Sources, Transformations, Syntheses, and Bioactivities of Monoterpene Pyridine Alkaloids and Cyclopenta[c]pyridine Derivatives

Monoterpene pyridine alkaloids (MTPAs) are alkaloids derived from iridoid glycosides (IGs). The common molecular structure of MTPAs is the pyridine ring, while some of them have a cyclopenta[c]pyridine skeleton. Some compounds containing this structure are potentially bioactive medicinal agents. In this paper, seven drug candidates (A–G), ninety natural source products (1–90), thirty-seven synthesized compounds (91–127), as well as twenty-six key intermediates (S1–S26) were summarized. We categorized five types of MTPAs and one type of cyclopenta[c]pyridine alkaloids in all. Additionally, their possible genetic pathways were proposed. Then, the chemical transformation, biotransformation, chemical synthesis, as well as the bioactivity of MTPAs and cyclopenta[c]pyridine derivatives were analyzed and summarized. Cyclopenta[c]pyridine derivatives can be concisely and chirally synthesized, and they have shown potentials with antibacterial, insecticidal, antiviral, anti-inflammatory, and neuropharmacological activities.


Introduction
The nitrogen atom in pyridines, which are prized scaffolds in medicinal chemistry, is critical to the pharmacological profile of many medications that contain this heterocycle [1]. All monoterpene pyridine alkaloids (MTPAs) have a pyridine structure, most of which possessed a cyclopenta[c]pyridine molecular skeleton. Monoterpenes, mostly iridoid glycosides (IGs), are presumed to be biological or chemical synthetic precursors of MTPAs [2]. IGs are a class of substances with a structure resembling iridodial (Schemes 1 and 2), a chemical frequently used by plants as a defensive component.
Alkaloids are nitrogenous heterocyclic metabolites characterized by their structural diversity and bioactivity. Alkaloids are fundamental in organic chemistry and synthetic drug discovery. The pyridine structure in MTPAs is a functional molecular backbone widely found in natural products and bioactive molecules. The cyclopenta[c]pyridine or pyridine structure is a key fragment in a large proportion of bioactive compounds. Compounds containing cycloalkane pyridine have been used as intermediates in the synthesis of alkaloids or precursors of bioactive agents [3] (Figure 1). Compound A is a highly selective and potent aldosterone synthase inhibitor with an IC 50 of 1 nM [4]. Ramelteon B's 4-aza counterpart is a strong melatonin receptor agonist [5]. Additionally, the naturally occurring alkaloid sinensine C has shown cytoprotective action that may be helpful [5]. Compound D exhibited FXIIa inhibitory activity with an IC 50 value in the range from 10 µM to 40 µM [6]. As a G-protein coupled receptor 40 (GPR40) agonist, compound

MTPAs and Their Activities
According to the different molecular skeletons and genetic pathways, we classified five types of transformation pathways from IGs to MTPAs. Five types were presented in Scheme 1: pyridine alkaloids derived from 4-demethyliridoids (Type I), pyridine alkaloids derived from iridoids (Type II), pyridine alkaloids derived from hemiacetal secoiridoids (Type III), pyridine alkaloids derived from secoiridoids (Type IV), and pyridines alkaloids derived from lactone secoiridoids (Type V). In addition, the phenyl-substituted cyclopenta[c]pyridine skeleton specifically existed in the genus Ganoderma (Type VI). In sum, Type I-V pyridine derivatives all originated from monoterpenoids. The Type I, II, and VI derivatives possessed the common cyclopenta[c]pyridine skeleton. Accordingly, this review has been organized in this manner. The category details in the following sections could help us obtain a clear picture of MTPAs and cyclopenta [c]pyridines, along with their origins, structures, sources, and bioactivities.
The ammonization and aromatization pathways from iridoids to pyridines were arranged and proposed (Scheme 2). Geraniol is an important precursor of MTPAs. Then, hydroxylation, oxidation and cyclization reactions on geraniol yield the intermediate iridoids [10]. Oxidation and hemiacetal formation lead to the production of the heterocyclic ring of iridoids [10]. Further ammonization and oxidation could provide the pyridine ring as follows (Scheme 2). At the beginning, secoiridoids are ammonified and dehydrated to afford enamines. Subsequently, nucleophilic addition/aromatization reactions of enamines could yield the pyridine ring.  Table 1, Type I) 4-Demethypyridine alkaloids, processing the 8-methylcyclopenta[c]pyridine skeleton, are derived from iridoid through the oxidation of 4-methyl, decarboxylation of 4carboxyl, ammonization, and aromatization (Scheme 1, Type I). In this section, nineteen 4-demethypyridine derivatives from plants are described, including three dimers (17)(18)(19).
Scrophularianine A (1), B (2), and C (3) were extracted and isolated from Scrophularia ningpoensis without using acids, bases, or nitrogen-containing salts [10]. In this case, these monoterpene alkaloids were thought to be natural MTPAs. MTPAs are mainly structurally related to iridoid compounds with the oxygen heterocycle being replaced by the pyridine ring. Plumerianine (4) was isolated from Plumeria acutifolia (Apocynaceae), using aqueous ammonia for alkaloid extraction. The iridoid glycosides from P. acutifolia were unsaturated at C-6 and C-7, while plumerianine was saturated at C-6 and C-7. Therefore, the author believed that plumerianine (4) was not an artifact from iridoid glycosides, but rather a natural product [11] .
Previously, lysine and quinolinic acid were thought to be the biosynthesis precursors of actinidine [19] . Here, we believe that IGs are more likely to be the precursors of actinidine, which are similar to that of monoterpene indole alkaloids [20] .
Previously, lysine and quinolinic acid were thought to be the biosynthesis precursors of actinidine [19]. Here, we believe that IGs are more likely to be the precursors of actinidine, which are similar to that of monoterpene indole alkaloids [20].

Pyridine Alkaloids Derived from Hemiacetal Secoiridoids (Figure 4, Table 3, Type III)
In this section, five pyridine compounds 42-46 derived from the hemiacetal secoiridoid were described with the pyrano-pyridine ring. Compounds 42-44 and 46 were isolated from plants, while compound 45 was obtained through microbial transformation of an IG substrate.

Number
Compound Name Source Reference

Pyridine Alkaloids Derived from Secoiridoids (Figure 5, Table 4, Type IV)
In this class, pyridines were directly derived from secoiridoid through ammonization and aromatization as chemical transformations. There were five monomers and four dimers.

Pyridine Alkaloids Derived from Secoiridoids (Figure 5, Table 4, Type IV)
In this class, pyridines were directly derived from secoiridoid through ammonization and aromatization as chemical transformations. There were five monomers and four dimers.

Pyridine Alkaloids Derived from Secoiridoids (Figure 5, Table 4, Type IV)
In this class, pyridines were directly derived from secoiridoid through ammonization and aromatization as chemical transformations. There were five monomers and four dimers.
Five alkaloids, sinensine A-E (72-76), were deduced from the fruiting bodies of Ganoderma sinense Zhao, Xu et Zhang, which is a traditional Chinese medicine [40,41]. With a protection rate of 70.90% and an EC 50 value of 6.23 µmol/L, Sinensine A (72) exhibits activity in preventing the damage caused by hydrogen peroxide oxidation on human umbilical cord endothelial cells (HUVEC) [41].

Generation of MTPAs and Their Activities
Based on the available reports of MTPAs and cyclopenta[c]pyridines, these alkaloids have the five following origins: Firstly, these natural products are obtained without using nitrogen containing chemicals (concentrated ammonia, ammonium salts, etc.) in the extraction and separation process [
In this paper, we summarized the chemical transformation, biotransformation, chemical synthesis, and bioactivities of the MTPAs and cyclopenta[c]pyridines. This could help us obtain a clear view of the chemistry and biology of MTPAs and cyclopenta[c]pyridines.

MTPAs Yielded by Chemical Transformation of IGs
Both (±)-27 and (±)-28 were supposed to be derived from 8-O-acetylharpagide, which is found in great quantities in the plant C. glutinosa. Naturally or in the presence of ammonia, 8-O-acetylharpagide may be converted to MTPAs (Scheme 3, intermediates: S1-S3, 9, and S4). The key step in their formation might be the Diels-Alder reaction of intermediates S3 and S4 to afford (±)-28 (exo type) and (±)-27 (endo type).
Penstemonoside was chemically converted to rhexifoline (34), which is shown in Scheme 5F. [23] At the same time, compound 34 was isolated from a hybrid species of Castilleja rbexifolia and Castilleja miniate by the same author, although aqueous ammonia was used in the extraction process [22] .
It was found that pterocenoids A (Scheme 7, 89) and two other iridoid dimers from Pterocephalus hookeri exhibited moderate inhibitory activity in the NF-кB pathway. This was also consistent with the application of their botanical source, which is used to treat inflammatory disease in Tibetan herbal medicine. Therefore, it was supposed that such iridoid dimers were effective anti-inflammatory components [48] .  (40), accompanied by ammonium acetate or NH 3 (g)/HCl (g) (Scheme 5A-E) [27]. The biogenic synthetic pathways of compound 40 are speculated upon in Scheme 6 [27], while the electron transfer of intermediate S10 is lightly revised, differing from the original article.
Penstemonoside was chemically converted to rhexifoline (34), which is shown in Scheme 5F. [23] At the same time, compound 34 was isolated from a hybrid species of Castilleja rbexifolia and Castilleja miniate by the same author, although aqueous ammonia was used in the extraction process [22].
It was found that pterocenoids A (Scheme 7, 89) and two other iridoid dimers from Pterocephalus hookeri exhibited moderate inhibitory activity in the NF-κB pathway. This was also consistent with the application of their botanical source, which is used to treat inflammatory disease in Tibetan herbal medicine. Therefore, it was supposed that such iridoid dimers were effective anti-inflammatory components [48].

MTPAs Generated from the Biotransformation of IGs
It has been reported that iridoid glycosides could be converted into MTPAs by fungi or human intestinal bacteria. Therefore, some researchers argued that the activities and potency of iridoid glycosides are attributed to their conversion to MPTAs [55] .
As mentioned previously, Aspergillus niger could convert swertiamarin to naphthyridine (57, Scheme 8). In another case, the asexual mycelium of the fungus Cordyceps sinensis was able to convert gentiopicroside into compound 57 as well (Scheme 8) [19].
In summary, both the chemical transformations and biotransformation of MTPAs form cyclopenta[c]pyridines molecular skeleton after amination of iridoids. Therefore, it is reasonable to speculate that MTPAs could be biosynthesized in a similar way by living organisms.

MTPAs Generated from the Biotransformation of IGs
It has been reported that iridoid glycosides could be converted into MTPAs by fungi or human intestinal bacteria. Therefore, some researchers argued that the activities and potency of iridoid glycosides are attributed to their conversion to MPTAs [55].
As mentioned previously, Aspergillus niger could convert swertiamarin to naphthyridine (57, Scheme 8). In another case, the asexual mycelium of the fungus Cordyceps sinensis was able to convert gentiopicroside into compound 57 as well (Scheme 8) [19].

MTPAs Generated from the Biotransformation of IGs
It has been reported that iridoid glycosides could be converted into MTPAs by fungi or human intestinal bacteria. Therefore, some researchers argued that the activities and potency of iridoid glycosides are attributed to their conversion to MPTAs [55] .
As mentioned previously, Aspergillus niger could convert swertiamarin to naphthyridine (57, Scheme 8). In another case, the asexual mycelium of the fungus Cordyceps sinensis was able to convert gentiopicroside into compound 57 as well (Scheme 8) [19].
In summary, both the chemical transformations and biotransformation of MTPAs form cyclopenta[c]pyridines molecular skeleton after amination of iridoids. Therefore, it is reasonable to speculate that MTPAs could be biosynthesized in a similar way by living organisms. Harpagide, harpagoside, or 8-O-p-coumaroylharpagide could be transformed to aucubinine B (5) by human intestinal bacteria (Scheme 9A) [54]. It was reported that aucubin can be converted to aucubinines A (90, Type I) and B (5) by human intestinal bacteria [57], as shown in Scheme 9B.

Chemical Synthesis of MPTAs/Cyclopenta[c]pyridines
In recent years, there have been many preeminent works on the total synthesis of MPTAs, and most of them employed one-step reaction to synthesize the target compounds. The early synthesis products were racemic, which was not reported in this paper. Additionally, all of the recent reports were chiral synthesis works, and are described in chronological order as follows.
In 2019, a straightforward tandem method for synthesizing pyridine derivatives in the absence of metals was described, and the chiral synthesis of (−)-actinidine (29) was finished in a single step (Scheme 10) [59] . Scheme 10. One-step synthesis of the monoterpene natural product, (−)-actinidine (29).
An efficient and economical two-step synthesis of the cyclopenta[c]pyridines was reported, using an iridoid (genipin) as the substrate [2] , as shown in Scheme 11. Additionally, the possible reaction mechanism was proposed, such as an aldol reaction. Compounds 91-112 were afforded in this way.
The insecticidal activities of the synthesized cyclopenta[c]pyridines 91-112 were also evaluated. Among those compounds, only compound 112 [2-(2-chloro-4-(trifluoromethoxy) phenyl)] exhibited activity against Plutella xylostella comparable to that of cerbinal, which was the natural precursor with an oxygen atom at the 2-position without modification. In view of this, the modification of the cyclopenta[c]pyridine skeleton at the 2position significantly increased the anti-TMV activity but was not beneficial for insecticidal activity [2] . In summary, both the chemical transformations and biotransformation of MTPAs form cyclopenta[c]pyridines molecular skeleton after amination of iridoids. Therefore, it is reasonable to speculate that MTPAs could be biosynthesized in a similar way by living organisms.

Chemical Synthesis of MPTAs/Cyclopenta[c]pyridines
In recent years, there have been many preeminent works on the total synthesis of MPTAs, and most of them employed one-step reaction to synthesize the target compounds. The early synthesis products were racemic, which was not reported in this paper. Additionally, all of the recent reports were chiral synthesis works, and are described in chronological order as follows.
In 2019, a straightforward tandem method for synthesizing pyridine derivatives in the absence of metals was described, and the chiral synthesis of (−)-actinidine (29) was finished in a single step (Scheme 10) [59].

Chemical Synthesis of MPTAs/Cyclopenta[c]pyridines
In recent years, there have been many preeminent works on the total synthesis of MPTAs, and most of them employed one-step reaction to synthesize the target compounds. The early synthesis products were racemic, which was not reported in this paper. Additionally, all of the recent reports were chiral synthesis works, and are described in chronological order as follows.
In 2019, a straightforward tandem method for synthesizing pyridine derivatives in the absence of metals was described, and the chiral synthesis of (−)-actinidine (29) was finished in a single step (Scheme 10) [59] . An efficient and economical two-step synthesis of the cyclopenta[c]pyridines was reported, using an iridoid (genipin) as the substrate [2] , as shown in Scheme 11. Additionally, the possible reaction mechanism was proposed, such as an aldol reaction. Compounds 91-112 were afforded in this way.
The insecticidal activities of the synthesized cyclopenta[c]pyridines 91-112 were also evaluated. Among those compounds, only compound 112 [2-(2-chloro-4-(trifluoromethoxy) phenyl)] exhibited activity against Plutella xylostella comparable to that of cerbinal, which was the natural precursor with an oxygen atom at the 2-position without modification. In view of this, the modification of the cyclopenta[c]pyridine skeleton at the 2position significantly increased the anti-TMV activity but was not beneficial for insecticidal activity [2] . An efficient and economical two-step synthesis of the cyclopenta[c]pyridines was reported, using an iridoid (genipin) as the substrate [2], as shown in Scheme 11. Additionally, the possible reaction mechanism was proposed, such as an aldol reaction. Compounds 91-112 were afforded in this way. The molecular skeleton of cyclopenta[c]pyridines was constructed in a one-step reaction between 1,4-dibromo-1,3-butadienes and 2,5-disubstituted pyrroles, using one-carbon expansion of the pyrrole skeleton to pyridine (Scheme 12) [60] . Additionally, the reaction used Pd(OAc)2 (10%) and cyclopentadiene-phosphine (L1) as the catalysts. Cyclopenta[c]pyridine compounds 113-115 were afforded.
The Kondrat'eva reaction was used to prepare annulated pyridines directly in a flow device [4,5] . However, the reaction conditions of high temperature and pressure were needed, as depicted in Scheme 13. Cyclopenta[c]pyridine compounds 116-126 were yielded.
A divergent retrosynthetic analysis strategy (Scheme 14) was used to synthesize a series of iridoid derivatives, including actinidine (4) [61] .  Figure 8). All the compounds were non-toxic against Nicotiana tabacum L. In subsequent anti-TMV activity tests, most of 91-112 showed good activities. Compound 109 [2-(4-methoxyphenyl)] had optimal anti-TMV activity with an inactivation effect of 40.2 ± 4.5%, a curative effect of 44.9 ± 4.0%, and a protection effect of 39.6 ± 2.3% at 500 µg/mL [2].  The insecticidal activities of the synthesized cyclopenta[c]pyridines 91-112 were also evaluated. Among those compounds, only compound 112 [2-(2-chloro-4-(trifluoromethoxy) phenyl)] exhibited activity against Plutella xylostella comparable to that of cerbinal, which was the natural precursor with an oxygen atom at the 2-position without modification. In view of this, the modification of the cyclopenta[c]pyridine skeleton at the 2-position significantly increased the anti-TMV activity but was not beneficial for insecticidal activity [2].

Conclusions
In total, we categorized six types of MTPAs and cyclopenta[c]pyridines by their origins and structures. MTPAs 1-58 and 75-90 originated from iridoids as natural, chemically transformed, enzyme catalyzed, or microbial transformed products. Phenyl-substituted cyclopenta[c]pyridine derivatives 59-84 were characteristic constituents in the genus Ganoderma and were proposed to be biosynthesized via meroterpenoid and threonine. To date, cyclopenta[c]pyridine compounds 4, 20, 29, and 91-127 have been concisely and chirally synthesized. The synthetic methods were concise, green, and productive. Additionally, MPTAs or cyclopenta[c]pyridines have shown potential with antibacterial, insecticidal, antiviral, and anti-inflammatory activities, as reported. It has been suggested that some of the iridoids were activated because of their transformations into MTPAs after ingestion. This was supported by the conversion of iridoids to MTPAs by intestinal microorganisms [55] . Meanwhile, iridoids are widely distributed and abundant in plants.
We believe that this paper will contribute to the further investigation of MTPAs and cyclopenta[c]pyridines regarding their origin, synthesis, and bioactivities. Therefore, further investigations of the chemistry and biology of MTPAs and cyclopenta[c]pyridines are expected.
Author Contributions: Conceptualization, F.T., C.W. and W.P.; investigation, X.Z., T.C. and L.T.; resources, Z.Z. and Y.H.; data curation, X.Z.; writing-original draft preparation, X.Z. and T.C.; writing-review and editing, X.Z. and T.C.; visualization, X.Z.; supervision, F.T. and C.L. All authors have read and agreed to the published version of the manuscript. To sum up, the total synthesis of the molecular skeleton of MTPAs and cyclopenta[c] pyridines is becoming increasingly concise, efficient, economical, and green.

Conclusions
In total, we categorized six types of MTPAs and cyclopenta[c]pyridines by their origins and structures. MTPAs 1-58 and 75-90 originated from iridoids as natural, chemically transformed, enzyme catalyzed, or microbial transformed products. Phenyl-substituted cyclopenta[c]pyridine derivatives 59-84 were characteristic constituents in the genus Ganoderma and were proposed to be biosynthesized via meroterpenoid and threonine. To date, cyclopenta[c]pyridine compounds 4, 20, 29, and 91-127 have been concisely and chirally synthesized. The synthetic methods were concise, green, and productive. Additionally, MPTAs or cyclopenta[c]pyridines have shown potential with antibacterial, insecticidal, antiviral, and anti-inflammatory activities, as reported. It has been suggested that some of the iridoids were activated because of their transformations into MTPAs after ingestion. This was supported by the conversion of iridoids to MTPAs by intestinal microorganisms [55]. Meanwhile, iridoids are widely distributed and abundant in plants.
We believe that this paper will contribute to the further investigation of MTPAs and cyclopenta[c]pyridines regarding their origin, synthesis, and bioactivities. Therefore, further investigations of the chemistry and biology of MTPAs and cyclopenta[c]pyridines are expected.