Sesterterpenoids

Abstract

Sesterterpenoids are known as a relatively small group of natural products. However, they represent a variety of simple to more complex structural types. This contribution focuses on the chemical structures of sesterterpenoids and how their structures are constructed in Nature.

1 Introduction

Sesterterpenoids are a relatively small group of natural products. Even though they belong to one of the largest families of natural products, the “terpenoids,” only around 1000 natural sesterterpenoids have been reported [1,2,3,4,5]. Considering that over 80,000 terpenoids have already been isolated [6,7,8], the number of known sesterterpenoids is quite small. Moreover, in almost all cases, their biological role is unknown. However, sesterterpenoids have been isolated from many kinds of organisms (e.g., plants, bacteria, fungi, lichens, insects, marine sponges, and other marine organisms) [1,2,3,4,5]. This fact implies that various organisms have the potential to produce sesterterpenoids.

In this contribution, we will introduce the chemical structures of sesterterpenoids. Although the number of sesterterpenoids is not very large, they have a large variety of simple to complicated chemical structures. Herein, we have classified the sesterterpenoids based on the number of carbocyclic moieties in their chemical structures. In addition, we will also explain how the structure of each sesterterpenoid is formed in Nature.

2 What Are the Sesterterpenoids?

2.1 “Sesterterpenoids” Are Members of the “Terpenoids”

As mentioned above, the sesterterpenoids are a subgroup of the terpenoids. Therefore, we will start by briefly describing the terpenoids. Terpenoids are defined as a group of natural products composed of simple “C₅” units, called isoprene units (Fig. 1). Thus, terpenoids are also called “isoprenoids.” In this definition, “C₅” means that a compound contains five carbon atoms. This notation will be frequently used in this chapter, and thus “C₂₅” refers to a compound containing 25 carbon atoms.

Fig. 1

Isoprene unit

For example, the chemical structure of sesterbrasiliatriene (1), a type of terpenoid, contains five isoprene units (Fig. 2b) [9]. In another example, four isoprene units (b) constitute the chemical structure (a) of 2 (Fig. 3) [10].

Fig. 2

Structure of 1. The structure of 1 contains five isoprene units. Each isoprene unit is shown by bold lines with different colors

Fig. 3

Structure of 2. The structure of 2 contains four isoprene units. Each isoprene unit is shown by bold lines with different colors

The origins of the isoprene units are dimethylallyl pyrophosphate (DMAPP) (3) and isopentenyl pyrophosphate (IPP) (4) (Fig. 4) [6,7,8]. Both are widely distributed in Nature, and generated via two kinds of metabolic pathways, known as the MVA (mevalonate) and MEP (methylerythritol phosphate) pathways [11, 12].

Fig. 4

Structures of dimethylallyl pyrophosphate (DMAPP) (3) and isopentenyl pyrophosphate (IPP) (4)

The biosynthesis of all terpenoids starts from condensation reactions of 3 and 4 to yield polyprenyl diphosphates, which are important intermediates of terpenoids. Each polyprenyl diphosphate is designated as follows: (C₁₀) geranyl diphosphate (GPP) (5), (C₁₅) farnesyl diphosphate (FPP) (6), (C₂₀) geranylgeranyl diphosphate (GGPP) (7), and (C₂₅) geranylfarnesyl diphosphate (GFPP) (8). These condensation reactions are catalyzed by enzymes called “prenyltransferases” (Fig. 5) [6,7,8].

Fig. 5

Condensation reaction catalyzed by prenyltransferases to form polyprenyl diphosphates, and structures of 5–8

In many cases, the polyprenyl diphosphates are subjected to cyclization reactions to form a carbocyclic moiety. These cyclization reactions are catalyzed by “terpene cyclases.” Generally, the terpene cyclases are divided into two classes, “type 1” and “type 2,” based on their catalytic mechanisms.

The type 1 terpene cyclases initiate the cyclization by heterolytic cleavage of the diphosphate moiety of the polyprenyl diphosphates. The heterolytic cleavage leads to the generation of cation intermediates, and the high energy of the cation intermediate is the driving force of the cyclization reaction. The cyclization reaction is finalized by either deprotonation or an attack by H₂O. For example, 1 is formed by a type 1 terpene cyclase (Fig. 6).

Fig. 6

Cyclization reaction to form sesterbrasiliatriene (1). This reaction is catalyzed by the type 1 terpene cyclase

The other class of terpene cyclases is known as the “type 2” terpene cyclases. The type 2 terpene cyclases also generate cation intermediates to initiate the cyclization reaction. However, the strategy to generate the cation intermediate is different from that of the type 1 terpene cyclases. The type 2 terpene cyclases generate the cation intermediate via the protonation of a double bond of the polyprenyl diphosphates. For example, 2 is formed by a type 2 terpene cyclase (Fig. 7).

Fig. 7

Cyclization reaction to form 2. This reaction is catalyzed by the type 2 terpene cyclase

After the fundamental carbon skeleton of the terpenoids is formed by the prenyltransferases and terpene cyclases, the intermediates of the terpenoids are converted into the final products by tailoring enzymes. A typical tailoring enzyme is cytochrome P450, which catalyzes an oxidation reaction. For instance, casbene (9) is converted to the oxidized products 10–12 by means of cytochrome P450 (Fig. 8) [13]. However, in addition to cytochrome P450, various other enzymes are also involved in the biosynthesis of terpenoids and expand their structural diversity.

Fig. 8

Compound 9 could be oxidized by a cytochrome P450, forming 10–12

For example, many kinds of tailoring enzymes (prenyltransferase, oxidase, aminotransferase, methyltransferase, sugar transferase, and ligase) are involved in the biosynthesis of brasilicardin A (13), a terpenoid with potent immunosuppressive activity (Fig. 9). After the formation of 15 via 7 and 14, these tailoring enzymes apparently convert 15 to 13 [14].

Fig. 9

Putative biosynthesis pathway of brasilicardin A (13). The functional groups of 13, which might be generated by the tailoring enzymes, are shown in red

2.2 Definition of “Sesterterpenoids”

The terpenoids are classified by the chain lengths of the polyprenyl diphosphates used in their biosynthesis. In the case of the sesterterpenoids, they are defined as compounds that are biosynthesized via geranylfarnesyl diphosphate (GFPP) (8) (Fig. 10).

Fig. 10

Definition of sesterterpenoids. The genuine sesterterpenoids should be biosynthesized via 8

For example, preasperterpenoid A (16) is biosynthesized via 8 (Fig. 11) [9]. Thus, 16 is a sesterterpenoid. Actually, 1 is also a sesterterpenoid, while 2 is not, by considering their biosynthesis pathways (Figs. 6 and 7). Compounds 9–15 are also not sesterterpenoids (Figs. 8 and 9).

Fig. 11

Biosynthesis of preasperterpenoid A (16). Compound 16 is a sesterterpenoid, since 16 is biosynthesized via 8

The other classes of terpenoids biosynthesized via different polyprenyl diphosphates are defined as follows: “hemiterpenoids” are from (C₅) 3 or 4, “monoterpenoids” are from (C₁₀) 5, “sesquiterpenoids” are from (C₁₅) 6, “diterpenoids” are from (C₂₀) 7, and “triterpenoids” are from (C₃₀) squalene (17) (Fig. 12).

Fig. 12

Classification of the terpenoids

In contrast to 5–8, 17 is generated by the condensation of two (C₁₅) 6 units. This condensation pattern is known as a tail-to-tail (Fig. 13b) linkage. The other polyprenyl diphosphates 5–8 exhibit only head-to-tail linkages (Fig. 13b).

Fig. 13

(a) The “head” and “tail” positions in the isoprene unit. (b) Compound 8 is formed only by the “head-to-tail” condensation of isoprene units, while 17 is formed not only by the “head-to-tail” linkage but also by the “tail-to-tail” linkage

2.3 Natural Products Confused with Sesterterpenoids

Since all genuine sesterterpenoids should be derived from GFPP (8), the basic carbon skeletons of many sesterterpenoids are composed of 25 carbon atoms. However, it should be noted that not all compounds with basic carbon skeletons consisting of 25 carbon atoms are sesterterpenoids. Herein, we introduce examples of natural products that could be confused with sesterterpenoids. When determining whether a compound is a sesterterpenoid, it is essential to consider its biosynthetic origin.

2.3.1 Meroterpenoids

One example of natural products that could be confused with the sesterterpenoids is a group of meroterpenoids containing a C₁₀ polyketide moiety (e.g., preterretonin A (18), protoaustinoid A (19), and andrastin E (20)) (Fig. 14) [15]. There are 25 carbon atoms in the basic carbon skeletons of these compounds. However, they are not biosynthesized via 8, but are generated from a C₁₅ terpenoid moiety and a C₁₀ polyketide moiety. These C₁₅ and C₁₀ moieties are combined in their biosynthesis to form the C₂₅ basic carbon skeleton.

Fig. 14

Biosynthesis of 18–20. In their basic carbon skeletons, there are 25 carbons. However, they are not sesterterpenoids

2.3.2 Highly Branched Isoprenoids

Compound 21 is a highly branched isoprenoid produced by the diatom Rhizosolenia setigera [16]. Five isoprene units are found readily in its structure (Fig. 15). Thus, 21 is a member of the terpenoids, and 25 carbon atoms exist in its basic carbon skeleton. However, 21 is not a sesterterpenoid, since 21 is not derived from the C₂₅ polyprenyl diphosphate 8, but from (C₁₀) 5 and (C₁₅) 6 (Fig. 16).

Fig. 15

Structure of 21. The structure of 21 has five isoprene units, but 21 is not a sesterterpenoid. The isoprene units are shown by bold lines

Fig. 16

Putative biosynthesis pathway of 21. Compound 21 is biosynthesized from 5 and 6, but not from 8

2.3.3 Other Notable Points

The examples shown in Sects. 2.3.1 and 2.3.2 suggest that not all compounds with 25 carbon atoms are sesterterpenoids. However, it should also be noted that the basic carbon skeletons of some sesterterpenoids are composed of fewer than 25 carbons, due to a degradation reaction during their biosynthesis. For example, even though ircinin-3 (22) from the sponge Ircinia oros possesses only 21 carbon atoms, 22 is a sesterterpenoid (Fig. 17) [17].

Fig. 17

Compound 22 is considered to be generated from 8. The C₄ partial structure, which is shown by bold blue lines in 8, is removed by the degradation reaction during the biosynthesis of 22

3 Linear Sesterterpenoids

The linear sesterterpenoids do not possess a carbocyclic moiety. Thus, the terpene cyclases are not involved in their biosynthesis. The C₂₅ polyprenyl chain of GFPP (8) is directly modified by tailoring enzymes to form a variety of linear sesterterpenoids.

One of the simplest linear sesterterpenoids is geranylfarnesol (23), discovered from the wax of the scale insect Ceroplastes albolineatus [18]. Another example of a simple linear sesterterpenoid is geranylnerolidol (24) from the fungus Cochliobolus heterostrophus [19]. The putative biosynthesis pathways of 23 and 24 should not be complicated, since the elimination of the diphosphate moiety and the attack of H₂O should be sufficient to form 23 and 24 from 8 (Fig. 18).

Fig. 18

Putative biosynthesis pathway of geranylfarnesol (23) and geranylnerolidol (24)

Actually, 23 and 24 are the simplest examples, and in many cases, further tailoring reactions occur to generate more functionalized linear sesterterpenoids. In spite of their simple basic carbon skeletons, many kinds of linear sesterterpenoids, especially from marine organisms, have been reported.

3.1 Linear Sesterterpenoids with a Furan Ring Moiety

A furan ring moiety is observed frequently in the structures of the linear sesterterpenoids. However, in almost all cases, the enzymes responsible for the formation of the furan moiety of the linear sesterterpenoids have not been identified. One example of a possible pathway for the biosynthesis of the furan skeleton is shown in Fig. 19. Other pathways for the formation of the furan ring could also be proposed as shown in Fig. 20.

Fig. 19

One example of the proposed pathways for the formation of the furan moiety

Fig. 20

Another pathway for the formation of the furan moiety

As examples of linear sesterterpenoids with a furan ring moiety, furospongin-3 (25) and furospongin-4 (26) were isolated from the marine sponge Spongia officinalis (Plate 1) (Fig. 21) [17]. Another example is idiadione (27), which was discovered in a different sponge, Spongia idia (Fig. 21) [20]. An epoxyfuranosesterterpene carboxylic acid (28) was isolated from a Western Australian sponge Spongia sp. [21]. These linear sesterterpenoids possess one furan ring moiety in their structures. In addition, other tailoring reactions (e.g., oxidation, reduction, methyl ester formation) also seem to occur in their biosynthesis.

Plate 1

Spongia officinalis, Greece. Photograph courtesy E. Voultsiadou et al., Creative Commons 2.5

Fig. 21

Structures of 25–28. The furan ring moieties are shown in red circles. The other functional groups, generated by oxidation, reduction, and methyl ester formation, are shown in blue, orange, and purple, respectively

3.2 Linear Sesterterpenoids with a 2-Furanone Moiety

Linear sesterterpenoids with a 2-furanone moiety also exist. The formation of the 2-furanone moiety should be similar to that of the furan ring moiety. Two possible pathways are shown in Figs. 22 and 23.

Fig. 22

Formation of the 2-furanone moiety

Fig. 23

An alternative pathway for the formation of the 2-furanone moiety

Two linear sesterterpenoids with a 2-furanone moiety, 29 and 30, were isolated from the Caribbean sponge Thorecta horridus (Fig. 24) [22]. In particular, 29 possesses potent inflammatory activity, inducing histamine release (in vitro), and causes edema in rat paws (in vivo).

Fig. 24

Structures of 29 and 30. The 2-furanone moieties are highlighted by blue circles

Compound 29 has also been reported from the Australian sponge Luffariella geometrica, and designated as luffarin Q [23]. Luffarin R (31) was also isolated from the same sponge (Fig. 25) [23]. Compound 31 possesses a γ-butyrolactone moiety in addition to the 2-furanone moiety.

Fig. 25

Structure of luffarin R (31), which possesses not only the 2-furanone moiety but also a γ-butyrolactone moiety

3.3 Linear Sesterterpenoids with a Tetronic Acid Moiety

The tetronic acid moiety is present in numerous linear sesterterpenoids, and many of them exhibit bioactivities. The tetronic acid moiety seems to be generated by an oxidation of the 2-furanone moiety (Fig. 26).

Fig. 26

Proposed pathway for the formation of the tetronic acid moiety

For example, 32 was isolated from the Australian sponge Psammocinia sp. (Fig. 27) [24] and has antimicrobial activity. A similar compound, isopalinurin (33), was reported from the South Australian sponge, Dysidea sp. (Fig. 27) [25]. Compound 33 is known as a moderate protein phosphatase inhibitor. In addition to the tetronic acid moiety, 32 and 33 also possess a furan ring moiety.

Fig. 27

Structures of 32 and 33. The tetronic acid and furan ring moieties are highlighted by orange and red circles, respectively

Variabilin (34), an antimicrobial linear sesterterpene with a tetronic acid moiety (Fig. 28) [26], was isolated from the Okinawan sponge, Amphidmedon sp. Compound 34 possesses a stereocenter at the C-18 position, and the absolute configuration of this position was determined as (S) by the synthesis of the degradation product of 34 [26].

Fig. 28

Structures of 34–36. The tetronic acid and branched-chain fatty acid ester are highlighted by orange and purple circles, respectively

An enantiomer of 34, (18R)-variabilin (35), was isolated from the Caribbean sponge Ircinia felix (Fig. 28) [27]. Together with 35, variabilin 11-methyloctadecanoate (36), a branched-chain fatty acid ester of 35, was also isolated [28].

Compounds 32–36 possess not only a tetronic acid moiety but also a furan ring moiety. Actually, many linear sesterterpenoids with a tetronic acid moiety have a furan ring moiety, and some of them possess more than one furan ring moiety in their chemical structures. For example, spongionellin (37) [29], dehydrospongionellin (38) [29], ircinin-1 (39) [30, 31], and ircinin-2 (40) [30, 31] have two furan ring moieties, in addition to a tetronic acid moiety (Fig. 29). Compounds 37 and 38 are from a Japanese sponge, Spongionella sp., and both inhibit the cell division of fertilized starfish (Asterina pectinifera) eggs. Compounds 39 and 40 were isolated from the sponge Ircinia oros, collected in the Bay of Naples along the south-western coast of Italy [30], and another sponge Ircinia sp., collected from the Island of Bora Bora in French Polynesia [31].

Fig. 29

Structures of 37–40. The tetronic acid and furan ring moieties are highlighted by orange and red circles, respectively. Compounds 37–40 possess two furan ring moieties and one tetronic acid moiety

3.4 Degraded Linear Sesterterpenoids

As mentioned in Sect. 2.3.3, the numbers of carbon atoms in some sesterterpenoids are less than 25, because of degradation reactions in their biosynthesis. Herein, we introduce the “C₂₁” and “C₂₄” linear sesterterpenoids.

3.4.1 “C₂₁” Linear Sesterterpenoids

The C₂₁ linear sesterterpenoids are one of the largest groups among the degraded linear sesterterpenoids. The C₂₁ linear sesterterpenoids are considered to arise from the cleavage of the tetronic acid moiety, which was introduced in Sect. 3.3. This hypothesis is supported by the co-occurrence of the C₂₁ linear sesterterpenoids (e.g. 22, ircinin-4 (41)) and the corresponding linear sesterterpenoids with a tetronic acid moiety (e.g., 39 and 40) (Figs. 17 and 30) [17]. A proposed mechanism of the degradation reaction is shown in Fig. 31 [1, 17]. Some sesterterpenoids with a tetronic acid moiety (e.g., 39 and 40) possess a double bond, which is attached to the tetronic acid moiety (Figs. 30 and 31). Thus, when this tetronic acid moiety becomes an opened form, a reactive α-dicarbonyl moiety is generated, and the α-dicarbonyl moiety is cleaved. For example, a hydroperoxide compound, which could be formed by autoxidation, is capable of cleaving an α-dicarbonyl compound [32]. However, this is just one possible way, and further studies are required to reveal the mechanism leading to the formation of the C₂₁ linear sesterterpenoids.

Fig. 30

Comparison of the structures of 22, 41, 39, and 40, which were all isolated from the same marine sponge, Ircinia oros. The double bonds attached to the tetronic acid moiety are highlighted by the bold red line. Compounds 22 and 41 are considered to be generated by the cleavage of 39 and 40, respectively. The structure of 22 is also shown in Fig. 17, and the structures of 39 and 40 are also shown in Fig. 29

Fig. 31

Proposed mechanism leading to the formation of the C₂₁ linear sesterterpenoids. Double bonds attached to the tetronic acid moiety are emphasized by bold red lines

Interestingly, many of the C₂₁ linear sesterterpenoids possess furan ring moieties at both ends of their structures. For example, untenospongin C (42), obtained from an Okinawan sponge Hippospongia sp. (Fig. 32) [33], exhibited cytotoxicity against murine lymphoma L1210 cells (in vitro experiment). Another example is isonitenin (43) from the sponge Spongia officinalis collected at O Grove, Pontevedra, Spain (Fig. 32) [34]. Anhydrofurospongin-1 (44) [35] and furospongin-1 (45) [36] have been found in both the Spongia officinalis and Hippospongia communis sponges, which were collected in the Bay of Naples, Italy (Fig. 32). In addition, 46 has been reported from a sponge Spongia sp. collected in Western Australia [37], and tetradehydrofurospongin-1 (47) has been found in both the Leiosella sp. and Spongia sp. sponges (Fig. 32) [37, 38].

Fig. 32

Structures of 42–47. These are C₂₁ linear sesterterpenoids, with the furan ring moiety at both ends of their structures

On the other hand, furospongolide (48), from the sponge Dysidea herbacea (Fig. 33) [39], possesses one furan ring moiety and one 2-furanone moiety at the ends of the molecule.

Fig. 33

Structure of furospongolide (48), which possesses one furan ring moiety and one 2-furanone moiety at the ends of the molecule

3.4.2 “C₂₄” Linear Sesterterpenoids

The C₂₄ linear sesterterpenoids are also considered to be formed from the linear sesterterpenoids with a tetronic acid moiety. In the case of the C₂₄ linear sesterterpenoids, decarboxylation occurs to remove one carbon atom from the molecule (Fig. 34).

Fig. 34

Proposed mechanism leading to the formation of the C₂₄ linear sesterterpenoids

The C₂₄ linear sesterterpenoids are exemplified by sarcotin P (49), from a sponge Sarcotragus sp. collected off Cheju Island, Korea (Fig. 35) [40]. Compound 49 might show toxicity to brine shrimp larvae, since this compound was isolated by a bioactivity-guided fractionation procedure that evaluated toxicity to brine shrimp larvae, although this was not confirmed.

Fig. 35

Structure of sarcotin P (49)

Halogenated C₂₄ linear sesterterpenoids also exist, and are exemplified by konakhin (50) [41], 51 [42], and 52 [42] (Fig. 36). Compound 50 was isolated from an unidentified sponge collected off the coast of Konakhè, near Dakar, Senegal, while 51 and 52 were obtained from a North Adriatic Sea collection of Ircinia oros.

Fig. 36

Structures of 50–52. Halogen atoms are shown in red

A proposed mechanism leading to the formation of the halogenated C₂₄ linear sesterterpenoids is shown in Fig. 37. In this pathway, after decarboxylation to form the C₂₄ fundamental carbon skeleton, a halogenation reaction occurs.

Fig. 37

Proposed mechanism leading to the formation of the halogenated C₂₄ linear sesterterpenoids

3.5 Linear Sesterterpenoids Containing a Nitrogen Atom

All linear sesterterpenoids shown above (22–52) are composed of only carbon, hydrogen, and oxygen atoms. However, some linear sesterterpenoids contain a nitrogen atom, as exemplified by the ircinialactams (53–55) (Fig. 38) [43], purified from Australian sponges of the family Irciniidae. From these sponges, the C₂₁ degraded compounds, 56 and 57, have also been isolated (Fig. 39) [43]. The proposed degradation mechanism is shown in Fig. 31. Compounds (53–57) are all modulators of glycine receptor chloride channels.

Fig. 38

Structures of the ircinialactams 53–55, which contain a nitrogen atom in their structures

Fig. 39

Structures of 56 and 57, which contain a nitrogen atom in their structures, and are members of the C₂₁ linear sesterterpenoids

4 Monocarbocyclic Sesterterpenoids

In the biosynthesis of the monocarbocyclic sesterterpenoids, terpene cyclases are responsible for the formation of the carbocyclic moiety (Figs. 6 and 7). As mentioned above, there are two kinds of terpene cyclases, types 1 and 2. Each cyclase can generate a variety of characteristic basic carbon skeletons of sesterterpenoids.

4.1 Monocarbocyclic Sesterterpenoids Constructed by the Type 1 Terpene Cyclases

4.1.1 14-Membered Ring

Monocarbocyclic sesterterpenoids constructed by the type 1 terpene cyclases are relatively rare. They are exemplified by ceriferol (58), ceriferic acid (59), ceriferol-I (60), 13-methoxycericerene (61), and ceriferol-II (62), which possess 14-membered ring systems (Fig. 40) [44,45,46,47,48,49]. They were isolated from the wax of the scale insect Ceroplastes ceriferus. In fact, scale insects are known as good sources of sesterterpenoids.

Fig. 40

Structures of 58–62

The mechanism of the 14-membered ring formation by the type 1 terpene cyclases is shown in Fig. 41. The cyclization reaction is initiated by the heterolytic cleavage of the diphosphate moiety of 8, and then the cyclization is finalized by the deprotonation or the attack of H₂O.

Fig. 41

The mechanism of 14-membered ring formation by the type 1 terpene cyclases

4.1.2 6-Membered Ring

The compound (−)-alotaketal A (63), which possesses a 6-membered ring system, was reported from a marine sponge, Hamigera sp., collected in Papua New Guinea (Fig. 42) [50], and is known to activate the cAMP cell signaling pathway. Its biosynthesis originates from geranylfarnesyl diphosphate (GFPP) (8).

Fig. 42

Structure and formation of (–)-alotaketal A (63)

4.2 Monocarbocyclic Sesterterpenoids Constructed by the Type 2 Terpene Cyclases

4.2.1 6-Membered Ring

The type 2 terpene cyclases also generate 6-membered ring systems. Moreover, most of the monocarbocyclic sesterterpenoids constructed by the type 2 terpene cyclases possess a 6-membered ring. For example, 64 [51], 65 [51], luffariolide H (66) [52], and luffariolide J (67) [52] have been reported (Fig. 43). Compounds 64 and 65 were isolated from the sponge Hyrtios cf. erecta, collected at Nananu-I-Ra, Fiji. Compounds 66 and 67 were reported from an Okinawan marine sponge, Luffariella sp., and exhibit antimicrobial activities against Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus.

Fig. 43

Structures of 64–67

Acantholide A (68) [53] and acantholide B (69) [53] also possess 6-membered rings (Fig. 44). They were isolated from an Indonesian sponge, Acanthodendrilla sp., and 69 has antimicrobial activities against Staphylococcus aureus and Bacillus subtilis.

Fig. 44

Structures of acantholide A (68) and acantholide B (69)

A cyclization mechanism for the formation of the 6-membered rings of 64–69 is shown in Fig. 45. Since their basic carbon skeletons are formed by the type 2 terpene cyclases, the cyclization reaction is initiated by the protonation of the double bond of geranylfarnesyl diphosphate (GFPP) (8).

Fig. 45

Cyclization mechanism for the formation of the 6-membered rings of 64–69

Another monocarbocyclic sesterterpenoid with a 6-membered ring is cyclolinteinone (70), isolated from the Caribbean sponge Cacospongia linteiformis (Fig. 46) [54]. The positions of the methyl groups on the 6-membered ring differentiate 70 from 64–69. Compound 70 can downregulate the protein expression of an inducible NO synthase and cyclo-oxygenase-2 via the inhibition of NF-ĸB activation.

Fig. 46

Structure of 70

A cyclization reaction leading to the formation of the basic carbon skeleton of 70 is shown in Fig. 47. In this proposed mechanism, a 1,2-hydride shift and a 1,2-alkyl shift occur to change the position of the methyl group on the 6-membered ring, and then deprotonation finalizes the reaction.

Fig. 47

Cyclization reaction leading to the formation of the basic carbon skeleton of 70

The structures of cyclolinteinol (71) and cyclolinteinol acetate (72) are similar to that of 70 (Fig. 48) [55]. They were isolated from the Caribbean sponge Cacospongia cf. linteiformis.

Fig. 48

Structures of cyclolinteinol (71) and cyclolinteinol acetate (72)

4.2.2 5-Membered Ring

Monocarbocyclic sesterterpenoids with 5-membered ring systems also exist. However, they are rare, as compared with the monocarbocyclic sesterterpenoids with 6-membered ring systems. Such sesterterpenoids are exemplified by 25-acetoxyluffariellins A and B (73 and 74) (Fig. 49) [56], isolated from the sponge Luffariella variabilis from the Great Barrier Reef, Australia. Notably, they are unstable in the sponge tissue, even though they are stable after isolation. Thus, the sponge apparently has some enzymes that can convert or degrade these compounds.

Fig. 49

Structures of 25-acetoxyluffariellins A (73) and B (74)

A proposed mechanism for the formation of the 5-membered ring system is shown in Fig. 50.

Fig. 50

Proposed mechanism for the formation of the 5-membered rings of 73 and 74

A different type of 5-membered ring is seen in the structures of acantholide D (75) and acantholide E (76) (Fig. 51) [53]. Actually, 75 and 76 were co-isolated with 68 and 69 from the Indonesian sponge, Acanthodendrilla sp. [53], and 76 exhibited cytotoxicity against the L5187Y mouse lymphoma cell line. A proposed cyclization mechanism for generating the basic carbon skeleton of 75 and 76 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 52.

Fig. 51

Structures of acantholide D (75) and acantholide E (76)

Fig. 52

Proposed cyclization mechanism for generating the basic carbon skeletons of acantholide D (75) and acantholide E (76)

5 Bicarbocyclic Sesterterpenoids

5.1 Bicarbocyclic Sesterterpenoids Constructed by the Type 1 Terpene Cyclases

5.1.1 15/5-Membered Ring System

Bicarbocyclic sesterterpenoids, constructed by the type 1 terpene cyclases, have been reported from fungi. Terpestacin (77), a representative compound with a 15/5-membered ring system (Fig. 53) [57, 58], has been isolated from the fungi Arthrinium sp. [57] and Phomopsis sp. XZ-26 [58]. Compound 77 reportedly inhibits tumor angiogenesis by binding to the 13.4-kDa subunit of the mitochondrial complex III and suppresses hypoxia-induced reactive oxygen species production and cellular oxygen sensing [59].

Fig. 53

Structures of 77–79, which possess a 15/5-membered ring system

Interestingly, the compound known as “siccanol,” isolated from the fungus Bipolaris sorokiniana NSDR-011, is also compound 77. Even though “siccanol” was initially reported as 11-epiterpestacin (78), an epimer of 77 (Fig. 53) [60], the total synthesis of 78 revealed that “siccanol” was not 78, but 77 [61].

Fusaproliferin (79), isolated from the fungus Fusarium proliferatum, also possesses the 15/5-membered ring system (Fig. 53) [62]. Compound 79 is an acetate ester of 77, and the stereochemistry of 79 was established by a synthesis approach [63]. A proposed cyclization mechanism for the formation of the 15/5-membered ring system starting from geranylfarnesyl diphosphate (8) is shown in Fig. 54. This cyclization involves a 1,5-hydride shift, which is seen frequently in the type 1 cyclization reactions of sesterterpenoids.

Fig. 54

Proposed cyclization mechanism for the formation of the 15/5-membered ring system

5.1.2 12/6-Membered Ring System

Emericellene A (80) and related compounds have been reported from an endophytic fungus, Emericella sp. AST0036, collected from a healthy leaf of the plant Astragalus lentiginosus (Fig. 55) [64]. Compound 80 possesses a 12/6-membered ring system. A proposed cyclization mechanism for generating the 12/6-membered ring system originating in geranylfarnesyl diphosphate (8) is shown in Fig. 55, and the formation of a 14-membered ring might be the first step in this reaction.

Fig. 55

Structure of mericellene A (80), and proposed cyclization mechanism for the formation of the 12/6-membered ring system

5.2 Bicarbocyclic Sesterterpenoids Constructed by the Type 2 Terpene Cyclases

The majority of bicarbocyclic sesterterpenoids constructed by the type 2 terpene cyclases possess 6/6-membered ring systems. An example of the 6/6-membered ring formation starting from geranylfarnesyl diphosphate (8) is shown in Fig. 56.

Fig. 56

One example of the 6/6-membered ring formation

Salvimirzacolide (81), with a 6/6-membered ring system, was isolated from the aerial parts of the plant Salvia mirzayanii (Fig. 57) [65]. Another example is salvileucolide methyl ester (82), which reportedly exists in the aerial parts of two Iranian Salvia species plants (Fig. 57) [66]. The structures of both 81 and 82 have been confirmed by X-ray crystallography.

Fig. 57

Structures of salvimirzacolide (81) and salvileucolide methyl ester (82)

In some cases, an alkyl shift occurs in the middle of the cyclization reaction. For example, the basic carbon skeleton of halisulfate-3 (83) is different from those of 81 and 82 (Fig. 58) [67]. Compound 83 is one of the metabolites of a sponge, Ircinia sp., which was collected in the Philippines. The cyclization reaction for the formation of the basic carbon skeleton of 83 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 59.

Fig. 58

Structure of halisulfate-3 (83)

Fig. 59

Proposed cyclization mechanism to generate the basic carbon skeleton of 83

Another example of an alkyl shift is found in the formation of thorectandrol A (84) and thorectandrol B (85) (Fig. 60) [68]. Compounds 84 and 85 were isolated from the sponge Thorectandra sp. collected in Palau, and both 84 and 85 inhibited the growth of the MALME-3M and MCF-7 cancer cells. A proposed cyclization mechanism for the formation of the basic carbon skeletons of 84 and 85 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 61. During this reaction, the alkyl shift occurs twice.

Fig. 60

Structures of thorectandrol A (84) and thorectandrol B (85)

Fig. 61

Proposed cyclization mechanism for generating the basic carbon skeleton of 84 and 85

5.3 Other Bicarbocyclic Sesterterpenoids

Even though most of the carbocyclic moieties of sesterterpenoids are formed by the terpene cyclases, some carbocyclic structures are generated in a different manner. For example, the bicarbocyclic ring systems of (+)-wistarin (86) [69, 70] and (−)-wistarin (87) [71] would not be formed by the typical terpene cyclases (Fig. 62). Compound 87 is an enantiomer of 86. Compound 86 was found in the sponge Ircinia wistarii from the Great Barrier Reef, Australia [69], while 87 was isolated from a sponge, Ircinia sp., collected at Hurghada, Red Sea, Egypt [71].

Fig. 62

Structures of (+)-wistarin (86) and (−)-wistarin (87)

A proposed biosynthesis of 86 is shown in Fig. 63. Actually, 86 seems to be biosynthesized via a linear sesterterpenoid 88, and the Diels–Alder reaction might occur to form the bicarbocyclic moiety of 86. In the same manner, 87 should be formed via ent-88.

Fig. 63

Proposed mechanism to generate the basic carbon skeleton of 86

The biosynthesis pathway of ircinianin sulfate (89) (Fig. 64) [72] should be similar to that of 86. Compound 89 is an unstable metabolite from the sponge Ircinia wistarii, collected from the Great Barrier Reef, Australia.

Fig. 64

Structure of ircinianin sulfate (89)

6 Tricarbocyclic Sesterterpenoids

A greater number of carbocyclic moieties increases the complexity of the structures of sesterterpenoids. Thus, sesterterpenoids with more than three carbocyclic rings exhibit considerable complexity. Moreover, the diversity of the basic carbon skeleton is also increased. Especially the type 1 terpene cyclases have great potential to generate various kinds of structures with more than three carbocyclic rings.

6.1 Tricarbocyclic Sesterterpenoids Constructed by the Type 1 Terpene Cyclases

6.1.1 5/8/5-Membered Ring System

A tricarbocyclic sesterterpenoid with a 5/8/5-membered ring system (90), from the fungi Ophiobolus miyabeanus and Helminthosporium oryzae, was found initially and characterized by Japanese [73] and Italian [74] groups, independently. The Japanese group designated this compound as ophiobolin, while the Italian group named it cochliobolin. In order to avoid confusion, a joint paper from these two groups was published, and this compound was renamed ophiobolin A (90) (Fig. 65) [75].

Fig. 65

Structure of ophiobolin A (90)

Many derivatives of 90 have been reported, and they are called ophiobolin-type sesterterpenoids. Examples of the ophiobolin-type sesterterpenoids, ophiobolins B-M (91–102), are shown in Figs. 66 and 67 [19, 76,77,78,79,80,81,82,83,84,85,86]. Notably, the ophiobolin-type sesterterpenoids are known as bioactive compounds. For example, 90, 91, 92, and 100 exhibited activity toward leukemia cells with the induction of apoptosis, at nanomolar concentrations [87].

Fig. 66

Structures of 91–96

Fig. 67

Structures of 97–102

A proposed cyclization mechanism for the formation of the 5/8/5-membered ring system starting from geranylfarnesyl diphosphate (8) is shown in Fig. 68. In this reaction, an 11/5-membered ring system first would be generated. Subsequently, a 1,5-hydride shift and the formation of another 5-membered ring would occur.

Fig. 68

Proposed cyclization mechanism for the formation of the 5/8/5-membered ring system

Epimers of many ophiobolins have also been reported, as exemplified by 6-epiophiobolin A (103) [88, 89], 6-epiophiobolin C (104) [85], 6-epiophiobolin I (105) [82], and 6-epiophiobolin K (106) [83] (Fig. 69).

Fig. 69

Structures of 103–106

Many ophiobolin-type sesterterpenoids have been described, and even now, the number of ophiobolin-type sesterterpenoids is increasing. For example, the new ophiobolin-type sesterterpenoids, asperophiobolins A (107), and ten other related new sesterterpenoids were reported in 2019 (Fig. 70) [90]. They were isolated from cultures of a mangrove endophytic fungus, Aspergillus sp. ZJ-68.

Fig. 70

Structure of asperophiobolin A (107)

6.1.2 5/12/5-Membered Ring System

Sesterterpenoids with 5/12/5-membered ring systems have been found in both a fungus and a plant. Variculanol (108) was isolated from the fungus Aspergillus variecolor [91], while nitinol (109) was reported from the plant Gentianella nitida, which is used in Peruvian folk medicine (Fig. 71) [92]. Compound 109 exhibits activity to enhance IL-2 gene expression in a human T cell line. A possible cyclization mechanism for the formation of the 5/12/5-membered ring system starting from geranylfarnesyl diphosphate (8) is shown in Fig. 72.

Fig. 71

Structures of variculanol (108) and nitinol (109)

Fig. 72

Proposed cyclization mechanism for the formation of the 5/12/5-membered ring system

6.1.3 11/6/5-Membered Ring System

Two groups of sesterterpenoids possess 11/6/5-membered ring systems. One is exemplified by flocerol (110) and floceric acid (111) from the secretions of the scale insect Ceroplastes floridensis, an orchard pest collected in Osaka, Japan (Fig. 73) [93]. The other is exemplified by stellatic acid (112) (Fig. 73) [94], isolated from the metabolites of the fungus Aspergillus stellatus.

Fig. 73

Structures of 110–112

A proposed cyclization mechanism for the formation of the 11/6/5-membered ring systems of 110 and 111 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 74. At first, an 11/5-membered ring system is generated. Importantly, the configuration of one of the two double bonds in the 11-membered ring is (Z). Next, a ring expansion from a 5-membered ring to a 6-membered ring occurs, and at the same time, a new 5-membered ring is generated to form the 11/6/5-membered ring system. Subsequently, deprotonation occurs to finalize the cyclization reaction.

Fig. 74

Proposed cyclization mechanism for the formation of the 11/6/5-membered ring system of 110 and 111

A cyclization reaction for generating the basic carbon skeleton of 112 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 75. There are several differences between the reactions shown in Figs. 74 and 75. First, the configuration of both double bonds in the 11-membered ring is (E) in Fig. 75. Second, the ring expansion from the 5-membered ring to the 6-membered ring occurs in a different manner. These two differences result in the generation of two different types of 11/6/5-membered ring systems.

Fig. 75

Proposed cyclization mechanism for the formation of the 11/6/5-membered ring system of 112

6.1.4 11/6/6-Membered Ring System

Floridenol (113) possesses an 11/6/6-membered ring (Fig. 76) [93] and was also isolated from the wax of the scale insect from which 110 and 111 were reported. The formation of the 11/6/6-membered ring system starting from geranylfarnesyl diphosphate (8) is illustrated in Fig. 77. The formation of 113 seems to have diverged from those of 110 and 111.

Fig. 76

Structure of floridenol (113)

Fig. 77

Proposed cyclization mechanism for the formation of the 11/6/6-membered ring system of 113

6.2 Tricarbocyclic Sesterterpenoids Constructed by the Type 2 Terpene Cyclases

6.2.1 6/6/6-Membered Ring Systems

Many tricarbocyclic sesterterpenoids constructed by the type 2 terpene cyclases exhibit 6/6/6-membered ring systems. For example, suvanine (114) [95] and lintenolide F (115) [96] possess the 6/6/6-membered ring system (Fig. 78). Compound 114 was isolated from a sponge, Ircinia sp., and its chemical structure has been confirmed by the X-ray crystallography of its degradation product [95], while 115 was isolated from a Caribbean sponge, Cacospongia cf. linteiformis [96].

Fig. 78

Structures of suvanine (114) and lintenolide F (115)

A proposed cyclization mechanism for the formation of the carbon skeleton of 114 starting from geranylfarnesyl diphosphate (8) is shown in Fig. 79a, while the cyclization reaction for that of 115 is illustrated in Fig. 79b.

Fig. 79

Proposed cyclization mechanisms for the formation of the 6/6/6-membered ring systems of (a) 114 and (b) 115

6.2.2 6/6/5-Membered Ring System

Hyrtiosal (116), which possesses a 6/6/5-membered ring system, was isolated from the Okinawan marine sponge Hyrtios erectus, collected at a coral reef off Ishigaki Island, Okinawa, Japan (Fig. 80) [97]. Compound 116 has been shown to inhibit the proliferation of KB cells. Its formation starting from geranylfarnesyl diphosphate (8) is illustrated in Fig. 80.

Fig. 80

Structure of hyrtiosal (116), and possible cyclization mechanism for the formation of the 6/6/5-membered ring system

6.2.3 3/6/6-Membered Ring System

Cacospongionolide (117), with a 3/6/6-membered ring system (Fig. 81) [98, 99], was isolated as a potent antitumor and ichthyotoxic agent from the sponge Cacospongia mollior, collected in the Northern Adriatic Sea. The chemical structure of 117 has been confirmed by the X-ray crystallography of its acetyl derivative.

Fig. 81

Structure of cacospongionolide (117)

A proposed cyclization mechanism for the formation of the 3/6/6-membered ring system starting from geranylfarnesyl diphosphate (8) is shown in Fig. 82. One methyl group of 8, highlighted with a red color in Fig. 82, might be involved in the formation of the cyclopropane ring of 117.

Fig. 82

Proposed cyclization mechanism for the formation of the 3/6/6-membered ring system of 117

6.2.4 6/5/4-Membered Ring System

Lintenone (118) is a representative sesterterpenoid with a 6/5/4-membered ring system (Fig. 83) [100]. Compound 118 was isolated from a Caribbean sponge, Cacospongia cf. linteiformis, and possesses potent ichthyotoxicity and antifeedant properties.

Fig. 83

Structure of lintenone (118)

One possible mechanism for the formation of the 6/5/4-membered ring system starting from geranylfarnesyl diphosphate (8) is shown in Fig. 84 [3]. In this proposal, the cyclization reactions occur twice to generate the characteristic 6/5/4-membered ring system. After a 6-membered ring is formed by the first cyclization reaction, an epoxide might be generated by tailoring enzymes. The second cyclization reaction would then be initiated by the protonation of the epoxide.

Fig. 84

Proposed cyclization mechanism for the formation of the 6/5/4-membered ring system of 118

6.3 Tricarbocyclic Sesterterpenoids Constructed by Both Type 1 and 2 Terpene Cyclases

In some sesterterpenoids, the type 1 and 2 terpene cyclases seem to work together to form the complex basic carbon skeleton, and many such sesterterpenoids have been isolated from marine organisms [101].

One example is ansellone A (119), isolated from the nudibranch Cadlina luteromarginata and a sponge, Phorbas sp. (Fig. 85) [102]. Analyses revealed that 119 activates the cAMP signaling pathway. In the proposed biosynthesis pathway, at first the type 1 cyclization starting from geranylfarnesyl diphosphate (8) occurs, and then the type 2 cyclization reactions form the basic carbon skeleton of 119 (Fig. 85) [101].

Fig. 85

Proposed biosynthesis pathway of ansellone A (119)

7 Tetracarbocyclic Sesterterpenoids

7.1 Tetracarbocyclic Sesterterpenoids Constructed by the Type 1 Terpene Cyclases

7.1.1 7/6/6/5-Membered Ring System

Aspergilloxide (120), isolated from a fungus, Aspergillus sp., has a 7/6/6/5-membered ring system (Fig. 86) [103]. A possible cyclization reaction to form the basic carbon skeleton starting from geranylfarnesyl diphosphate (8) is also shown in Fig. 86.

Fig. 86

Structure of aspergilloxide (120), and possible cyclization reaction for the formation of the 7/6/6/5-membered ring system

7.1.2 5/8/6/6-Membered Ring System

Asperterpenol A (121) and a derivative have been reported from a mangrove endophytic fungus, Aspergillus sp. 085242 (Fig. 87) [104]. Compound 121 is an acetylcholinesterase inhibitor. Their tetracarbocyclic skeletons would be formed starting from geranylfarnesyl diphosphate (8) as shown in Fig. 87.

Fig. 87

Structure of asperterpenol A (121), and possible cyclization reaction for the formation of the 5/8/6/6-membered ring system

7.1.3 5/8/6/5-Membered Ring System

There are two types of 5/8/6/5-ring systems. One is exemplified by variecolin (122), which has been isolated from some fungi, including Aspergillus variecolor MF138 [105], Emericella purpurea [106], and Emericella aurantio-brunnea [107] (Fig. 88). Compound 122 possesses immunosuppressive activity, and the formation of its 5/8/6/5-membered ring system is shown in Fig. 88. In this reaction, an 11/6/5-membered ring system is first formed from geranylfarnesyl diphosphate (8), and then protonation occurs to start a second round of cyclization, and the 5/8/6/5-membered ring system is generated.

Fig. 88

Structure of variecolin (122), and possible cyclization reaction for the formation of the 5/8/6/5-membered ring system of 122

The other type of 5/8/6/5-membered ring systems is exemplified by aleurodiscal (123), from the corticioid fungus Aleurodiscus mirabilis [108], and nitidasin (124), from the plant Gentianella nitida [109, 110] (Fig. 89). The formation of the 5/8/6/5-membered ring systems of 123 and 124 is initiated by generating a 15/5-membered ring system (Fig. 89), while that of 122 starts from the generation of the 11/5-membered ring system (Fig. 88).

Fig. 89

Structures of aleurodiscal (123) and nitidasin (124), and possible cyclization reaction for the formation of the 5/8/6/5-membered ring systems of 123 and 124

7.1.4 5/5/6/5- and 5/6/6/5-Membered Ring Systems

The 5/5/6/5-membered ring system is exemplified by mangicol A (125) [111], while the 5/6/6/5-membered ring system is found in the structure of neomangicol A (126) (Fig. 90) [112]. A proposed cyclization mechanism for the formation of the 5/5/6/5-membered ring systems is shown in Fig. 91. Since both 125 and 126 were isolated from the same fungus, Fusarium heterosporum, it is proposed that the 5/6/6/5-membered ring system of 126 is generated starting from geranylfarnesyl diphosphate (8) by the conversion of a precursor possessing the 5/5/6/5-membered ring system [111].

Fig. 90

Structures of mangicol A (125) and neomangicol A (126)

Fig. 91

Possible cyclization reaction for the formation of the 5/5/6/5-membered ring system of mangicol A (125)

7.2 Tetracarbocyclic Sesterterpenoids Constructed by the Type 2 Terpene Cyclases

7.2.1 6/6/6/6-Membered Ring System

Most tetracarbocyclic sesterterpenoids constructed by the type 2 terpene cyclases exhibit a 6/6/6/6-membered ring system and are among the most common sesterterpenoids. Scalarin (127) was the first of this type of compound to be isolated [113, 114]. The chemical structure of 127 and a cyclization mechanism for the formation of the 6/6/6/6-membered ring system starting from geranylfarnesyl diphosphate (8) are shown in Fig. 92.

Fig. 92

Structure of scalarin (127), and possible cyclization reaction for the formation of the 6/6/6/6-membered ring system of 127

7.2.2 6/6/5/7-Membered Ring System

Salmahyrtisol A (128) [115] and hippospongide A (129) (Fig. 93) [116] possess a 6/6/5/7-membered ring system. Compounds 128 and 129 were isolated from the sponges Hyrtios erecta from the Red Sea and Hippospongia sp. from coral reefs off the coast of Tai-tung, Taiwan, respectively. From these two sponges, 116 with a 6/6/5-membered ring system has also been isolated. Considering the structural relationship among 128, 129, and 116, 116 might be a biosynthetic intermediate of 128 and 129.

Fig. 93

Structures of 116, 128, and 129. The structure of 116 is also shown in Fig. 80. Compound 116 is a possible intermediate of 128 and 129

8 Pentacarbocyclic Sesterterpenoids

Pentacarbocyclic sesterterpenoids are rare, and the complexity of their structures is quite high. In particular, the type 1 terpene cyclases are known to generate fascinating pentacarbocyclic skeletons.

8.1 Pentacarbocyclic Sesterterpenoids Constructed by the Type 1 Terpene Cyclases

8.1.1 5/6/5/6/5-Membered Ring System

Peniroquesine A (130) and its derivatives, which possess 5/6/5/6/5-membered ring systems, have been isolated from the fungus Penicillium roqueforti YJ-14 (Fig. 94) [117]. Compound 130 is a potent inhibitor of nitric oxide production in LPS-activated RAW264.7 macrophages. During the proposed cyclization reaction for the formation of the 5/6/5/6/5-membered ring system starting from geranylfarnesyl diphosphate (8), several complex rearrangements could occur (Fig. 94).

Fig. 94

Structure of peniroquesine A (130), and possible cyclization reaction for the formation of the 5/6/5/6/5-membered ring system

8.1.2 5/7/3/6/5-Membered Ring System

Asperterpenoid A (131), with a 5/7/3/6/5-membered ring system, has been isolated from a mangrove endophytic fungus, Aspergillus sp. 16-5c (Fig. 95) [118]. Compound 131 is a strong inhibitor of Mycobacterium tuberculosis protein tyrosine phosphatase B. Its formation from geranylfarnesyl diphosphate (8) is illustrated in Fig. 95.

Fig. 95

Structure of asperterpenoid A (131), and possible cyclization reaction for the formation of the 5/7/3/6/5-membered ring system of 131

8.1.3 5/3/7/6/5- and 5/4/7/6/5-Membered Ring Systems

Aspterpenacid A (132) [119] has a 5/3/7/6/5-membered ring system, while astellatol (133) [120] possesses a 5/4/7/6/5-membered ring system (Fig. 96). Compounds 132 and 133 were isolated from the fungi Aspergillus terreus H010 and Aspergillus variecolor, respectively. Proposed pathways for the formation of the 5/4/7/6/5- and 5/3/7/6/5-membered ring systems starting from geranylfarnesyl diphosphate (8) are also shown in Fig. 96.

Fig. 96

Structures of 132 and 133, and possible cyclization reactions for the formation of the basic carbon skeletons of 132 and 133

8.1.4 5/5/5/6/5-Membered Ring System

Retigeranic acid A (134) [121, 122], retigeran-11-ol (135) [123], and 4-hydroxyretigeran-11-ol (136) [123] possess 5/5/5/6/5-membered ring systems, which originate from geranylfarnesyl diphosphate (8) (Fig. 97). Compounds 135 and 136 were isolated from the lichen Leprocaulon microscopicum. Compound 134 was isolated from lichens of the Lobaria retigera group (Plate 2), and 134 reportedly exists as a mixture with retigeranic acid B (137), an epimer of 134, in Nature (Fig. 98) [124].

Fig. 97

Structures of 134–136, and possible cyclization reactions for the formation of the basic carbon skeleton of 134–136

Plate 2

Lobaria retigera (Bory) Trevisan, Maungataniwha Ecological District. Photograph courtesy D. J. Galloway, CCBY Auckland Museum, Creative Commons 4.0

Fig. 98

Structure of retigeranic acid B (137)

9 Hexacarbocyclic Sesterterpenoids

Niduterpenoid A (138) and niduterpenoid B (139) possess hexacarbocyclic 5/5/5/5/3/5-membered ring systems (Fig. 99) [125]. Both compounds were isolated from Aspergillus nidulans. Compound 138 lacks cytotoxicity, but abrogates 17-estradiol-induced cell proliferation. The cyclization reaction for the formation of the hexacarbocyclic system starting from geranylfarnesyl diphosphate (8) is quite complicated, as shown in Fig. 100. After the formation of the intermediate A, with a 5/5/5/6/5-membered ring system, further rearrangements occur to form the hexacarbocyclic structure. Notably, the 5/5/5/6/5-membered ring system of the intermediate A is distinct from those of 134–137 (Figs. 97 and 98).

Fig. 99

Structures of niduterpenoid A (138) and niduterpenoid B (139)

Fig. 100

Possible cyclization reactions for the formation of the hexacarbocyclic skeleton of 138 and 139. The intermediate A possesses a 5/5/5/6/5-membered ring system, which is distinct from that of 134–137

10 Sesterterpenoids Found by a Genome-Based Approach

Recently, a genome-based approach to the search for novel sesterterpenoids has been reported [126, 127]. As in a typical search for new natural products, researchers extract mixtures of compounds from natural sources and search for new compounds in the crude extracts. However, in the genome-based approach, investigators extract the genomic DNA from such natural resources and perform genome sequencing. From the obtained genomic data, a search is made for genes that could be involved in sesterterpenoid biosynthesis. These genes are expressed inducibly utilizing genetic engineering techniques. If the expressed genes are responsible for the formation of unknown sesterterpenoids, then these new sesterterpenoids can be isolated. By utilizing this approach, several new sesterterpenoids have been identified from fungi, plants, and bacteria.

10.1 5/5/5/6/5-Membered Ring System

A genome-based approach generated quiannulatene (140), with a 5/5/5/6/5-membered ring system (Fig. 101) [128]. The gene responsible for the production of 140 was found from the genomic data of the fungus Emericella variecolor NBRC 32302. Notably, the 5/5/5/6/5-membered ring system of 140 is different from those of 134–137 (Figs. 97 and 98). It is proposed that 140 is generated by the deprotonation of the intermediate A in Fig. 100. The detailed cyclization mechanism leading to the formation of 140 has been investigated by both computational approaches [129, 130] and isotope labeling experiments [128]. From the plant Arabidopsis thaliana, a gene for the biosynthesis of ent-140 has also been found [131]. In addition, from the plant Brassica oleracea, a gene for the production of boleracene (141) has been identified (Fig. 101) [131]. The stereochemistry of 141 is different from those of 140 and ent-140.

Fig. 101

Structures of quiannulatene (140), ent-140, and boleracene (141), and formation of 140. The formation of intermediate A is shown in Fig. 100

10.2 5/8/6/5-Membered Ring System

Compound Bm2 (142) [132] and sesterfisherol (143), with a 5/8/6/5-membered ring system, were also discovered by the genome-based approach (Fig. 102) [133, 134]. The genes responsible for the production of 142 and 143 were found in the genomes of the fungi Bipolaris maydis ATCC48331 and Neosartorya fischeri, respectively. In fact, 123 and 124, which were mentioned in Sect. 7.1.3, also possess similar 5/8/6/5-membered ring systems (Figs. 89 and 102). However, the stereochemistry and positions of the double bonds of 142, 143, 123, and 124 are different from each other. A possible cyclization reaction starting from geranylfarnesyl diphosphate (8) leading to the formation of 142 and 143 is shown in Fig. 103.

Fig. 102

Structures of 142, 143, and 123 and 124

Fig. 103

Formation of 142 and 143

10.3 11/6/5-Membered Ring Systems

(+)-Thalianatriene (144), which is also known as (+)-arathanatriene, possesses an 11/6/5-membered ring system (Fig. 104) [131, 135]. The gene encoding the synthase of 144 has been identified in the Arabidopsis thaliana genome. In addition, a gene involved in the production of a related compound, caprutriene (145), has been found in the genome of the plant Capsella rubella [131].

Fig. 104

Structures of (+)-thalianatriene (144) and caprutriene (145)

In Sect. 6.1.3, two kinds of 11/6/5-membered ring systems were introduced. However, the 11/6/5-membered ring systems of 144 and 145 are different from the two known 11/6/5-membered ring systems. The formation of 144 and 145 from geranylfarnesyl diphosphate (8) starts from the generation of a 15/5-membered ring system (Fig. 105), while the formation of the other two 11/6/5-membered ring systems is initiated by the formation of the 11/5-membered ring system (Figs. 74 and 75).

Fig. 105

Formation of 144 and 145, and comparison with those of 110–112

10.4 6/6/7/5- and 6/11/5-Membered Ring Systems

A sesterterpene synthase, identified from the genetic data of the plant Capsella rubella, was found to produce (−)-caprudiene A (146), (−)-caprutriene B (147), and (+)-caprutriene C (148) (Fig. 106) [136]. Compound 146 possesses a 6/6/7/5-membered ring system, while 147 and 148 have 6/11/5-membered ring systems. In addition to 146–148, this enzyme also produces (+)-brassitetraene A (149) and (+)-brassitetraene B (150) with 15/5-membered ring systems. In fact, 149 and 150 are considered as intermediates of 146–148. Thus, after the formation of 149 and 150 starting from geranylfarnesyl diphosphate (8), a second round of cyclization, initiated by the protonation of 149 and 150, occurs to form 146–148. Other genes for the production of related sesterterpenoids with a 6/6/7/5-membered ring system have also been found in the genomes of the plants Arabidopsis thaliana and Brassica rapa [136].

Fig. 106

Structures and formation of 146–150

10.5 5/4/5- and 4/5/5-Membered Ring Systems

A terpene cyclase designated as “spata-13,17-diene synthase” was found in the marine bacterium Streptomyces xinghaiensis by the genome-based approach [137]. This enzyme has the potential to produce prenylspata-13,17-diene (151), geranylkelsoene (152), and other C₁₅ sesqui- and C₂₀ di-terpenoids. Compound 151 possesses a 5/4/5-membered ring system, while 152 has a 4/5/5-membered ring system (Fig. 107).

Fig. 107

Structures and formation of prenylspata-13,17-diene (151) and geranylkelsoene (152)

10.6 6/8/6/5-Membered Ring System

Astellifadiene (153) is a sesterterpenoid with a 6/8/6/5-membered ring system (Fig. 108) [138]. The formation of the 6/8/6/5-membered ring system from geranylfarnesyl diphosphate (8) requires two cyclization reactions. In the first cyclization, an 11/6/5-membered ring is generated, and then deprotonation finalizes the reaction. Next, protonation occurs to initiate the second round of cyclization, and the basic carbon skeleton of 153 is formed. The gene for the biosynthesis of 153 has been found in the genome of the fungus Emericella variecolor NBRC 32302.

Fig. 108

Structure and formation of astellifadiene (153)

10.7 5/12/5-Membered Ring System

Sesterbrasiliatriene (1) [9], betaestacin I (154) [132], and Bm1 (155) [132] have 5/12/5-membered ring systems (Fig. 109) and were found by the genome-based approach. The genes responsible for the production of 1, 154, and 155 are from the fungi Penicillium brasilianum NBRC 6234, Phoma betae PS-13, and Bipolaris maydis ATCC48331, respectively. Of these, 108 and 109 with 5/12/5-membered ring systems were isolated from Nature, as mentioned in Sect. 6.1.2. However, the configurations and positions of the double bonds of 1, 154, 155, 108, and 109 are different from each other.

Fig. 109

Structures of 1, 154, 155, 108, and 109. Compounds 1, 154, and 155 were discovered by a genome-based approach. Structures of 108 and 109 are also shown in Fig. 71

10.8 Genes for the Formation of a Linear Sesterterpenoid

Genes for the biosynthesis of linear sesterterpenoids have also been found. For example, a gene from the bacterium Bacillus clausii encodes an enzyme that can transform geranylfarnesyl diphosphate (8) into a linear sesterterpene, hydrocarbon β-geranylfarnesene (156) (Fig. 110) [139].

Fig. 110

Structure and formation of β-geranylfarnesene (156)

10.9 Genes Encoding a Membrane-Bound Sesterterpene Cyclase

The typical terpene cyclases, which catalyze type 1 terpene cyclization reactions, are soluble proteins. However, there are also membrane-bound terpene cyclases for type 1 cyclization reactions, and they are referred to as UbiA-type terpene cyclases. A gene encoding a UbiA-type terpene cyclase involved in the biosynthesis of sesterterpenoids has been found in the bacterium Streptomyces somaliensis [140]. This enzyme can convert geranylfarnesyl diphosphate (8) to somaliensenes A (157) and B (158) (Fig. 111).

Fig. 111

Structures and formation of somaliensenes A (157) and B (158)

10.10 A Sesterterpenoid Produced by an Artificially Engineered Enzyme

In many cases, fungal sesterterpene synthases (C₂₅) and diterpene synthases (C₂₀) exist as chimeric enzymes, composed of a terpene cyclase and a prenyltransferase [126, 127]. In other words, the terpene cyclase and the prenyltransferase are linked together (Fig. 112). The reactions catalyzed by these two enzymes are shown in Figs. 5–7. The fusion of these two enzymes is considered to provide a catalytic advantage, because the physical proximity of the active sites of the two enzymes can enhance product flux [141, 142]. Polyprenyl diphosphates 7 and 8, which are produced by the prenyltransferase, could be efficiently moved into the active site of the terpene cyclase if these enzymes are linked together, namely, exist near each other.

Fig. 112

Constitution of the fungal chimeric diterpene synthase and sesterterpene synthase. The chimeric terpene synthase consists of two domains. The C-terminal domain possesses the prenyltransferase activity, while the N-terminal domain exhibits the terpene cyclase activity

The prenyltransferase domain of the fungal diterpene synthase (C₂₀) might produce mainly the (C₂₀) polyprenyl diphosphate 7, while that of sesterterpene synthase might yield primarily the (C₂₅) version 8. Therefore, even when the terpene cyclase domain of a fungal diterpene cyclase has the potential to cyclize not only 7 but also 8, the major products of the enzyme should be diterpenes (C₂₀), because the prenyltransferase domain supplies principally (C₂₀) 7, not (C₂₅) 8, to the terpene cyclase domain.

Accordingly, a protein engineering experiment, in which the prenyltransferase domain of a fungal diterpene synthase is exchanged with that of a sesterterpene synthase, could enable the terpene cyclase domain of the diterpene synthase to produce sesterterpenoids, since the prenyltransferase domain of the sesterterpene synthases can supply a sufficient amount of 8.

A protein engineering experiment based on this hypothesis has been reported [143]. This study utilized a fungal diterpene cyclase, designated as EvVS. The wild-type EvVS produces only C₂₀ variediene (159). However, after its prenyltransferase domain was exchanged artificially with that of a sesterterpene synthase by genetic engineering, this enzyme produced a sesterterpene, (2E)-α-cericerene (160) (Figs. 113 and 114). A similar approach using a different fungal diterpene synthase has also been reported [144].

Fig. 113

Reaction catalyzed by the wild-type fungal diterpene synthase (EvVS), which produces 159. Since the prenyltransferase domain of this enzyme mainly produces 7, the terpene cyclase domain primarily accepts 7. Thus, only the cyclized diterpene 159 is produced by the wild-type EvVS

Fig. 114

Reaction catalyzed by the engineered EvVS. The prenyltransferase domain of EvVS was exchanged with that of a sesterterpene synthase. In the case of the engineered EvVS, 8 is primarily supplied to the terpene cyclase domain. Therefore, the terpene cyclase domain starts to accept 8 and produces the cyclized sesterterpene 160

10.11 Tailoring Enzymes for the Derivatization of Sesterterpenoids

In addition to the enzymes responsible for the formation of the basic carbon skeletons of the sesterterpenoids, modification enzymes, which can attach a functional group to these compounds, have been found by the genome-based approach. For example, from the fungus Talaromyces wortmannii ATCC 26942, a cytochrome P450, which can convert 131 to a new sesterterpenoid, asperterpenoid C (161), has been identified (Fig. 115) [145]. The cytochrome P450 catalyzes an oxidation reaction and attaches a hydroxy group to 131.

Fig. 115

Structure and formation of asperterpenoid C (161). The structure of 131 is also shown in Fig. 95

Another example refers to the tailoring enzymes for the derivatization of 154 [146]. Analyses revealed that three cytochrome P450s, from the fungi Phoma betae and Colletotrichum orbiculare, are involved in the conversion of 154 into the new sesterterpenoids 162–168 (Fig. 116).

Fig. 116

Structures and formation of 162–168. Reactions catalyzed by different enzymes are shown by arrows with different colors. The structure of 154 is also shown in Fig. 109

In addition, cytochrome P450s for the formation of new sesterterpenoids, quiannulatic acid (169) and sesterfisheric acid (170), have also been identified (Fig. 117) [128, 133].

Fig. 117

Structures and formation of 169 and 170. The structures of 140 and 143 are also shown in Figs. 101 and 102

10.12 Genes for the Biosynthesis of Known Sesterterpenoids or Their Precursors

The genome-based approach has also identified the genes involved in the biosynthesis of known sesterterpenoids. Herein, such examples are introduced. Importantly, in many cases, the genome-based approach enables the isolation of the biosynthetic precursors of the known sesterterpenoids, which have never been isolated from Nature.

10.12.1 Stellatic Acid

The gene for the production of stellata-2,6,19-triene (171) was found in the genome from the fungus Emericella variecolor NBRC 32302 (Fig. 118) [147]. In fact, 170 is a biosynthetic precursor of stellatic acid (112) and has not been reported from natural sources. Moreover, a cytochrome P450 for the conversion of 170 into 112 has also been identified from the same fungal strain.

Fig. 118

Structures of 171 and 112. The structure of 112 is also shown in Fig. 73

10.12.2 Ophiobolin F

A gene encoding a sesterterpene synthase for the production of ophiobolin F (95) has been found in the genome from the fungus Aspergillus clavatus (Figs. 66 and 112) [148]. Indeed, this enzyme is the first example of a sesterterpene synthase.

The gene for the biosynthesis of 95 has also been found in the genome from the fungus Aspergillus ustus 094102, and the genes responsible for the accumulation of 95 in this fungus have been investigated in detail [149, 150]. Based on this information, the production of 95 in Escherichia coli has been accomplished [151].

10.12.3 Mangicol A

The gene encoding a sesterterpene synthase for the production of mangicdiene (172) has been found in the genome from the fungus Fusarium graminearum J1-012 (Fig. 119) [152]. Compound 172 is considered to be a biosynthetic intermediate of mangicol A (125).

Fig. 119

Structures of 172 and 125. The structure of 125 is also shown in Fig. 90

10.12.4 Retigeranic Acid B

The gene for the biosynthesis of retigeranin B (173) has been found in the genome from the plant Arabidopsis thaliana (Fig. 120) [131, 135]. Compound 173 is considered to be a biosynthetic intermediate of retigeranic acid B (137).

Fig. 120

Structures of 173 and 137. The structure of 137 is also shown in Fig. 98

10.12.5 Astellatol

The gene for the production of astellatene (174) has been identified in the genome from the plant Arabidopsis thaliana (Fig. 121) [131]. Compound 174 might be a precursor of astellatol (133). Incidentally, the genes for the production of 174 (Fig. 121) and ent-140 (Fig. 101) reportedly play an important role in the root microbiota assembly of the plant [153]. This is one of the few examples of an investigation into the biological roles of sesterterpenoids.

Fig. 121

Structures of 174 and 133. The structure of 133 is also shown in Fig. 96

10.12.6 Terpestacin

Four genes for the biosynthesis of terpestacin (77) have been identified in the genome from the fungus Bipolaris maydis [132, 154]. One of the four genes encodes a sesterterpene synthase that produces 175. The other three genes encode oxidases, two cytochrome P450s, and a single flavin-dependent oxidase. These oxidases could convert 175 into 176, 177, 178, and 77 (Fig. 122).

Fig. 122

Structures and formation of 175–178, and 77. The structure of 77 is also shown in Fig. 53

11 Conclusions

This contribution provides an overview of the chemical structures of sesterterpenoids. Even though only relatively few sesterterpenoids are known, their structures are quite fascinating. In particular, the complexity of polycarbocyclic sesterterpenoids is quite high. There are many stereocenters in their structures, and their stereochemistry is well controlled during the cyclization reactions leading to the formation of their basic carbon skeletons. Moreover, many sesterterpenoids are known as bioactive compounds.

Considering that some sesterterpenoids with novel chemical structures have been reported very recently, we can look forward to many exciting discoveries of unknown sesterterpenoids in the near future. Therefore, the present authors believe that it is worthwhile maintaining a sharp focus on sesterterpenoid research.