13 C-NMR Data from Coumarins from Moraceae Family

Species from Moraceae family stand out in popular medicine and phytotherapy, have been for example used as expectorants, bronchodilators, anthelmintics and treatment of skin diseases, such as vitiligo, due to the presence of compounds with proven biological activity, as the coumarins. Coumarins are lactones with 1,2-benzopyrone basic structure, and are widely distributed in the plant kingdom, both in free form, and in glycosylated form. This work reports a literature review, describing the data of 13C NMR from 53 coumarins isolated from the family Moraceae, and data comparison between genera who presented photochemical studies, in order to contribute to the chemotaxonomy of this family.


Introduction
The Moraceae family has 6 tribes, 63 genera and about 1500 species found in the tropics, subtropics and, in a smaller proportion, in temperate regions.Among the main genera are the Ficus, with about 600 species and Dorstenia, with about 125 species [1].
Moraceae representatives can be found as shrub, tree, herb or subshrub, feature woody stem, alternate leaves, unisexual flowers and fruits in small nuts form [2]. Some of its species have great importance in fruit growing, in the production of heavy wood, in the textile industry, in the production of latex and also for ornamental purposes [3] [4].
Species from Moraceae family also stand out in popular medicine and phytotherapy, have been for example, used as expectorants, bronchodilators, in the treatment of Chagas disease, anthelmintics and treatment of skin diseases such as vitiligo, for example [5].Those therapeutic effects are due to the presence of compounds with proven biological activity, such as flavonoids and coumarins [6] [7].The Brosimum genus, for example, features species high in coumarin, as is the case of Brosimum rubescens, whose wood owns xanthyletin, a coumarin with antiplatelet, antifungal and herbicide activities [8].The isolation and the study of coumarins biological effects like this one, has been of great importance for the understanding of the results obtained in folk medicine use of these plants, as well as the development of treatment in some diseases [9].

Coumarins
Coumarins are lactones with 1,2-benzopyrone basic structure, and are widely distributed in the plant kingdom, both in free form, and in glycosylated form [10]. Biosynthesized via the shikimic acid, with cinnamic acid as an intermediate, simple coumarins, by the addition of a furan ring in the process can become the furocoumarins, which could be linear, such as psoralen, or angular, such as angelicin.However, if a pyran ring is added instead of a furan ring in the process, it generates a pyranocoumarin, such as for example the xanthyletin (Figure 1).Structures containing two or three simple coumarins linked to each other are named bis-coumarins and triscoumarins, respectively.The name coumarin, originated from coumarou, a Caribbean name of the tree Tonka (Dipteryxodorata), from which was isolated the compound in 1820 [11].
The coumarins hold several biological activities such as anticoagulant, antimicrobial, vasodilatory, sedative, analgesic and photosensitizer, been the last one more frequent in linear furocoumarins, also known as psoralens.The photosensitizing activity intensity varies according to the furocoumarin structure, having the psoralen as more active than the hydroxylated molecules or with less unsaturation [11].This effect arises by the interaction of these compounds with ultraviolet radiation and can be an issue for humans, causing severe burns.However, its proper medical use can be useful for the treatment of diseases such as vitiligo, which causes a gradual skin depigmentation.Psoralens, due to their extended chromophore group, absorb in the UV region and allow this radiation to stimulate the melanin formation.The oral administration of a xanthotoxin dose, for example, following by the patient's exposure to ultraviolet radiation, causes pigmentation of the skin.This type of treatment is called PUVA (psoralen + UV-A), and is also efficient in the psoriasis treatment, a disease characterized by reddened lesions and increase in cell proliferation.In this case, the reaction inhibits DNA replication and consequently reduces the cell division rate (Figure 2) [9] [10].
Due to their flat nature, psoralens intercalate into DNA, and this allows a cycloaddition reaction initiated by UV between the pyrimidine bases, mainly thymine and the furan ring in the psoralens.The second cycloaddition can then occur, involving now the psoralens pyran ring, promoting interchain cross-links in nucleic acid [10].In Moraceae family, coumarins feature more than 135 occurrences in its main genera, been more frequent the presence of linear furocoumarines [12].From the species Brosimum gaudichaudii, for example, were isolated so far 10 coumarins, been 8 linear furocoumarins and two pyranocoumarins, in addition to other compounds [13] [14].
This paper reports a literature review, describing the data of 13 C NMR from 53 coumarins isolated from the Moraceae family.From this group, several appear repeatedly in different species, such as psoralen (27), for example.Table 1 lists the coumarins obtained in each gender without mentioning the duplicate cases.The structures are shown in Figures 3-6.

Results and Discussion
The simple coumarin isolated from Moraceae family (Figure 3), have their 13  Table 3 lists the 13 C NMR data from the Moraceae family isolated furocoumarins.This kind of coumarin is the one that appears most often in the studied species, highlighting the linear furocoumarins such as psoralen (27).In this case, the signals to C-2' (δ C 147.0) and C-3' (δ C 106.6) evidence the presence of methine carbons typical from furan ring.The sign for the C-2', higher than the C-3', explained by the fact that this carbon is directly linked to the oxygen atom and so, more unprotected.In the molecules 35 to 39 C-2' is further substituted  .This difference is due to the presence of methoxyl on luvangetin C-8, which makes these carbons more vulnerable.In dihydroxanthyletin (56), the carbons C-2' and C-3' feature signs δ C 32.4 and δ C 21.9, respectively, indicating that they are methylene and not methine as in other molecules.In the case of the only isolated angular pyranocoumarin, the seselin (57), the found signal for C-8 (δ C 144.1) indicates that it is linked to the C-4' and not at the C-6, which signal is δ C 113.8.
The only bis-coumarin found in Moraceae family so far are fatouain-G (58) and the fatouain-H (59), both isolated from Fatoua genus.The link between the simple coumarin which form the fatouain-G occurs between the carbons C-8 and C-8', through an oxygen atom.In the case of fatouain-H, the molecules links occurs between the C-8' carbon of a molecule and the C-1' carbon belonging to the side chain of other, also through an oxygen atom.Twenty-nine carbon atoms signals are identified in each compound, which are described in Table 5.

Conclusions
Until the present moment, coumarins were only found in 6 from the 63 genera from Moraceae family, mainly in Ficus, Brosimum and Fatoua.The simple coumarin representing 42.4% of the total, furocoumarines, found mainly in the genus Ficus, representing 47.4%, while the other 10.2% are consisted of pyranocoumarins, and bis-coumarin, been the latter found only in the genres Fatoua (Figure 7(a)).
From the genus Ficus, were isolated 27 from the 59 coumarins found so far, been 15 furocoumarins.In addition, 20 of these substances are exclusive to this genus.The genus Brosimum features 14 coumarins, been 9 furocoumarins while the genus Dorstenia features 10 furocoumarins and a total of 13 coumarins.The smallest number of occurrences is in the Morus and Streblus genera, having been isolated only 2 simple coumarins in each.The Fatoua genus features 17 coumarins from all kinds found in Moraceae, mainly simple coumarin.This Table 2. 13 C NMR data from simple coumarins isolated from Moraceae family.genus, native to eastern Asia, contains only 3 species and all compounds were found in Fatouapilosa (Figure

7(b)).
The compounds with the highest number of occurrences in the family are the linear furocoumarins, especially the psoralen (27) and the bergapten (26), which together with the simple coumarin umbelliferone (2), appear in four from the six genera mentioned.
Since most Moraceae species has not yet been chemically studied, it is necessary to proceed these studies in order that it contributes to the family taxonomic classification.In this scenario, the coumarins can contribute as potential Moraceae genera chemotaxonomic markers.
C NMR chemical shift data listed in Table 2.The C-2 of most structures presents indicative signs of carbon α-carbonyl, β-unsaturated, δ C 158.9 to 162.9, characteristic of lactone ring without substituent in the C-3 and C-4 carbon atom.The exceptions are the compound 18, which has the C-3 replaced, presenting C-2 with δ C 164.5, and the compound 10, where C-3 and C-4 are methylene carbons.This way, because there are fewer resonance structures in the molecule, C-2 becomes more unprotected, presenting δ C 177.0.The signs of C-5 (δ C 127.8), C-6 (δ C 124.3), C-7 (δ C 131.3) and C-8 (δ C 116.8) from coumarins (1), are characteristic for the benzene ring from the benzopyran nucleus.As these carbons are replaced in other molecules shown in Figure 3, the signals diversify, for example, the C-5 from substance 18, with δ C 157.5 due to the unprotection caused the presence of the methoxyl group attached to this carbon.

Table 4
with signs between δ C 90.3 to 91.4, while in the compound 34, the signal is δ C 165.4, due to C-2' be a quaternary carbon.In the case of angular furocoumarins C-8 shows signs suggesting his involvement with the furan ring, in the C-6's place.In angelicin (49), for example, C-6 and C-8 are δ C 108.0 and δ C 117.0 signals respectively, while in the psoralen the displacements are δ C 125.0 for C-6 and 93.8 to δ C C-8. lists the 13 C NMR data from pyranocoumarins found until now in the Moraceae family.The luvangetin (54) and Xanthyletin (55), linear pyranocoumarins, show signals which indicate existence of a six-membered ring linked to the benzopyran nucleus benzene's section.In luvangetin, the methine carbon C-3' and C-4' feature chemical shift δ C 131.3 and δ C 121.1, respectively, while these signals on xanthyletin are δ C 104.4 for C-3' and δ C 113.0 for C-4'

Table 4 .
13C NMR data from pyranocoumarins isolated from Moraceae family.

Table 5 .
13C NMR data from bis-coumarins isolated from Moraceae family.