, México ‡ Laboratorio de Química Orgánica, Unidad de Biotecnología, Centro de Investigación Científica de Yucatán, Mérida, México ABSTRACT: The Yucatan Peninsula possesses a unique climate, geology, landscape, and biota that includes a distinct flora of over 2300 species; of these, close to 800 plants are used in what is known as Mayan traditional medicine, and about 170 are listed as native or endemic. Even though the flora of the Yucatan peninsula has been widely studied by naturalists and biologists, to date, phytochemical and pharmacological knowledge of most of the plants, including the medicinal plants, is limited. Presently, phytochemical studies carried out on plants from the Yucatecan flora have resulted in the identification of a wide variety of natural products that include flavonoids, terpenoids, polyketides, and phenolics with cytotoxic, antiprotozoal, antibacterial, antiinflammatory, analgesic, antioxidant, and antifungal activities. This review describes the main findings in over 20 years (1992 to 2018) of exploring the natural product diversity of the Yucatecan flora.

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INTRODUCTION The Mexican states of Campeche, Quintana Roo, and Yucatan belong to what is known biogeographically as the Yucatan Peninsula Biotic Province.1 This natural region possesses a unique geology, geomorphology, landscape, and biota that, historically, influenced and shaped what is known as the Mayan culture.2 Additionally, these unique characteristics, together with the annual precipitation, the clear-cut occurrence of the wet and dry seasons, and the particular drainage provided by the limestone plaque that makes up the peninsula, have resulted in the development of a distinctive native flora and played a major role in defining the distribution of the various species around the peninsula.3 The biodiversity of the Yucatecan flora includes approximately 2300 species of flowering plants.4,5 Of these, 115 (5%) plant species are considered endemic,2 and over 30% (812) of them are used in Mayan traditional medicine to treat a number of diseases.6,7 Since the main causes of mortality in the rural areas of Yucatan continue to be respiratory and gastrointestinal health problems, an important fraction of the Yucatecan medicinal plants is used to cure microbial infections and inflammation symptoms associated with various ailments.8,9 Medicinal plants are recognized as a potential source of a wide range of structurally diverse natural products, many with interesting biological activities, which can be used either as pharmaceuticals directly or in the development of new and better pharmaceuticals.10−13 To date, the flora of the Yucatan peninsula, which has been studied extensively by both biologists and naturalists,6 has received little attention for its © XXXX American Chemical Society and American Society of Pharmacognosy

potential as a source of novel bioactive secondary metabolites. This review describes the main findings in over 20 years (1992 to 2018) of exploring the natural product diversity of the Yucatecan flora.

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SCREENING THE MAYAN PHARMACOPEIA The best represented plant families in the Yucatan Peninsula are the Leguminosae, Poaceae, Asteraceae, and Orchidaceae, representing over 1200 (50%) of the species in the Yucatecan flora.14 Other families with a high number of taxa include the Euphorbiaceae (113), Rubiaceae (68), and Apocynaceae (60).2 The first studies exploring the potential of Yucatecan medicinal plants as sources of novel bioactive metabolites were limited to isolated reports that included the classification of the indigenous uses of over 1500 species and their evaluation in different assay models15,16 and the screening of native medicinal plants for antioxidant, antifungal, antibacterial, antimycobacterial, DNA-interaction, β-glucosidase inhibition, and cytotoxic activities.17−19 Additional screening programs of medicinal plants used ethnomedical information to search for natural products with antiprotozoal activity, particularly against Leishmania spp., Giardia lamblia, and Trypanosoma cruzi,20−22 with cytotoxic activity against different cell lines,23,24 with activity to prevent the formation of advanced glycation Special Issue: Special Issue in Honor of Drs. Rachel Mata and Barbara Timmermann Received: November 13, 2018

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DOI: 10.1021/acs.jnatprod.8b00959 J. Nat. Prod. XXXX, XXX, XXX−XXX

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products,25 and with activity against infectious bowel diseases.26 The results obtained from these screening campaigns were used as background information to select the plant species that resulted in the isolation and identification of many of the bioactive natural products that are described in the following sections.

Flavones. The hexane-soluble portion of the leaf methanolic extracts of L. xuul and L. yucatanensis also yielded a number of 2,2-dimethylpyranoflavones, including 5,4′dihydroxy-3′-methoxy-(7,6:2″,3″)-6″,6″-dimethylpyranoflavone (5) and 5,4′-dimethoxy-(7,6:2″,3″)-6″,6″-dimethylpyranoflavone (6),27 identified as new natural products. Of the two flavones, 6 showed antiprotozoal activity when tested against Leishmania spp. and Trypanosoma cruzi, as well as cytotoxic activity against P388DI leukemia and PC-3 prostate adenocarcinoma cell cultures.30 Additionally, the previously reported flavones cirsimaritin (7) and sorbifolin (8) and their corresponding glucosides, cirsimarin (9) and sorbifolin-6-O-βglucopyranoside (10), were isolated from Aphelandra scabra (Vahl) Sm. (Acanthaceae), a shrub used commonly in Mayan traditional medicine as a carminative and to alleviate infections; of the four pure metabolites, only cirsimaritin (7) showed antiprotozoal activity against G. lamblia.31

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NATURAL PRODUCTS FROM THE YUCATAN FLORA The secondary metabolites derived from the study of the native flora of the Yucatan Peninsula are widely diverse in terms of their structure and biological activity. Since the Yucatecan flora is particularly rich in species belonging to the Leguminosae family, the study of many of these plants has resulted in the identification of a variety of novel bioactive flavonoids, including flavones, flavanones, flavonols, flavans, chalcones, and pterocarpans. Similarly, the study of species of the Euphorbiaceae family led to the isolation of diterpenes and triterpenes with antimicrobial and anti-inflammatory properties, while other terpenoids produced by different species of the Yucatecan flora vary from monoterpenes to sesquiterpenes and triterpenoid saponins, as well as steroids and terpenoids with novel skeletons. Finally, cyclic peptides, anthraquinones, oxylipins, catechols, phenolic lipids, and benzochromenes are also reported from various species of the Yucatecan flora. A detailed listing of the species investigated, the identified metabolites, and their biological activities are listed below. Chalcones. In the initial investigation of the phytochemical components from Lonchocarpus spp., the chromatographic fractionation of the hexane-soluble portion of the leaf methanolic extracts of Lonchocarpus xuul Lundell and L. yucatanensis Pittier led to the isolation of the new chalcone 4,2′-dimethoxy-6′-hydroxylonchocarpin (1).27 In addition, purification of the root extract of L. xuul yielded two isocordoin derivatives identified as dihydroisocordoin (2) and flemistrictin B (3);28 a third chalcone, having the same molecular formula and similar spectroscopic data to those of 3, was also isolated from the root extract of L. xuul and identified as epi-flemistrictin B (4). The configuration at the C-2″ position of the epimeric chalcones 3 and 4 was established on the basis of theoretical calculations of the H-2″ chemical shift for each of the epimeric structures; the results showed that the H-2″ in the alpha orientation appears at a significantly higher field than that in the beta orientation.29

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Flavans. The bark and root extracts of Lonchocarpus spp. from the Yucatecan flora proved to be rich sources of 2,2dimethylpyranoflavans, including the new compounds xuulanin (11) and 3β-methoxyxuulanin (12), together with 3β,4β,5trimethoxy-4′-hydroxy-(6:7)-2,2-dimethylpyranoflavan (13), 3β-hydroxy-4β,5-dimethoxy-(6:7)-2,2-dimethylpyranoflavan (14), and 3β,4β-dihydroxy-5-methoxy-(6:7)-2,2-dimethylpyranoflavan (15).27,32 Testing of these new flavans for antiprotozoal and cytotoxic activity showed 3-hydroxy-4,5dimethoxy-(6:7)-2,2-dimethylpyranoflavan (14) as being selective and highly active against Plasmodium falciparum. The lack of activity of structurally related flavans 11, 13, and 15 suggested that the OH-3 and OMe-4 groups in the flavan skeleton are important for the expression of antiplasmodial activity.30

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sesquiterpenes such as α-humulene (24), β-caryophyllene (25), and β-caryophyllene oxide (26).37 The phytochemical study of the high-polarity fraction from the root extract of Thevetia gaumeri Hemsley (Apocynaceae), a plant used in Yucatecan traditional medicine as an antimalarial and to heal wounds, led to the isolation of an iridoid glucoside identified as theveridoside (27).38 In a different study, directed toward identifying native Yucatecan plants as potential sources of antiprotozoal metabolites, a leaf extract of Serjania yucatanensis Standl. (Sapindaceae), an endemic plant commonly used in Yucatecan traditional medicine to treat infections, showed marked in vitro and in vivo activities against Trypanosoma cruzi.22 The bioassay-guided purification of the crude extract yielded a bioactive fraction containing a mixture of the sesquiterpene βcaryophyllene oxide (26) and the triterpene lupenone (28), both of which were not active when tested separately.39 Recently, the synergistic effect of a 1:4 mixture of 26 and 28 was confirmed when tested against epimastigote forms of T. cruzi.40 The nor-isoprenoids blumenol A (29) and blumenol B (30), together with loliolide (31), were isolated from the leaf extract of Heliotropium angiospermum Murray (Boraginaceae), a plant commonly used in Yucatan as an anti-inflammatory and wound-healing agent. Initial testing of the leaf extract of H. angiospermum showed a positive response for DNA-interacting activity when tested in a DNA-methyl green assay.41 The Urechitols: Tri-Nor Sesquiterpenes with a Novel Skeleton. One of the plants most commonly used in Yucatecan traditional medicine for the treatment of lesions derived from leishmaniosis is Pentalinon andrieuxii (syn. Urechites andrieuxii) (Müll. Arg.) B.F. Hansen & Wunderlin (Apocynaceae).42 During the search for leishmanicidal agents from Yucatecan medicinal plants, fractionation of the root extract of P. andrieuxii yielded two new but inactive secondary metabolites; these structurally unusual tri-nor sesquiterpenoids were designated as urechitol A (32) and urechitol B (33).43 Xray crystallography of 32 confirmed a proposed novel skeleton named “campechane” (34). Recently, as part of a project directed toward establishing the biosynthetic origin of the urechitols and the campechane skeleton, and after using herb chronology for the first time in a tropical plant,44 it was established that the amount of urechitol A in the root tissue increases with plant development and that its biosynthesis might be more related to ontogeny than phenology.45 Diterpenes. During the search for bioactive metabolites from Chiococca alba (L.) Hitchc. (Rubiaceae), considered one of the 10 most popular medicinal plants in the Yucatan peninsula, the purification of the root extract yielded a new and unusual nor-seco-pimarane identified as 4-acetyl-4,8,9β-trimethyl-8-vinyldecahydrobenzo[de]chromen-2-one, designated with the trivial name merilactone (35).46 The biogenetic origin of 35, proposed to initiate from a pimardiene diterpene that undergoes a ring fission and subsequent lactonization, remains unconfirmed. Additional purification of the root extract of C. alba resulted in the identification of three new ent-kaurane diterpenes, of which 17-hydroxy-16α-kauran-3-one (36) was reported as the first ent-kaurane with antimicrobial activity.47 The other two ent-kauranes were identified as 1-hydroxy-18-nor-kaur-4,16dien-3-one (37) and 15-hydroxykaur-16-en-3-one (38), together with the previously reported metabolites kaur-16-en19-ol (39), kaurenoic acid (40), and ribenone (41).48 The

Flavonols. These metabolites, like other flavonoids, are recognized for their antioxidant activity and are often isolated as glycosides.33 A recent phytochemical study Sideroxylon fetidissimum Jacq. subsp. gaumeri Pittier (T.D. Penn) (Sapotaceae) resulted in the isolation of kaempferol-3-Orutinoside (16) from the ethanolic leaf extract, which had shown DNA-interacting activity when tested in a DNA-methyl green assay.34 Additionally, a series of flavonol-rhamnosides identified as rhamnitrin (rhamnetin-3-O-α-L-rhamnopyranoside, 17), afzelin (kaempferol-3-O-α-L-rhamnopyranoside, 18), and quercitrin (quercetin-3-O-α-L-rhamnopyranoside, 19) were isolated from the acetone−water leaf extract of Lysiloma latisiliquum (L.) Benth. (Fabaceae), a tannin-rich forage plant commonly used in rural Yucatan to feed goats. Quercitrin (19), which has previously been reported as having antiinflammatory, leishmanicidal, and antidiarrheal activity, showed anthelmintic activity against Hemonchus contortus, an important gastrointestinal nematode of small ruminants.35 Chart 4

Pterocarpans. A new pterocarpan, aeschynocarpin (20), isolated from the methanol extract of the root bark of Aeschynomene fascicularis Schltdl. & Cham. (Fabaceae), a plant used in Mayan traditional medicine to treat warts, showed selective cytotoxic and antiproliferative activities on moderate (DU-145) and malignant (PC-3) prostate cancer cell lines. The already known 2-methoxymedicarpin (21), which was also isolated from the same extract, did not show significant activity.36 Chart 5

Monoterpenes and Sesquiterpenes. An investigation on the phytochemical diversity of the essential oils from 14 wild populations of Lippia graveolens Kunth (Mexican oregano), using a principal component analysis of the GCFID and GC-MS chromatographic profiles, allowed the grouping of the 14 wild populations into three distinct chemotypes: two phenolic chemotypes showed either carvacrol (22) or thymol (23) as the main component (>75%) in the essential oil, while the composition of the oil from a third, nonphenolic chemotype showed a mixture of oxygenated C



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Finally, a phytochemical study of the leaves and roots of Jatropha gaumeri Greenm. (Euphorbiaceae), a plant widely recognized for its medicinal properties in the Yucatan Peninsula, resulted in the isolation of 2-epi-jatrogrossidione (51), a rhamnofolane diterpene, together with 15-epi-4Ejatrogrossidentadione (52), a lathyrane-type diterpene, both skeletons distinctive of the Jatropha genus.53 The rhamnofolane diterpene 51 showed significant antimicrobial activity against Bacillus subtilis, comparable to that of amikacin. Steroids and Triterpenes. During the search for novel leishmanicidal metabolites, two pregnanes were isolated from the root extract of P. andrieuxii. While the spectroscopic data of the first product proved to be identical to that of 3β,14βdihydroxypregn-5-en-18-oic acid (18−20)-lactone (53), the aglycone of amaloside C, as previously reported from Amalocalyx yunnanensis Tsiang (Apocynaceae),54 the second metabolite was identified as 3β,14β,20-trihydroxy-5β-pregn18oic acid (18−20)-lactone (54), a new natural pregnane.55 An additional natural pregnane was isolated from Sansevieria hyacinthoides (L.) Druce (Dracaenaceae), an ornamental and medicinal plant widely grown in Yucatan, as part of a search for new sources of steroidal sapogenins. The 1β,3β-dihydroxy5,16-pregnadien-20-one (55) was identified together with the known 25S-ruscogenin (56), with the former compound being the first pregnane reported from the family Dracaenaceae.56 A phytochemical study of the leaf extract of Tillandsia fasciculata Swarts (Bromeliaceae), an epiphytic plant found commonly in the Yucatan Peninsula, produced two new cycloartanes, identified as cyclolaudenyl formate (57) and (24S)-24-isopropenyl cycloartanone, with the trivial name tillandsinone (58), together with the known cycloartanes cyclolaudenone (59) and cyclolaudenol (60).57 It is worth mentioning that triterpenes and sterols having nonconventional side chains, such as that in 58, are rare in terrestrial plants and so far have only been detected in species from the Orchidaceae and Violaceae families. A similar study on T. brachycaulos Schltdl. (Bromeliaceae) resulted in the isolation of two new 24-isopropenyl lanostanoids identified as (24S)-24isopropenyl-29-nor-5α-lanosta-7-en-3-ol (61) and (24S)-24isopropenyl-29-nor-5α-lanosta-7-en-3-one (62).58 Both lanostanoids proved to be inactive when tested for antimicrobial activity in several organisms. A project directed toward studying the composition of the cuticular wax of Cocos nucifera L. (Arecaceae) and its potential

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results of these phytochemical studies identified the root extract of C. alba as an important source of novel labdane, pimarane, and ent-kaurane diterpenoids. An additional new entkaurane glycoside, isolated from the seed extract of Pithecellobium albicans (Kunth) Benth. (Fabaceae), a tree used as an antiseptic and to heal wounds, was identified as (−)-19β-D-glucopyranosyl-6,7-dihydroxykaurenoate (42).49 The same purification yielded the stigmastane spinasterol-βD-glucopyranoside (43). Members of a different class of diterpenes, all having a podocarpane skeleton, were isolated from a root bark extract of Crossopetalum gaumeri (Loes.) Lundell (Celastraceae), an endemic medicinal plant from the Yucatan Peninsula used to treat dysentery and snake bites. Four new diterpenes, designated as crossogumerins A−D (44−47), were isolated together with six previously reported podocarpanes. Only two of the diterpenes, crossogumerin B (45) and nimbiol (48), showed significant activity against HeLa cells.50 SAR studies suggested that an epoxide in ring B and a hydrogen bond donor were required for cytotoxicity. Recently, a bioassay-guided purification of the leaf extract of Cnidoscolus souzae McVaugh (Euphorbiaceae), commonly known as “chaya” and recognized as one of the most popular medicinal and edible plants in the Yucatan Peninsula, resulted in the identification of 7-deoxynimbidiol (49), a diterpene with a potent antioxidant activity.51 Similarly, the purification of a root extract of C. souzae led to the identification of a novel dimeric derivative of 49, designated as dinimbidiol ether (50), which also showed antioxidant activity in the DPPH assay.52 D



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activities when tested against Leishmania amazonensis and Trypanosoma cruzi var. tulahuen, respectively. Similarly, a search for new natural products with potential anticancer activity from the aerial parts of Phoradendron vernicosum Greenm. (Santalaceae), a native plant used in the traditional medicine to treat cancer-like symptoms, yielded three new lupane-type triterpenes, designated as 3α,24dihydroxylup-20(29)-en-28-oic acid (75), 3α,23-dihydroxy30-oxo-lup-20(29)-en-28-oic acid (76), and 3α,23-O-isopropylidenyl-3α,23-dihydroxylup-20(29)-en-28-oic acid (77). Compound 77 showed cytotoxic selectivity against the nasopharyngeal carcinoma (KB) cell line.63 Two new oleanane triterpenoids, identified as 21-hydroxyolean-12-en-3-one (78) and dzununcanone (79), a seco-dinor derivative of pristimerine, together with the already known (21R)-hydroxy-3-oxofriedelane (80), pristimerine (81), tingenone (82), and xuxuarine (83), were isolated from the root bark of Hippocratea excelsa H.B.K. (Celastraceae), a plant recognized for its medicinal and insecticidal properties. On testing all the isolated metabolites against Giardia intestinalis, 81 and 82 were found to be the most active.64 The difference in the antigiardial activity of 79 and 81 suggested that either the A ring or the quinone-methide functionalization is essential for the resultant biological activity of these molecules. During a phytochemical study of the stem extract of P. andrieuxii, a triterpene initially identified by GC-MS as lupeol acetate (84) was isolated. However, both the 1H and 13C NMR spectra of the pure metabolite showed a number of signals that

application as a chemotaxonomic marker for disease resistance and susceptibility of coconut palms to Lethal Yellowing Disease (LYD) led to the identification of lupeol methyl ether (63), skimmiwallin (64), and isoskimmiwallin (65) as the three major components in the cuticular wax.59 Additional studies on the chemical composition of the cuticular wax of C. nucifera resulted in the identification of the skimmiwallinol derivatives skimmiwallinol acetate (66), isoskimmiwallinol acetate (67), skimmiwallinone (68), isoskimmiwallinone (69), and skimmiwallinin (70) as minor components.60,61 Interestingly, 70 was first reported from Skimmia wallichii Hook.f. & Thomson ex Gamble (Rutaceae), a plant growing in Nepal and totally unrelated to C. nucifera. Possible explanations for this chemotaxonomic coincidence include the hypothesis that the biosynthetic pathway leading to the synthesis of cycloartanes is common to most angiosperms and that parallel evolution resulted in the production of the same type of metabolites by both species.61 A search for new leishmanicidal agents from plants of the Yucatecan flora resulted in the identification of 3-Oacetylceanothic acid (71), a new ceanothane-type triterpene, together with the known triterpenes ceanothic acid (72), ceanothenic acid (73), and betulinic acid (74) from the root extract of Colubrina greggii S. Watson var. yucatanensis M.C. Johnst. (Rhamnaceae), a shrub used for the treatment of liver diseases, ulcerations, and tuberculosis in Mayan traditional medicine.62 The natural ceanothanes and some synthetic derivatives showed moderate leishmanicidal and trypanocidal E



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could not be accounted for in the proposed structure. A careful analysis of the fragmentation pattern of the isolated metabolite allowed the identification of the correct structure as lupeol-3(3′R-hydroxy)stearate (85), also known as procrim b.65 The initial identification of 85 as lupeol acetate (84) can be explained by the fact that thermolysis of β-hydroxy-esters occurs readily under GC-MS analysis conditions. Saponins. A bioassay-guided purification of the cytotoxic root extract of Sideroxylon fetidissimum Jacq. subsp. gaumeri Pittier (T.D. Penn) (Sapotaceae), an endemic species of the Yucatecan flora reportedly used in traditional medicine,4 led to the identification of six saponins (86−91), with five of these not previously reported. The cytotoxic evaluation of the original saponin fraction, as well as some individual components, and a 5:4 mixture of the saponins 3-O-(β-Dglucopyranosyl)-28-O-(α-L-rhamnopyranosyl-(1→3)-β-D-xylopyranosyl-(1→4)[β-D-apiofuranosyl-(1→3)]-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl)-16α-hydroxyprotobassic acid and 3-O-(β-D-apiofuranosyl-(1→3)-β-D-glucopyranosyl)28-O-(α-L-rhamnopyranosyl-(1→3)[β-D-xylopyranosyl-(1→ 4)]β-D-xylopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-αL-arabinopyranosyl)-16α-hydroxyprotobassic acid, showed the most potent cytotoxic activity among the saponins investigated.66 Similarly, the bioassay-guided purification of an antifungal and cytotoxic root extract of Jacquinia f lammea Millsp. ex Mez [syn. Bonellia f lammea (Millsp. ex Mez) Ståhl & Källersjö] (Theophrastaceae), a plant used in the traditional medicine to treat colds and fever, led to the identification of sakurasosaponin (92) as the active principle of the extract.67,68 Phenolic Metabolites. The bioassay-guided purification of a stem extract of Bakeridesia gaumeri (Standl.) D.M. Bates (Malvaceae), an endemic plant of the Yucatan peninsula used commonly to treat dysentery and diarrhea, led to the isolation of two metabolites with antioxidant activity that were identified as 7-hydroxycadalenal (93) and trans-clovamide (94). The potent antioxidant activity of 94 suggested it to be the metabolite responsible for this same type of activity of the stem crude extract.69 Similarly, a bioassay-guided purification of the leaf extract of Byrsonima bucidaefolia Standl (Malpighiaceae), a native plant of the Yucatecan flora used in the treatment of asthma, fever, and skin infections, resulted in the identification of methyl gallate (95) and methyl m-trigallate (96) as the metabolites responsible for the antioxidant activity of the crude extract. However, both metabolites were confirmed as artifacts of the extraction/purification process, possibly resulting from transesterification of precursor gallotannins.70 More recently, a mixture of thymol (23) and 3-methyl-4isopropylphenol (97), together with the new 3,4-O-dicaffeoylquinic acid methyl ester (98) and the previously reported dicaffeoylquinic acid derivatives, 3,5-O-dicaffeoyl-epi-quinic acid methyl ester (99) and 3,5-O-dicaffeoylquinic acid (100), were identified as the bioactive products responsible for analgesic and anti-inflammatory effects shown by the root extract of Calea urticifolia (Mill.) DC. (Asteraceae), a native plant used to treat inflammation and pain in Yucatecan traditional medicine. The results of this investigation suggested that the anti-inflammatory activity of these metabolites is related to their effects as radical scavengers.71 Bonediol (101), a new alkyl catechol isolated from Bonellia macrocarpa (Cavanilles) Ståhl & Källersjö (Theophrastaceae), showed antiproliferative activity against KB, Hep-2, and SiHa cancer cell lines.72

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Other Metabolites. An early phytochemical study of the resin of Bursera simaruba (L.) Sarg. (Burseraceae), a tree used in Yucatecan traditional medicine to alleviate problems derived from dermatitis, resulted in the identification of picropolygamain (102), a previously reported 1-aryltetralin lignan lactone, which showed activity when tested in the brine shrimp lethality assay and against three human tumor cell lines.73 A series of naphthoquinones isolated from Diospyros anisandra Blake (Ebenaceae), an endemic medicinal plant of the Yucatecan flora, provided an interesting insight on the structure−activity relationship of the different metabolites when tested against different strains of Mycobacterium tuberculosis. Plumbagin (103) and its dimers, maritinone (104) and 3,3′-biplumbagin (105), were 32 times more potent than rifampicin when tested against the pan-resistant strain of M. tuberculosis, without being toxic to normal cell lines. The diversity of the isolated naphthoquinone structures and their differences in terms of mycobacterial activity suggested that the location of the dimeric bond is important for the expression of antituberculosis activity.74,75 A phytochemical investigation of the root extract of C. greggi yielded two bioactive metabolites identified as the athraquinone chrysophanol (106), active against Bacillus subtilis and G



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Staphylococcus aureus,76 and discarine B (107), a cyclic dipeptide with moderate antiprotozoal activity against T. cruzi var. tulahuen.62 A different class of metabolites, the benzochromenes (6,6dimethyl-2-methoxy-6H-benzo[c]chromen-9-yl)methanol (108) and 2-methoxy-6,6-dimethyl-6H-benzo[c]chromen-9carbaldehyde (109), isolated from the root extract of Bourreria pulchra Millsp. (Boraginaceae), a medicinal plant with DNAinteracting activity, also exhibited antiprotozoal properties, with 108 being particularly active against L. mexicana and T. cruzi.77 The oxylipin (3S)-16,17-didehydrofalcarinol (110), isolated from Tridax procumbens L. (Asteraceae), a medicinal plant of the Yucatecan flora, showed antiprotozoal activity against promastigotes and intracellular amastigotes of L. mexicana.78

The results showed that that the activity against intracellular amastigotes is independent of nitric oxide production, confirming that the inhibitory effect results from the direct interaction between molecule and parasite. A different acetylenic metabolite, 17-octadecen-6-yn-oic acid (111), isolated from the stem bark of Alvaradoa amorphoides Liebm. (Picramniaceae), used in Mayan traditional medicine to treat skin disorders, showed a moderate cytotoxic activity but a high selectivity toward tumor cells.79

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CONCLUDING REMARKS

The results obtained after more than 20 years of phytochemical investigation demonstrate the importance of the Yucatecan flora as a source of new and bioactive natural products. Some of the plants, particularly those native and H



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endemic, are of limited distribution and many occupy ecosystems that currently are threatened or disappearing because of continuous urban growth. The impact of the loss of these plants, in the Yucatan Peninsula or elsewhere, cannot be dismissed or ignored; these species not only represent an important source of still-unknown natural bioactive metabolites but are also unique plants, adapted to the soil and weather of the place where they grow. Demonstrating their importance as natural sources of future pharmaceuticals and their impact in the future of human health care will result in their value being recognized so as to ensure their conservation.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +52-999-9428330. Fax: +52-999-981-3900. E-mail: [email protected]. ORCID

Luis M. Peña-Rodríguez: 0000-0001-6511-5122 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors wish to recognize the importance of the work done by many colleagues, including undergraduate and graduate students, working in the field of natural products in different institutions of the Yucatan Peninsula who are responsible for the advancement in the knowledge of the bioactive metabolites produced by plants from the Yucatecan flora. Additionally, the authors wish to acknowledge the financial support of the different institutions (Centro de ́ de Yucatán, Universidad Autónoma de Investigación Cientifica Yucatán) and agencies (Consejo Nacional de Ciencia y Tecnologia,́ International Foundation for Science, Programa Iberoamericano de Ciencia y Tecnologiá para el Desarrollo, British Council, Servicio Alemán de Intercambio Académico, Fomix Yucatán, Alfa Program-Europe Aid Co-operation Office, Agencia Española de Cooperación Internacional, Comisión ́ Nacional de Investigación Cientifica y Tecnológica, Conselho ́ Nacional de Desenvolvimiento Cientifico e Tecnológico) that have it made possible to carry out the research projects for which the results are presented in this review.

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DEDICATION Dedicated to Dr. Rachel Mata, National Autonomous University of Mexico, Mexico City, Mexico, for her pioneering work on bioactive natural products.

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REFERENCES

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Natural Products from the Yucatecan Flora: Structural Diversity and

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