A Comprehensive Review of the Classification, Sources, Phytochemistry, and Pharmacology of Norditerpenes

Norditerpenes are considered to be a common and widely studied class of bioactive compounds in plants, exhibiting a wide array of complex and diverse structural types and originating from various sources. Based on the number of carbons, norditerpenes can be categorized into C19, C18, C17, and C16 compounds. Up to now, 557 norditerpenes and their derivatives have been found in studies published between 2010 and 2023, distributed in 51 families and 132 species, with the largest number in Lamiaceae, Euphorbiaceae, and Cephalotaxaceae. These norditerpenes display versatile biological activities, including anti-tumor, anti-inflammatory, antimicrobial, and antioxidant properties, as well as inhibitory effects against HIV and α-glucosidase, and can be considered as an important source of treatment for a variety of diseases that had a high commercial value. This review provides a comprehensive summary of the plant sources, chemical structures, and biological activities of norditerpenes derived from natural sources, serving as a valuable reference for further research development and application in this field.


Introduction
Diterpenes are natural terpenes composed of twenty carbon atoms in their molecules and are formed by the polymerization of four isoprene units.They are widely distributed in plants, particularly in plant-secreted milk and resin.In addition to plants, diterpenes can also be found in fungal metabolites and marine organisms.Generally consisting of 20 carbons, diterpenes can give rise to norditerpenes with fewer carbon atoms due to the absence of one to three carbon atoms within the diterpene core structure.C19 norditerpenes, which lack one carbon atom, represent the most common structural type among norditerpenes.Natural sources of norditerpenes exhibit diverse pharmacological activities including antiinflammatory, anti-tumor, and antimicrobial effects.Therefore, extensive attention has been drawn toward research on norditerpenes.Norditerpene alkaloids are a class of norditerpenes.Yong Shen and coworkers reviewed 337 naturally occurring diterpene alkaloids, including 251 norditerpene alkaloids, derived from studies published between 2008 and 2018 [1].To avoid the duplication of previous work, this article reviews the structural types and biological activities of norditerpenes (norditerpene alkaloids are not included) derived from studies published between 2010 and 2023.In general, 557 norditerpenes and their derivatives were found in the natural world, distributed into 132 species and 51 families (Table 1).This provides the basis for further research on the discovery of natural product drugs.
Table 1.Sources of 557 norditerpenes (families, genera, and species and the corresponding quantity of the compounds).

Labdane
Labdane norditerpenes are commonly found as bicyclic diterpenes, with a transfused A/B ring in the nuclear parent and a side chain typically consisting of a six-carbon open chain.The presence of hydroxyl groups on the side chain allows for easy dehydration and condensation reactions, leading to the formation of a five-membered ring.Labdane-type diterpenes with both an open-chain structure and a five-membered ring in the side chain have a wide distribution (Table 2, Figure 2).

Labdane
Labdane norditerpenes are commonly found as bicyclic diterpenes, with a trans-fused A/B ring in the nuclear parent and a side chain typically consisting of a six-carbon open chain.The presence of hydroxyl groups on the side chain allows for easy dehydration and condensation reactions, leading to the formation of a five-membered ring.Labdane-type diterpenes with both an open-chain structure and a five-membered ring in the side chain have a wide distribution (Table 2, Figure 2).

Clerodane
Clerodane norditerpenes consist of a fused-ring decalin moiety (C1-C10) and a sixcarbon side chain at C-9.Based on the A/B ring junction configuration and the substituents on C-8 and C-9, its skeletons can be classified into four types (Figure 3).
Compound 29 is characterized by a double bond between carbon atoms C-3 and C-4.Compounds 30-31 have a fused tricyclic ring system with a 6/6/6 configuration.Compound 32 belongs to the bioactive clerodane class of 19-nor-diterpenes, featuring a cyclohexenone decalin ring.Compound 33 is a dehydrogenated derivative of compound 34, resulting in the removal of hydrogen atoms from positions C11-C12.Compounds 35-37

Clerodane
Clerodane norditerpenes consist of a fused-ring decalin moiety (C 1 -C 10 ) and a six-carbon side chain at C-9.Based on the A/B ring junction configuration and the substituents on C-8 and C-9, its skeletons can be classified into four types (Figure 3).3, Figure 4).3, Figure 4).

Pimarane
Pimarane norditerpenes are tricyclic diterpenes and are widely distributed in nature.Pimarane norditerpenes are mainly divided into four types (Figure 5): pimarane, isopimarane, ent-pimarane, and ent-isopimarane.Isopimarane norditerpenes are a class of compounds classified by pimarane norditerpenes according to the difference of chiral centers in the molecule, and they are also the largest number of pimarane norditerpenes (Table 4, Figure 6).

Pimarane
Pimarane norditerpenes are tricyclic diterpenes and are widely distributed in nature.Pimarane norditerpenes are mainly divided into four types (Figure 5): pimarane, isopimarane, ent-pimarane, and ent-isopimarane.Isopimarane norditerpenes are a class of compounds classified by pimarane norditerpenes according to the difference of chiral centers in the molecule, and they are also the largest number of pimarane norditerpenes (Table 4, Figure 6).

Pimarane
Pimarane norditerpenes are tricyclic diterpenes and are widely distributed in nature.Pimarane norditerpenes are mainly divided into four types (Figure 5): pimarane, isopimarane, ent-pimarane, and ent-isopimarane.Isopimarane norditerpenes are a class of compounds classified by pimarane norditerpenes according to the difference of chiral centers in the molecule, and they are also the largest number of pimarane norditerpenes (Table 4, Figure 6).

Abietane
Abietane norditerpenes are tricyclic diterpenes commonly formed through rearrangements of pimarane norditerpenes.The core structure consists of a hydrogenated phenanthrene with an isopropyl group at C-13, geminal dimethyl groups at C-4, and a methyl group at C-20.Ring B and the side chains on the C ring can easily undergo rearrangement to form a five-membered ring, with some quinone structures also found on the C ring.Abietane norditerpenes are primarily classified into abietane type, ent-abietane type, and seco-abietane type (in Table 5, Figure 7).

Kaurane
Kaurane norditerpenes represent a class of tetracyclic diterpenes characterized by the hydrophenanthrene core skeleton.These compounds can be classified into two configurations, namely kaurane and ent-kaurane.It is worth noting that the ent-kaurane-type norditerpenes exhibit remarkable abundance (Table 6, Figure 8).

Cembranoid
Cembranoid-type norditerpenes are macrocyclic diterpenes that belong to a class of natural products characterized by fourteen-membered rings and possess three symmetrically distributed methyl groups and one isopropyl group.Isopropyl-cembrane-type norditerpenes, primarily formed through isopropyl or isopropenyl substitution, represent the most common cembrane-type norditerpenes (Table 8, Figure 10).

Abietane
Compound 365 is a new abietane type and has been reported as a 20-acetyl derivative of 15,16-dinorpymara-8,11,13-trien-12-ol, known as salyunnanin F. Compound 368 is a diastereomer of 367.Compounds 370-375 exhibit an ether bridge between C-18 and C-6 or C-7.Compounds 378-388 are dinorditerpenes derived from an abietane-type skeleton with a seven-membered ring in the tricyclic skeleton.Compound 387 is a unique C18 norditerpene bearing a special seco-ring C. Compounds 389-397 belong to a special class of tetracyclic abietane-type dinorditerpenes.The stem bark of Trigonostemon chinensis yielded two novel dimeric degraded diterpenes, compounds 398-399, featuring a homodimeric biaryl skeleton derived from the rearrangement of chiral nonracemic abietane-type norditerpenes.This structural motif is connected through an axially chiral biaryl 11,11′linkage.

Abietane
Compound 365 is a new abietane type and has been reported as a 20-acetyl derivative of 15,16-dinorpymara-8,11,13-trien-12-ol, known as salyunnanin F. Compound 368 is a diastereomer of 367.Compounds 370-375 exhibit an ether bridge between C-18 and C-6 or C-7.Compounds 378-388 are dinorditerpenes derived from an abietane-type skeleton with a seven-membered ring in the tricyclic skeleton.Compound 387 is a unique C18 norditerpene bearing a special seco-ring C. Compounds 389-397 belong to a special class of tetracyclic abietane-type dinorditerpenes.The stem bark of Trigonostemon chinensis yielded two novel dimeric degraded diterpenes, compounds 398-399, featuring a homodimeric biaryl skeleton derived from the rearrangement of chiral nonracemic abietane-type norditerpenes.This structural motif is connected through an axially chiral biaryl 11,11 -linkage.

Other Compounds
Compound 429 is an oxidized derivative of the common C20 labdane precursor and is identified as a 15,16-dinor labdane diterpene.Compounds 430-435 are determined to be 14,15-bisnor labdane diterpenes.Compounds 436-437 present the 6,7-dinorlabdane diterpenes with a peroxide bridge.Compound 438 is a special norditerpene glucoside and is defined as lyonivaloside I.

Chemical Constituents of C17 Norditerpenes
Seven major types of C17 norditerpenes have been reported in nature: the labdane type, abietane type, podocarpane type, briarane type, cassane type, cembrane type, and kaurane type.Additionally, there are other trinorditerpenes with special structures and some podocarpane dimers in nature (Table 11, Figure 13).

Abietane
Compounds 470-477 are 15,16,17-bis-norditerpenes.Compound 479 is the 16-OH derivative of 478.Compound 480 represents a rare skeleton of a 20-nor-abietane.Compound 482 is defined as the C-7 epimer of compound 485, while compounds 484-486 are aromatic tetranuclear terpenoids with unprecedented carbon skeletons from S. digitaloides.Compounds 487-488 possess a unique γ-lactone subunit moiety positioned between C-8 and C-20, leading to the generation of the carbonyl carbon at C-13 through the degradation of the isopropyl group.

Chemical Constituents of C16 Norditerpenes
Four main types of C16 norditerpenes have been found in nature: the labdane type, clerodane type, xeniaphyllane type, and abietane type.In addition to the common four types, there are also other norditerpenoids with unique structures and some dimers in nature sources (Table 12, Figure 14).

Labdane
C16-labdane norditerpenes are common bicyclic diterpenes with four fewer carbon atoms.Compounds 522-525 are known as bicyclic norditerpenoids.Compound 525 is the first to be reported in nature.Compound 526 is a rare rearranged labdane-type tetranorditerpenoid with a fused tricarbocyclic system (6/6/5) and an α,β-unsaturated cyclopentenone unit in ring C. Compounds 527 and 528 represent a pair of new labdanetype tetranorditerpenoid epimers, which are the first known examples of naturally derived labdane tetranorditerpenoids. Compounds 531-541 are a series of tetracyclic tetranorlabdane diterpenoids.

Others
Compounds 542-543 exhibit clerodane-type tetranorditerpenoids. Compound 544 is a novel abietane tetranorditerpenoid, known as castanol C. Compound 545 possesses an unprecedented carbon skeleton derived from xeniaphyllane.Compound 546 is a newly reported tetranorditerpenoid featuring a special fused ring system of 6/6/5.Compound 547 is a new C16 tetranorditerpenoid lactone with an uncommon tetracyclic fuse system

Labdane
C16-labdane norditerpenes are common bicyclic diterpenes with four fewer carbon atoms.Compounds 522-525 are known as bicyclic norditerpenoids.Compound 525 is the first to be reported in nature.Compound 526 is a rare rearranged labdane-type tetranorditerpenoid with a fused tricarbocyclic system (6/6/5) and an α,β-unsaturated cyclopentenone unit in ring C. Compounds 527 and 528 represent a pair of new labdane-type tetranorditerpenoid epimers, which are the first known examples of naturally derived labdane tetranorditerpenoids. Compounds 531-541 are a series of tetracyclic tetranorlabdane diterpenoids.

Pharmacological Activities
Norditerpene, a substance of profound pharmacological significance, manifests diverse primary pharmacological effects and biological activities encompassing cytotoxicity, antiinflammatory activity, and antibacterial and antiviral actions, as well as antioxidant potential.
Compound 208, obtained from the twigs and leaves of C. fortune, dose-dependently inhibited TNF-α-induced NF-κB activation with an IC 50 value of 0.10 µM, which was similar to the inhibitory effect of the positive control MG132 (a proteasome inhibitor, IC 50 = 0.15 µM).These results suggest that the tropone moiety is important for the cytotoxicity and the inhibition of NF-κB signaling [78].
Compounds 493 and 508 exhibited potent inhibitory effects on LPS-stimulated NO releases and pro-inflammatory mediators, with IC 50 values of 4.9 and 12.60 µM, respectively, by suppressing iNOS and COX-2 expressions to prevent NO production [139].13-episcabrolide C (263) inhibited the production of IL-12 and IL-6 in LPS-stimulated BMDCs (bone marrow-derived cells, IC 50 = 5.30 ± 0.21 and 13.12 ± 0.64 µM, respectively).This suggests that the C-13 methoxyl moiety may play an important role in anti-inflammatory activity [82].Scrodentoids H,I (307-308) exert anti-inflammatory effects by reducing LPS-induced inflammation and inhibiting the JNK/STAT3 pathway in macrophages.STAT proteins play a pivotal role in modulating cytokine-mediated inflammatory responses, and STAT3 is highly correlated with inflammatory responses.In response to inflammatory stimuli, STAT3 acts as a transcription factor that directly governs the expression of pro-inflammatory cytokines.Scrodentoids H and I might be beneficial in the treatment of inflammatory diseases, like ulcerative colitis and atherosclerotic diseases [105].
Sinusiaetone A (316) from S. siaesensis exhibited significant inhibition against LPSinduced inflammation in BV-2 microglia at a concentration of 20 µM and also decreased the mRNA levels of pro-inflammatory cytokines IL-6 and IL-1β [109].

Antioxidative Activity
Compound 82 showed antioxidant activity comparable to α-tocopherol, exhibiting an IC 50 value of approximately 0.6 mg/mL for DPPH scavenging activity, and it can serve as a natural alternative to synthetic antioxidants [30].
The radical quenching analysis revealed that compound 279 exhibited a higher antioxidant activity (IC 50 value of 0.60 mg/mL) compared to α-tocopherol.This suggests the potential of compound 279 as a natural antioxidant in future applications, attributed to its low hydrophobicity and spatial variability [89].

Cell Proliferation Activity
Compounds 100, 477, and 473 exhibited inhibitory effects on concanavalin A-induced T cell proliferation (IC 50 = 13.6,1.66, and 2.09 µM, respectively), as well as lipopolysaccharideinduced B cell proliferation (IC 50 = 22.4,1.37, and 3.31 µM, respectively), without exhibiting any obvious cytotoxicity to T cells and B cells [37,146].Compounds 258 and 261 showed strong inhibitory activities against Con A-induced T lymphocyte proliferation, with IC 50 values of 23.7 and 8.69 µM, respectively.The remarkable enhancement in activity can be attributed to the configurational inversion at C-5 in compound 261 [81].
Compound 515 has been confirmed to promote the proliferation and differentiation of umbilical cord-derived mesenchymal stem cells into keratinocyte-like cells at a concentration of 10 µM [158].[23].Compounds 95-97 showed potent biological activities against some marine organisms.Compound 97 was highly toxic to A. salina, with an LC 50 value of 6.36 µM.Moreover, compound 96 displayed significant toxicity toward C. marina and H. akashiwo (LC 50 = 0.81 and 2.88 µM, respectively), while compound 95 exhibited higher effectiveness against Alexandrium sp., with an LC 50 value of 8.73 µM [36].Compounds 143 and 152-154 selectively inhibited BChE, with IC 50 values of 2.4, 7.9, 50.8, and 0.9 µM, respectively.Moreover, compounds 143 and 154 moderately inhibited AChE, with IC 50 values of 329.8 µM and 342.9 µM, respectively [54].Compounds 249-252 effectively inhibited Th17 differentiation, exhibiting IC 50 values ranging from 2 to 18.07 µM.Compounds 250-251 were more effective than the positive control digoxin, which is a classical inhibitor of Th17 differentiation [80].Compound 364 inhibited the acetyl transfer activity of M. tuberculosis GlmU, with an IC 50 value of 41.85 µM, representing a novel therapeutic target for tuberculosis [120].Compound 371 can significantly inhibit the formation of macrophage foam cells induced by oxidized low-density lipoprotein, suggesting its potential as a protective agent against atherosclerosis [134].Compounds 454-456 displayed antifobrotic activities on TGF-β1induced rat renal proximal tubular cells, effectively attenuating the excessive production of collagen I and α-SMA [141].Compound 505 exhibited inhibitory activities against PTP1B and was a moderate time-dependent inactivator of PTP1B, with k i value of 0.11 M −1 s −1 [6].

Other Activities
Compound 539 exhibited a mortality rate of 30% in P. redivivus and 28% in C. elegans within a 24 h period at a concentration of 400 mg/L, whereas the control group (5% acetone) only resulted in a mortality rate of 1.5% during the same time frame [161].The anti-AD activity of compound 547 was comparatively weaker than memantine (p < 0.05), and it can be regarded as an anti-AD compound candidate [170].
Most norditerpenes exhibited anti-tumor, anti-inflammatory, anti-bacterial, and antioxidant properties, as well as inhibitory effects against HIV and α-glucosidase.Recent research suggests that norditerpenes may be a possibility for the future development of anti-tumor drugs.For example, euphorane C (139) inhibited the proliferation of K562 cells (IC 50 = 3.59 µM) and provided the possibility for developing anti-leukemia drugs.Cephinoid H (208) isolated from C. fortunei showed the strongest cytotoxic activities, with IC 50 values of 0.10, 0.13, and 0.14 µM against cell lines A549, Hela, and SGC-7901, respectively.It can be used as a candidate drug for treating various types of cancer.In Table 14, most norditerpenes have inhibitory effects on lung cancer, breast cancer, and cervical cancer cells.We should find appropriate targets to explore their mechanisms and focus on their in vivo activities in the future.With the rapid development of nanomaterials, we can combine effective norditerpenoids with them to improve their targeting and efficacy.Due to antibiotic resistance and side effects, it is meaningful to discover new antibiotics.Actinomadurol (64) has good antibacterial activity and provides the possibility for the discovery of antibiotics.At the same time, the structure-activity relationship was studied, which found that the hydroxyl group at C-7 affected antibacterial activity.CH 3 O-12 and the 3,20-epoxy moiety in 17-nor-pimarane diterpenes can function as activating groups, while the sugar moiety at C-2 might be an inactivated group.This is beneficial for the design and synthesis of new antibacterial drugs.Norditerpenes produce anti-inflammatory effects by influencing recognized markers of inflammatory processes such as IF, NO levels, nuclear factor kappa-B (NF-κB), and tumor necrosis factor-alpha (TGF-α).In the future, norditerpenes may be a useful and safe method for treating inflammatory diseases, such as rheumatoid arthritis, and can play a similar role as ibuprofen and dexamethasone.Inhibited IL-1β secretion and maturations of caspase-1 in a dose-dependent manner 9.9 ± 1.5 µM [15] 18(4→14), 19(4→8)-bis-abeo-nor-isopimarane-1,5diene-3-yl-3β-methoxy propyl pentanoate (82) Inhibited of pro-inflammatory cyclooxygenases (COX-2, COX-1) and 5-lipoxygenase (5-LOX) enzymes 0.75 mg/mL [30] 6-((E)-12-(furan-13-yl)-10-methylpent-10-en-9-yl)-6,7,8,8atetrahydro-3Hisochromen-1-(5H)-one (279) Inhibited of 5-LOX enzymes 0.92 mg/mL [89] (2S,3R,5S,9S,10S,13S)-2-O-Ecinnamoyl-3-hydroxy-16-nor-entpimar-8( 14)-en-15-oic acid (110) Inhibited the NF-κB pathway in LPS-stimulated RAW264.7 cells 14.7 ± 1.8 µM [39] cephalotanin A (190) Evaluated in an NF-kB pathway luciferase assay for inhibitory effects 4.12 ± 0.61 µM [73] salvialba acid (163) Lowered the levels of ICAM-1 and VCAM-1 in HAECs induced by TNF-α 20 µM caused significant reductions in cell viability; 0.05, 0.5, 5, and 10 µM did not affect cell viability [60] cephinoid H (208) Inhibited TNF-α-induced NF-κB activation 0.  Inhibited the production of NO and TNF-α in LPS-induced macrophages <25.0 µM [40,137] flickinflimilin A (446) Inhibited the production of NO and TNF-α in LPS-induced macrophages <25.0 µM [40,137] norflickinflimiod E (447) Inhibited the production of NO and TNF-α in LPS-induced macrophages <25.0 µM [40,137] norflickinflimiod F (448) Inhibited the production of NO and TNF-α in LPS-induced macrophages <25.0 µM [40,137] przewalskin (373) Inhibited iNOS expression in J774A. 1  Although current research has shown that these compounds exhibit various biological activities, most of the research mainly focuses on in vitro cell activity assays.It is necessary to investigate their in vivo activities.Further clinical trials are crucial to confirm the pharmacological effects of norditerpenes in order to fully illustrate their therapeutic effects on diseases.We hope that this review can promote research on norditerpenes.
tions 17 and 12, accompanied by oxidation occurring at position C-12.Compounds 43-52 possess a butenolide moiety extending from C-19 to C-6.Compound 53 demonstrates a similar structure, albeit featuring a double bond between C-5 and C-10.Compound 54 consists of a unique cage-like tetracyclic ring system, fused in a pattern of 6/6/6/5, which is formed by the incorporation of a 5,12-epoxy ring.Compound 55 is identified as an exceptionally symmetrical diterpene dimer characterized by the formation of a cyclobutane ring through [2 + 2] cycloaddition (Table

Figure 3 .
Figure 3. Basic skeletons of clerodane-type C19 norditerpenes.Compound 29 is characterized by a double bond between carbon atoms C-3 and C-4.Compounds 30-31 have a fused tricyclic ring system with a 6/6/6 configuration.Compound 32 belongs to the bioactive clerodane class of 19-nor-diterpenes, featuring a cyclohexenone decalin ring.Compound 33 is a dehydrogenated derivative of compound 34, resulting in the removal of hydrogen atoms from positions C 11 -C 12 .Compounds 35-37 exhibit a distinct 3,5(10)-diene moiety.Compounds 38-40 belong to the furanoditerpenes of the 18-nor-clerodane class.Compounds 43-44 display an opened lactone ring at positions 17 and 12, accompanied by oxidation occurring at position C-12.Compounds 43-52 possess a butenolide moiety extending from C-19 to C-6.Compound 53 demonstrates a similar structure, albeit featuring a double bond between C-5 and C-10.Compound 54 consists of a unique cage-like tetracyclic ring system, fused in a pattern of 6/6/6/5, which is formed by the incorporation of a 5,12-epoxy ring.Compound 55 is identified as an exceptionally symmetrical diterpene dimer characterized by the formation of a cyclobutane ring through [2 + 2] cycloaddition (Table3, Figure4).

Compounds 34 , 43 ,
and 55 demonstrated the NGF-mediated promotion of neurite outgrowth on PC12 cells at a concentration of 10 µM [17].Compound 509 showed a potent neuroprotective effect against a hydrogen peroxidation-induced reduction in cell viability in PC12 cells at a concentration of 1 µM [151,154].Compound 58 displayed the most effective inhibitory effect on osteoclast differentiation, exhibiting IC 50 values of 0.7 µM.It downregulated the expression levels of osteoclast-related genes and promoted the apoptosis of osteoclasts.Compounds 58-60 inhibited osteoclast formation, with IC 50 ranging from 0.7 to 4.0 µM, thereby demonstrating their antiosteoporosis effects

Table 9 .
Chemical constituents of other compounds of C19 norditerpenes.