Abstract
Homoisoflavonoids are rare compounds distributed within a few families of plants including species from Fabaceae. The genus Caesalpinia, the main focus of this chapter, is a prolific source of these unique natural products. Homoisoflavonoids from Caesalpinia spp. are associated to ethnopharmacological uses for diverse purposes. In this sense, the following chapter sheds light on the occurrence, biosynthesis, isolation, synthesis, and structural analysis of these compounds from species of the genus Caesalpinia and their biological potential.
Keywords
- Caesalpinia
- Homoisoflavonoids
- natural products
- biological activities
1. Introduction
The genus
Associated to these biological properties, these plants are chemically composed by different classes of metabolites including steroids, organic acids, chromenes, diterpenes, triterpenes, polyphenols, tannins, anthraquinones, alkaloids, and flavonoids, which comprise the natural product diversity of this genus.
Besides these compounds, species from the genus
In this sense, it is important to define the general characteristics of flavonoids, once they are the core subunits of biflavonoids and cover the rare class of homoisoflavonoids. In general, flavonoids are low molecular weight polyphenols, brightly colored due to their absorptions of UV light, and the most common structures are associated to antioxidant properties [8–10]. Flavonoids, classified as phytoalexins, are produced as a response to microbial infection in plants. They have a notorious participation into the scientific scenario due to the beneficial association to the humans’ daily basis intake of nutrients as functional foods improving human health [8, 10].
The consumption of functional foods, or nutraceuticals, is strongly associated to these compounds. In addition, the ingestion of flavonoids from functional foods implicates in lowering blood triglycerides and homocysteine, decreasing blood pressure, acting against inflammatory, platelet antiaggregation processes, and the improvement of endothelial function [11]. These compounds are also associated to another range of biological properties lowering the incidence of cancer, including prostate, stomach, breast, and lung cancers [12]. In addition, various protective effects of flavonoids have demonstrated them as important multi‐target agents [13, 14].
In that regard, the genus
An interesting point is that homoisoflavonoids can also be found as dimers. Biflavonoids compounds are dimers of flavonoids assembled in diverse manners by different species. The number of possibilities for these structures (involving all classes of flavonoids) points to more than 20,000 different molecules. However, not all these have been encountered in nature so far, summing to 500 representatives [15]. From these, less than 10 are constituted by homoisoflavonoids subunits.
As homoisoflavonoids and their dimers from the genus
2. General classification and biosynthesis of flavonoids
The classification of flavonoids consists in two main groups, the 2‐phenylchromans and the 3‐phenylchromans. Compounds presenting the 2‐phenylchroman core, in which the aromatic ring B is connected to C‐2 atom, include flavonols, flavanones, flavan‐3‐ols, flavones, anthocyanins, and proanthocyanidins. On the other hand, compounds with the 3‐phenylchroman group, in which the aromatic ring B is connected to C‐3 atom, include isoflavonoids named isoflavones, isoflavans, and pterocarpans. Another group, named neoflavonoids, in which the benzene ring B is connected to C‐4 atom, is less common. There are cases in which the ring C occurs as an isomeric form presenting a five‐membered ring, which is associated to the formation of aurones. Another class of phenolic compounds, named chalcones, is not considered true flavonoids due to their lack on the aromatic C ring but still considered members of the flavonoids family. In the same way, a closely related group compounds, the stilbenes, are important due to their biological potential [16]. A brief representation of each class of flavonoids and their sources is demonstrated in Figure 1.
These structures are important for the recognition and classification of biflavonoids moieties, once they could exist as complex structures presenting aurones, isoflavonoids, neoflavonoids, chalcones, and other moieties as well as dimers of homoisoflavonoids.
Flavonoids are products from the phenylpropanoid building block cinnamoyl‐CoA, in which chain extension is provided by three units of malonyl‐CoA [17]. Cinnamoyl‐CoA is derived from the amino acids phenylalanine and tyrosine which are converted by phenylalanine and tyrosine ammonia lyases to cinnamic acid and
3. Occurrence of homoisoflavonoids in Caesalpinia spp.
Homoisoflavonoids have a general structure of 16 carbons containing two phenyl rings and one heterocyclic ring. Homoisoflavonoids are biosynthesized from cinnamic acid derivatives along with malonyl‐CoA subunits. The resulting compound, an aromatic polyketide, is the precursor of chalcones. In the following step, the aromatic polyketide undergoes a Claisen and enolization reactions, which lead to the formation of the chalcone backbone. An additional carbon is added to the chalcone, provided by S‐methyl moiety from methionine, creating the homoisoflavonoid skeleton containing 16 carbons. Thus, there is the formation of 3′‐hydroxyl‐chalcone as a precursor, which is transformed to 3‐benzylchroman‐4‐one. Subsequently, different cyclization leads to the formation of other types of homoisoflavonoids (Figure 2).
The existence of these compounds is associated to the genus
The classification of homoisoflavonoids comprises five main groups named scillascillin, brazilin, caesalpin, protosappanin, and sappanins. Homoisoflavonoids from the class scillascillins exhibit a spiro ring with four members between rings C and D. However, species from the genus
The most common class of homoisoflavonoids in the genus
In this aspect, the species
Rao and collaborators tested the compound
The species
Phytochemical studies on ethanolic extracts of
The species
Species
Other sappanin‐type compounds such as (3
The species
Homoisoflavonoids classified as protosappanins are commonly associated to the species
4. Biflavonoids containing homoisoflavonoids subunits in Caesalpinia spp.
Flavonoids can also exist as dimers, named biflavonoids, which represents flavonoids linked by C–C or C–O–C bond in order to form a flavonoid‐flavonoid structure. The connection can occur in several modes in the three rings of the flavan nucleus. The ring A could be linked to the ring A′, indicated as A‐A. This could also occur between the rings A‐C, B‐B, C‐B, among other possibilities that are enlarged by functional groups as OH, MeO, C═O, C═C. The occurrence of common biflavonoids in the genus
Furthermore, certain species from the
The presence of rare caesalpins is correlated to
5. Isolation, synthesis, and structural analysis of homoisoflavonoids
Due to the intrinsic interest in homoisoflavonoids and their biological activities, several works have been discussing different structural aspects of homoisoflavan nucleus‐bearing organic compounds [6, 7]. The structural uniqueness of these compounds and their potent biological activities makes them a target of choice for studies in natural products research on the determination of absolute configurations, organic synthesis, isolation, and structural determination [7].
The isolation of homoisoflavonoids involves different chromatographic techniques. Homoisoflavonoids are generally separated after treatment of the organic extract (MeOH, CHCl3) with several chromatographic phases. The use of column chromatography steps (using silica gel and/or Sephadex LH‐20), preparative thin layer chromatography, as well as high performance liquid chromatography (HPLC) methods (semi‐preparative and preparative) have been used to purification [7]. In addition, there are other methods used to the isolation of flavonoids, such as counter current chromatography [37] can be adopted for the isolation of homoisoflavonoids and flavonoids.
Besides the isolation of naturally occurring homoisoflavonoids from the species
The structures of homoisoflavonoids have been unambiguously established by analysis of spectroscopic NMR data supported by analysis of UV and MS spectra. These analyses confirm the presence of the 15‐carbon backbone related to classic flavonoids, and the 16‐carbon skeleton with two phenyl rings (A and C) and one heterocyclic ring (B) separated by an additional carbon, forming the homoisoflavonoids skeleton [24, 29, 31].
Analysis of the 1H and 13C NMR spectra indicates the presence of carbonyl groups at
The extra carbon existing in homoisoflavonoids compared to ordinary flavonoids can be aliphatic displaying 13C and 1H NMR signs at
The compounds
Homoisoflavonoids present signals of absorptions in the UV spectrum at
The absolute stereochemistry can be established by circular dichroism analysis by comparison to models with known stereochemistry. The compound
6. Conclusion
The chemical space related to natural products is associated to important scientific findings in what to extent the discovery of important new chemical entities. In this sense, the genus
Acknowledgments
The authors acknowledge the CAPES, CNPq, FAPEMIG, FAPESP, and FINEP for subsidies and funding.
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Notes
- The authors declare no conflict of interests.