Chemical Structures of Lignans and Neolignans Isolated from Lauraceae

Lauraceae is a good source of lignans and neolignans, which are the most chemotaxonomic characteristics of many species of the family. This review describes 270 naturally occurring lignans and neolignans isolated from Lauraceae.


Introduction
Lignans are widely distributed in the plant kingdom, and show diverse pharmacological properties and a great number of structural possibilities. The Lauraceae family, especially the genera of Machilus, Ocotea, and Nectandra, is a rich source of lignans and neolignans, and neolignans represent potential chemotaxonomic significance in the study of the Lauraceae. Lignans and neolignans are dimers of phenylpropane, and conventionally classified into three classes: lignans, neolignans, and oxyneolignans, based on the character of the C-C bond and oxygen bridge joining the two typical phenyl propane units that make up their general structures [1]. Usually, lignans show dimeric structures formed by a β,β'-linkage (8,8'-linkage) between two phenylpropanes units. Meanwhile, the two phenylpropanes units are connected through a carbon-carbon bond, except for the 8,8'-linkage, which gives rise to neolignans. Many dimers of phenylpropanes are joined together through two carbon-carbon bonds forming a ring, including an 8,8'-linkage and another carbon-carbon bond linkage; such dimers are classified as cyclolignans. When the two phenylpropanes units are linked through two carbon-carbon bonds, except for the 8,8'-linkage, this constitutes a cycloneolignan. Oxyneolignans also contain two phenylpropanes units which are joined together via an oxygen bridge. Herein, lignans and neolignans are classfied into five groups: lignans, cyclolignans, neolignans, cycloneolignans, and oxyneolignans on the basis of their carbon skeletons and cyclization patterns. The majority of lignans isolated from Lauraceae have shown only minor variations on well-known structures; for example, a different degree of oxidation in the side-chain and different substitutions in the aromatic moieties, including hydroxy, methoxy, and methylenedioxy groups. Since the nomenclature and numbering of the lignans and neolignans in the literature follow different rules, the trivial names or numbers of the compounds were used to represent them. Furthermore, the semi-systematic names of compounds and their corresponding names in the literature are summarized in the Supporting Information. Herein, we give a comprehensive overview of the chemical structures of lignans and neolignans isolated from Lauraceae.

Lignans
This section covers lignans formed by an 8,8'-linkage between two phenyl propane units, which are subclassified according to the pattern of the oxygen rings as depicted in Figure 1.
This section covers lignans formed by an 8,8'-linkage between two phenyl propane units, which are subclassified according to the pattern of the oxygen rings as depicted in Figure 1. The semi-systematic names of those lignans without trivial names and their corresponding names in found in the literature are given in Table SI-

Cyclolignans
There are three main types of cyclolignans isolated from nature, including 2,7'-cyclolignans, 2,2'-cyclolignans, and 7,7'-cyclolignans. Cyclolignans are not so common in Lauraceae. We have only retrieved less than 10 2,7'-cyclolignans isolated from Lauraceae. The semi-systematic names of those cyclolignans without trivial names and their corresponding names in the literature are given in Table SI-1 (Supporting Information).

Cyclolignans
There are three main types of cyclolignans isolated from nature, including 2,7'-cyclolignans, 2,2'-cyclolignans, and 7,7'-cyclolignans. Cyclolignans are not so common in Lauraceae. We have only retrieved less than 10 2,7'-cyclolignans isolated from Lauraceae. The semi-systematic names of those cyclolignans without trivial names and their corresponding names in the literature are given in Table  SI-1 (Supporting Information).

Cycloneolignans
Cycloneolignans are responsible for the chemotaxonomic characteristics of some genera in the Lauraceae family, such as Aniba, Licaria, and Nectandra. Most cycloneolignans isolated from Lauraceae belong to the categories of 7.

Cycloneolignans
Cycloneolignans are responsible for the chemotaxonomic characteristics of some genera in the Lauraceae family, such as Aniba, Licaria, and Nectandra. Most cycloneolignans isolated from Lauraceae belong to the categories of 7.

Cycloneolignans
Cycloneolignans are responsible for the chemotaxonomic characteristics of some genera in the Lauraceae family, such as Aniba, Licaria, and Nectandra. Most cycloneolignans isolated from Lauraceae belong to the categories of 7.

7.3',8.5'-Cycloneolignans
Macrophyllin B (233) was purified from an unclassified Nectandra species collected at Rosa de Maio, a locality on the Manaus-Itacoatiara highway (8 km), Amazonas [41]. Nectamazins A-C (234-236), macrophyllin B (233), denudanolide D (237), and kadsurenin C (238) isolated from leaves of N. amazonum Nees showed inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [63]. A phytochemical exploration of the leaves of O. macrophylla afforded ocophyllols A-C (239-241). Their absolute configurations were established by derivatizing them with (R)-and (S)-MTPA, and then analyzing the NMR data, as well as by a comparison of their circular dichroism (CD) data with that of a related compound whose absolute configuration was previously established by single-crystal X-ray analysis. Moreover, ocophyllols A-C (239-241) showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [70]. Cinerin B (242), cinerin C (243), cinerin A (244), and cinerin D (245) were isolated from the leaves of P. cinereum. Again, their CD data was used to determine the absolute configuration of these compounds. Cinerin C (243) was the first known macrophyllin-type cycloneolignan, which was isolated from the trunk wood of Licaria macrophylla Kosterm and named as macrophyllin A [81]. Cinerin A-D also showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [82]. Compound 246 and macrophyllin B (233) were identified in the ethanolic extract of leaves of P. cinereum [28] (Figure 13). , and kadsurenin C (238) isolated from leaves of N. amazonum Nees showed inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [63]. A phytochemical exploration of the leaves of O. macrophylla afforded ocophyllols A-C (239-241). Their absolute configurations were established by derivatizing them with (R)-and (S)-MTPA, and then analyzing the NMR data, as well as by a comparison of their circular dichroism (CD) data with that of a related compound whose absolute configuration was previously established by single-crystal X-ray analysis. Moreover, ocophyllols A-C (239-241) showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [70]. Cinerin B (242), cinerin C (243), cinerin A (244), and cinerin D (245) were isolated from the leaves of P. cinereum. Again, their CD data was used to determine the absolute configuration of these compounds. Cinerin C (243) was the first known macrophyllin-type cycloneolignan, which was isolated from the trunk wood of Licaria macrophylla Kosterm and named as macrophyllin A [81]. Cinerin A-D also showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [82]. Compound 246 and macrophyllin B (233) were identified in the ethanolic extract of leaves of P. cinereum [28] ( Figure 13).

7.1',8.3'-Cycloneolignans
Ocobullenone (247) was the first naturally occurring bicyclooctanoid found to exhibit the 7.1', 8.3' linkage, and it was isolated from the chloroform extract of the bark of O. bullata [83]. Iso-ocobullenone (248) was also isolated from the chloroform extract of the bark of O. bullata, and its structure was confirmed by single-crystal X-ray analysis [69] (Figure 14).

Oxyneolignans
An ether oxygen atom provides the linkage between the two phenylpropane units, giving rise to oxyneolignans. Oxyneolignans are rarely distributed in Lauraceae. Less than 10 oxyneolignans have been found to occur in the Lauraceae family, belonging to two categories: 7.3',8.4'-dioxyneolignans and 8,4'-oxyneolignans ( Figure 15).

7.1',8.3'-Cycloneolignans
Ocobullenone (247) was the first naturally occurring bicyclooctanoid found to exhibit the 7.1', 8.3' linkage, and it was isolated from the chloroform extract of the bark of O. bullata [83]. Iso-ocobullenone (248) was also isolated from the chloroform extract of the bark of O. bullata, and its structure was confirmed by single-crystal X-ray analysis [69] (Figure 14). , and kadsurenin C (238) isolated from leaves of N. amazonum Nees showed inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [63]. A phytochemical exploration of the leaves of O. macrophylla afforded ocophyllols A-C (239-241). Their absolute configurations were established by derivatizing them with (R)-and (S)-MTPA, and then analyzing the NMR data, as well as by a comparison of their circular dichroism (CD) data with that of a related compound whose absolute configuration was previously established by single-crystal X-ray analysis. Moreover, ocophyllols A-C (239-241) showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [70]. Cinerin B (242), cinerin C (243), cinerin A (244), and cinerin D (245) were isolated from the leaves of P. cinereum. Again, their CD data was used to determine the absolute configuration of these compounds. Cinerin C (243) was the first known macrophyllin-type cycloneolignan, which was isolated from the trunk wood of Licaria macrophylla Kosterm and named as macrophyllin A [81]. Cinerin A-D also showed some inhibition activity against the platelet-activating factor (PAF)-induced aggregation of rabbit platelets [82]. Compound 246 and macrophyllin B (233) were identified in the ethanolic extract of leaves of P. cinereum [28] ( Figure 13).

7.1',8.3'-Cycloneolignans
Ocobullenone (247) was the first naturally occurring bicyclooctanoid found to exhibit the 7.1', 8.3' linkage, and it was isolated from the chloroform extract of the bark of O. bullata [83]. Iso-ocobullenone (248) was also isolated from the chloroform extract of the bark of O. bullata, and its structure was confirmed by single-crystal X-ray analysis [69] (Figure 14).

Oxyneolignans
An ether oxygen atom provides the linkage between the two phenylpropane units, giving rise to oxyneolignans. Oxyneolignans are rarely distributed in Lauraceae. Less than 10 oxyneolignans have been found to occur in the Lauraceae family, belonging to two categories: 7.3',8.4'-dioxyneolignans and 8,4'-oxyneolignans ( Figure 15).

Oxyneolignans
An ether oxygen atom provides the linkage between the two phenylpropane units, giving rise to oxyneolignans. Oxyneolignans are rarely distributed in Lauraceae. Less than 10 oxyneolignans have been found to occur in the Lauraceae family, belonging to two categories: 7.3',8.4'-dioxyneolignans and 8,4'-oxyneolignans ( Figure 15).

8,4'-Oxyneolignans
Machilin C (253), D (254), and E (255) were first obtained from the methanolic extract of the bark of M. thunbergii [2]. Odoratisol B was obtained from the air-dried bark of the Vietnamese medicinal plant M. odoratissima Nees. This compound showed the same relative structure as machilin C (253), but was termed odoratisol B in the article [19]. Perseal A (256) and perseal B (257), which have a C-1' formyl side chain instead of a propenyl group, were isolated from the chloroform-soluble fraction of the leaves of P. obovatifolia. They showed significant cytotoxicity against P-388, KB 16, A549, and HT-29 cancer cell lines [67] (Figure 17).

Uncommon Lignans
This section covers lignans and neolignans that contain uncommon skeletons. The molecular backbone of compounds 258-267 consists of a unique C6-C3 unit, and an ether oxygen atom provides the linkage between the phenyl and propyl groups. The semi-systematic names of those uncommon lignans without trivial names and their corresponding names in the literature are given in Table SI  The trunk wood of L. rigida Kosterm contained eusiderin (249) and eusiderin B (250) [79]. The trunk wood of an unclassified Aniba species collected at the Ducke Forest Reserve, Manaus also yielded the benzodioxane-type neolignan eusiderin (249), eusiderin-F (251), and eusiderin-G (252) [50,77]. Eusiderin (249) was also found to be present in the ethanolic extract of wood of O. costulatum [78] (Figure 16).

8,4'-Oxyneolignans
Machilin C (253), D (254), and E (255) were first obtained from the methanolic extract of the bark of M. thunbergii [2]. Odoratisol B was obtained from the air-dried bark of the Vietnamese medicinal plant M. odoratissima Nees. This compound showed the same relative structure as machilin C (253), but was termed odoratisol B in the article [19]. Perseal A (256) and perseal B (257), which have a C-1' formyl side chain instead of a propenyl group, were isolated from the chloroform-soluble fraction of the leaves of P. obovatifolia. They showed significant cytotoxicity against P-388, KB 16, A549, and HT-29 cancer cell lines [67] (Figure 17).

Uncommon Lignans
This section covers lignans and neolignans that contain uncommon skeletons. The molecular backbone of compounds 258-267 consists of a unique C6-C3 unit, and an ether oxygen atom provides the linkage between the phenyl and propyl groups. The semi-systematic names of those uncommon lignans without trivial names and their corresponding names in the literature are given in Table SI

8,4'-Oxyneolignans
Machilin C (253), D (254), and E (255) were first obtained from the methanolic extract of the bark of M. thunbergii [2]. Odoratisol B was obtained from the air-dried bark of the Vietnamese medicinal plant M. odoratissima Nees. This compound showed the same relative structure as machilin C (253), but was termed odoratisol B in the article [19]. Perseal A (256) and perseal B (257), which have a C-1' formyl side chain instead of a propenyl group, were isolated from the chloroform-soluble fraction of the leaves of P. obovatifolia. They showed significant cytotoxicity against P-388, KB 16, A549, and HT-29 cancer cell lines [67] (Figure 17).

8,4'-Oxyneolignans
Machilin C (253), D (254), and E (255) were first obtained from the methanolic extract of the bark of M. thunbergii [2]. Odoratisol B was obtained from the air-dried bark of the Vietnamese medicinal plant M. odoratissima Nees. This compound showed the same relative structure as machilin C (253), but was termed odoratisol B in the article [19]. Perseal A (256) and perseal B (257), which have a C-1' formyl side chain instead of a propenyl group, were isolated from the chloroform-soluble fraction of the leaves of P. obovatifolia. They showed significant cytotoxicity against P-388, KB 16, A549, and HT-29 cancer cell lines [67] (Figure 17).

Uncommon Lignans
This section covers lignans and neolignans that contain uncommon skeletons. The molecular backbone of compounds 258-267 consists of a unique C6-C3 unit, and an ether oxygen atom provides the linkage between the phenyl and propyl groups. The semi-systematic names of those uncommon lignans without trivial names and their corresponding names in the literature are given in Table SI

Uncommon Lignans
This section covers lignans and neolignans that contain uncommon skeletons. The molecular backbone of compounds 258-267 consists of a unique C6-C3 unit, and an ether oxygen atom provides the linkage between the phenyl and propyl groups. The semi-systematic names of those uncommon lignans without trivial names and their corresponding names in the literature are given in Table SI-5  (Supporting Information).

Conclusions
A renewed interest in compounds isolated from natural resources has led to an enormous class of pharmacologically active compounds. Lignans and neolignans have been revealed to show significant pharmacological activities, including antitumor, anti-inflammatory, immunosuppression, cardiovascular, antioxidant, and antiviral activities [85,86]. The Lauraceae family, especially the genera of Machilus, Ocotea, and Nectandra, represents a rich source of lignans and neolignans. Moreover, neolignans are responsible for the potential chemotaxonomic significance found in the study of Lauraceae. Studies on lignans and neolignans in Lauraceae were mainly carried out in the 1980s. There have been more studies concerning the identification of lignans and neolignans in Lauraceae, but less on the biological activities of these compounds. Among the lignans and neolignans isolated from Lauraceae, the biological activities of sesamin and yangambin have been studied more, while there are relatively few articles published on other compounds. Sesamin, a 7.9',7'.9-diepoxylignan present in many species in the Lauraceae family such as N. amazonurn, M. thunbergii, P. pyrifolia, C. burmanii, and N. turbacensis, showed significant anticancer properties [87]. Yangambin (51) which was the major constituent of O. duckei, showed diverse biological activities [88]. Therefore, it is extremely urgent to expand the scope of research on the lignans and neolignans in Lauraceae, with the aim of discovering all biological activities of these

Conclusions
A renewed interest in compounds isolated from natural resources has led to an enormous class of pharmacologically active compounds. Lignans and neolignans have been revealed to show significant pharmacological activities, including antitumor, anti-inflammatory, immunosuppression, cardiovascular, antioxidant, and antiviral activities [85,86]. The Lauraceae family, especially the genera of Machilus, Ocotea, and Nectandra, represents a rich source of lignans and neolignans. Moreover, neolignans are responsible for the potential chemotaxonomic significance found in the study of Lauraceae. Studies on lignans and neolignans in Lauraceae were mainly carried out in the 1980s. There have been more studies concerning the identification of lignans and neolignans in Lauraceae, but less on the biological activities of these compounds. Among the lignans and neolignans isolated from Lauraceae, the biological activities of sesamin and yangambin have been studied more, while there are relatively few articles published on other compounds. Sesamin, a 7.9',7'.9-diepoxylignan present in many species in the Lauraceae family such as N. amazonurn, M. thunbergii, P. pyrifolia, C. burmanii, and N. turbacensis, showed significant anticancer properties [87]. Yangambin (51) which was the major constituent of O. duckei, showed diverse biological activities [88]. Therefore, it is extremely urgent to expand the scope of research on the lignans and neolignans in Lauraceae, with the aim of discovering all biological activities of these compounds.