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The drug likeness analysis of anti-inflammatory clerodane diterpenoids

Chinese Medicine volume 15, Article number: 126 (2020) Cite this article

Abstract

Inflammation is an active defense response of the body against external stimuli. Long term low-grade inflammation has been considered as a deteriorated factor for aging, cancer, neurodegeneration and metabolic disorders. The clinically used glucocorticoids and non-steroidal anti-inflammatory drugs are not suitable for chronic inflammation. Therefore, it’s urgent to discover and develop new effective and safe drugs to attenuate inflammation. Clerodane diterpenoids, a class of bicyclic diterpenoids, are widely distributed in plants of the Labiatae, Euphorbiaceae and Verbenaceae families, as well as fungi, bacteria, and marine sponges. Dozens of anti-inflammatory clerodane diterpenoids have been identified on different assays, both in vitro and in vivo. In the current review, the up-to-date research progresses of anti-inflammatory clerodane diterpenoids were summarized, and their druglikeness was analyzed, which provided the possibility for further development of anti-inflammatory drugs.

Background

Inflammatory diseases include a vast array of disorders and defense reaction of organisms against external stimulations that are characterized by inflammation symptoms, such as allergy, autoimmune diseases, asthma, glomerulonephritis, hepatitis, inflammatory bowel disease (IBD), reperfusion injury and transplant rejection [1,2,3]. Long term low-grade inflammation has been considered to play a deteriorated role in many diseases, such as aging, cancer, metabolic disorders, and neurodegeneration [4,5,6,7]. The occurrence of chronic diseases has triggered prolonged inflammation that induces the expression of robust pro-inflammatory mediators and cytokines [8, 9], which lead to the pathogenesis of inflammation-associated chronic diseases. Tumor necrosis factor (TNF)-α is one of the most potent pro-inflammatory cytokines and signals [10, 11]. Through binding to its receptors, TNFR1 and TNFR2, TNF-α plays critical roles in apoptosis, cell proliferation and immune responses [11, 12]. Interleukin-1β (IL-1β) is one of the inflammatory markers belonging to the IL-1 family of cytokines [13, 14]. IL-6 and IL-12 display a pro-inflammatory action via stimulating IL-1 secretion [15]. IL-10, as the most important anti-inflammatory cytokine, represses pro-inflammatory responses and limits inflammation-induced tissue disruptions [16, 17]. Prostaglandin E2 (PGE2) is derived from arachidonic acid produced by cyclooxygenase (COX)-1 and/or COX-2 [18], which is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis [19]. Nitric oxide (NO) is free radical acting as a cellular signaling molecule in inflammation process [20, 21]. NO is synthesized from I-arginine through the action of nitric oxide synthase (NOS) family [22], which has been associated with the pathogenesis and progression of inflammatory-related diseases [20, 23]. Macrophages exit throughout the body, which play important roles in tissue development, inflammation and anti-pathogenic defense [24,25,26]. A variety of biologically active molecules related to the beneficial and harmful consequences of inflammation are produced by macrophages. Therefore, therapeutic intervention for macrophages and their related products has attracted widespread attention in the treatment of inflammatory diseases. [24, 27].

Currently, the clinically used inflammation-treating drugs include non-steroidal anti-inflammatory drugs (NSAID) and glucocorticoids (SAID). Both classes of anti-inflammatory drugs could induce unpleasant side effects, and not suitable for chronic use [28,29,30]. Thus, it’s urgent to discover and develop new effective and safe drugs to alleviate inflammation. Tons of scientific evidence has indicated that natural medicines represent a big treasure to develop potential therapeutic agents for inflammation-related diseases [31, 32]. The clerodane diterpenoids are a large class of naturally occurring bicyclic diterpenoids (Fig. 1), found in lots of plant species, especially the families of Labiatae, Euphorbiaceae and Verbenaceae [33]. More and more research interests have been attracted in recent years for their wide and potent biological activities [34]. Salvinorin A, a clerodane diterpenoid isolated from Salvia divinorum, was found as an agonist of the κ-opioid receptor. It is the first opioid receptor agonist without nitrogen and non-alkaloid hallucinogen. Many clinical trials results support the physiological effects of salvinorin A is mediated through κ-opioid receptor‒serotonin-2A pathway [35,36,37,38,39,40]. A lot of studies have disclosed the potential anti-inflammatory activity of clerodane diterpenoids. Herein, an up-to-date and comprehensive review of clerodane diterpenoids with anti-inflammatory property was provided, and their drug-likeness was analyzed through SwissADME, which enable further development of clerodane diterpenoids for the treatment of inflammation related diseases.

Fig. 1
figure 1

Skeletons of clerodane diterpenoids and ent-diterpenoids

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Clerodane diterpenoids with anti-inflammatory property

Data was collected from Web of Science, Google Scholar, Scopus, and Pubmed via using the keywords clerodane diterpenoid and inflammation, and a total of 65 clerodane diterpenoids were found with anti-inflammatory property (Fig. 2). Either in vitro or in vivo bioassays have been used to determine the anti-inflammatory activity of clerodane diterpenoids. To better organize the review, the clerodane diterpenoids were introduced based on the anti-inflammatory bioassays (Table 1).

Fig. 2
figure 2

Structures of clerodane diterpenoids with anti-inflammatory activity

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Table 1 Clerodane diterpenoids with anti-inflammatory activity
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Lipopolysaccharide (LPS), a major constituent of the outer leaflet of Gram-negative bacterial outer membrane, is synthesized on the cytoplasmic membrane and transferred to the outer membranes [41, 42]. LPS treated murine microglial BV-2 cells are widely used for anti-inflammatory drug screening and underlying mechanism investigation. Using the above mentioned model, 18 clerodane diterpenoids including scutebarbatine (14), scutebarbatine B (16), scutebatas B (17), scutebarbatine X (18), ajugapantin H (22), scutebaabaatine W (38), ajugapantins E (48), ajugapantins F (49), ajugapantins G (50), ajugacumbin A (51), scutelapenes B (52), scutelapenes C (53), scutelapenes D (54), scutelapenes A (57), scutelapenes E (58), ajugapantin C (59), (12S,2′′S)-6α,19-diacetoxy-18-chloro-4α-hydroxy-12-(2-methylbutanoyloxy)-neo-clerod-13-en-15,16-olide (60), and 6α,19-diacetoxy-4α-hydroxy-1β-tigloyloxyneo-clerod-12-en-15-oic acid methyl ester-16-aldehyde (61) were found to inhibit NO production [43‒46]. Among them, compounds 22, 50 and 59 were discovered to downregulate iNOS and COX-2 expression [47].

LPS-stimulated murine-derived RAW264.7 macrophages have been widely used as a bioassay to investigate anti-inflammatory activity [48, 49]. Using this model, 29 clerodane diterpenoids including 16-oxocleroda-3,13-dien-15-oic acid (1), neoclerod-13Z-ene-3α,4β,15-triol (4), 16-hydroxycleroda-3,13-dien-15,16-olide (7), 15-methoxypatagonic acid (12), 16-hydroxycleroda-3,13-dien-16,15-olide-18-oic acid (13), scutebarbatine A (14), scutebarbatine Y (15), scutebarbatine B (16), 3β,4β:15,16-diepoxy-13(16),14-clerodadiene (19), cathayanalactones A (20), cathayanalactones B (21), crotonolide K (25), furocrotinsulolide A acetate (26), 15,16-epoxy-3β-hydroxy-5(10),13(16),14-ent-halimatriene-17,(12S)-olide (27), crotonolide F (28), scutebatin C (33), scutebarbatine W (34), scutebata P (35), scutebatin A (36), scutebatin B (37), 6S-crotoeurin C (41), crotoeurin C (42), 3S-methoxylteucbin (44), 3R-methoxylteucbin (45), 19-acetyl-teuspinin (46), jamesoniellide Q (47), 11-hydroxyfruticolone (55), ajugacumbin J (56), and 6α-acetoxyteuscordin (63) were found to inhibit NO production [50‒59], and compounds 12 and 13 were further found to reduce IL-6, IL-1β, and TNF-α production in dose-responsive manners [50].

Besides being deputed to host defense against microorganisms, neutrophils display fundamental roles both in inflammation and tissue damages [60]. N-formylmethionyl-leucyl-phenylalanine (fMLP) is a potent polymorphonuclear leukocyte chemotactic factor and a macrophage activator [61]. Neutrophils function as the first-line defense against invading bacteria fungi and protozoa [62], which are major effector cells to identify novel antibiotics and elucidate the pathogenesis behind neutrophil-mediated inflammatory disorders [63]. In fMLP/CB-stimulated human neutrophils, five clerodane diterpenoids including 16-hydroxycleroda-3,13(14)E-dien-15-oic acid (2), 16-oxocelroda-3,13(14)E-dien-15-oic acid methyl ester (3), (4-2)abeo-16-2,13Z-clerodadien-15,16-olide-3-al (5), 16-3,13Z-kolavadien-15,16-olide-2-one (6), and 16-hydroxycelroda-3,13-dien-15,16-olide (7) from the bark of Polyalthia longifolia var. pendula showed anti-inflammatory activity [64]. (‒)-Hardwickiic acid (8) showed anti-inflammatory activity on neutrophils through suppressing both superoxide anion generation (IC50 = 4.40 ± 0.56 μM) and elastase release (IC50 = 3.67 ± 0.20 μM) [65]. 16-Hydroxycleroda-3,13(14)E-dien-15-oic acid (2) was isolated from the same species, which concentration-dependently inhibited the generation of superoxide anion and the release of elastase in fMLP/CB-stimulated human neutrophils, with IC50 values of 3.06 ± 0.20 and 3.30 ± 0.48 μM, respectively [66].

TPA (12-O-tetradecanoylphorbol 13-acetate) induces keratinocytes proliferation, TNF-α production, and the formation of leukotriene B4 (LTB4), to induce oxidative stress and cutaneous inflammation [67, 68]. Mice overexposed to TPA exhibit an inflammatory phenotype characterized by the increased ear thickness, macrophage infiltration, and epidermal hyperplasia [69]. In TPA-induced CD-1 auricular pavilion mice, two benzoyl ester clerodane diterpenoids, 15,16-epoxy-8α-(benzoyloxy)methyl-2α-hydroxycelroda-3,13(16),14-trien-18-oic acid (10) and 15,16-epoxy-8α-(benzoyloxy)methyl-2-oxocelroda-3,13(16),14-trien-18-oic acid (11) isolated from the leaves and stems of Dodonaca polyandra, showed maximum inhibition of inflammation (70‒76%) at the dose of 0.10 and 0.39 mg/ear, respectively [70]. Hautriwaic acid (9), isolated from Dodonaca viscosa leaves, relieved ear edema in TPA-induced mice at the dose of 0.25, 0.5, and 1.0 mg/ear (60.2, 70.2 and 87.1% inhibition, respectively) [71]. Tehuanins G (11), isolated from the aerial parts of Salvia herbacea, exhibited the comparable effect as that of indomethacin in TPA-induced mice [72]. Tillifodiolide (40), isolated from Salvia tiliifolia, dose-dependently decreased ear edema in TPA-induced ear edema [73].

Carrageenan is a phlegmatic agent for rat and mice paw edema [74]. Carrageenan-induced paw edema has been described as a local and acute inflammatory process [75]. Caseargrewiin F (64) and casearin B (65) (0.5 mg/kg) showed a reduction of paw edema in the carrageenan-induced rats, compared to that of indomethacin [76]. Trans-dehydrocrotonin (30), isolated from the barks of Croton cajucara (Euphorbiaceae), alleviated carrageenan-induced paw edema in rats [77]. Tillifodiolide (40), isolated from Salvia tiliifolia Vahl (Lamiaceae), dose-dependently inhibited paw edema in the carrageenan test [73]. Nepetolide (43), a tricyclic clerodane-type diterpenoid isolated from Nepeta suavis, reduced carrageenan-induced paw edema at the dose of 20 mg/kg [78]. In carrageenan-induced pleurisy, salvinorin A (24) suppressed LTB4 production in exudates, and reduced the phlogistic process in lung [79].

In teleocidin induced mouse ear inflammation, cajucarinolide (31) and isocajucarinolide (32), two clerodane diterpenoids isolated from the cortices of Croton cajucara (Euphorbiaceae), inhibited inflammation in mouse ear at the dosage of 5.6 and 3.0 μg/ear [80].

In TPA-induced acute and chronic mouse ear edema models, polyandric acid A (10) from the Australian medicinal plant Dodonaea polyandra, inhibited IL-1β and IL-6 production, ear thickness and myeloperoxidase (MPO) accumulation [81].

Stomach illnesses are common health problems worldwide [82]. In indomethacin-induced gastric ulcer rats, epoxy clerodane diterpene (5R,10R)-4R,8R-dihydroxy-2S,3R:15,16-diepoxycleroda-13(16),17,12S,18,1S-dilactone (39), isolated from Tinospora cordifolia, showed a gastroprotective effect. Epoxy clerodane diterpene reversed indomethacin-induced increases of ulcer index (UI) and MPO activity, downregulation of PGE2, and decreases of IL-4 and IL-10. Pre-administration of the specific COX-1 inhibitor and nonspecific NOS inhibitor totally blocked the ulcer-healing activity of epoxy clerodane diterpene, indicating the involvement of PGE2 and NOS in the ulcer healing activity of epoxy clerodane diterpene [83].

IBD is caused by microbial infiltration or immunocyte attack, which is a general term for ulcerative colitis and Crohn’s disease [84]. The treatment of IBD remains unsolved. By using dextran sulfate sodium (DSS)/azoxymethane (AOM) induced IBD mouse model, 16-hydroxycleeroda-3,13-dien-15,16-olide (7), isolated from Polyalthia longifolia var. pendula Linn. (Annonaceae), was demonstrated to ameliorate the inflammatory symptoms [85].

Dextran-induced edema induces an anaphylactoid reaction, which is widely used as an acute experimental model of inflammation [86]. Trans-crotonina showed inhibitory effect at the rate of 31.9% in dextran-induced edema [80]. Histamine is known to increase vascular permeability [87]. Histamine-induced edema is widely used to screen anti-inflammatory drugs [88]. Trans-crotonina showed inhibitory effect in histamine-induced edema [80].

Arachidonic acid-derived LTs are highly related to inflammatory diseases such as asthma, allergic rhinitis and cardiovascular disease [89]. Calcium ionophore A23187-stimulated peritoneal macrophages (PM) were used as an in vitro model to evaluate SA-indcued production of LT [90]. SA concentration-dependently inhibited LTB4 biosynthesis in isolated PM, and suppressed myeloperoxidase activity, cell infiltration, LTC4 production, and vascular permeability, in the peritoneal cavity, but not the production of PGE2 [79].

In summary, a total of 65 clerodane diterpenoids were reported with potential anti-inflammatory property. While, their anti-inflammatory activity was only evaluated on either in vitro cellular models or in vivo animal models, no clinical study was carried out till now. In the future, clinical trials must be performed to authenticate the therapeutic effect of clerodane diterpenoids in alleviating inflammatory responses.

Comparison of drug-likeness of anti-inflammatory clerodane diterpenoids with marketed drugs

SwissADME is a tool provided by the Swiss institute of Bioinformatics [93], which was used to predict molecular descriptors of the above summarized clerodane diterpenoids. To better summarize the drug-likeness properties of all these compounds, the following descriptors were described, inluding molecular weight (MW), number of hydrogen bond acceptors (HBA) and donors (HBD), number of stereogenic centers, and number of rotatable bonds (RB). The fraction of sp3 carbon (Fsp3) is defined as the ratio of sp3 hybrid carbon to the total carbon number. The fraction of carbon and aromatic heavy atoms (Far) is the ratio of the number of aromatic heavy atoms to the total number of heavy atoms [94].

The predicted results were shown in Additional file 1: Table S1, which were grouped according to the previously described categories. Absorption, distribution, metabolism, and excretion (ADME) are critical factors in drug development [95], drug similarity and medicinal chemistry friendliness. Additional file 1: Table S2 showed the physicochemical properties, molecular polar surface area (PSA), pharmacokinetics, LogS and iLOGP, as well as bioavailability characteristics of clerodane diterpenoids (Supplementary Material). Especially for LogP [96] and LogS [97], more than one algorithm was used.

To better compare those anti-inflammatory clerodane diterpenoid derivatives with marketed drugs, the MW, HBA, HBD [98], Log P, PSA, RB, and stereogenic centers were evaluated; and the marketed drugs were divided into natural products, natural products derivatives, natural product type macrocycles, polycyclic compounds, synthetic compounds, and assumed synthetic compounds [99, 100] (Fig. 3).

Fig. 3
figure 3

Mean values of MW (a), stereogenic centers (b), LogP (c), HBA (d), HBD (e), PSA (f), RB (g). Anti-inflammatory clerodane diterpenoids (CD) (red), synthetic (dark blue), assumed synthetic (dark grey), natural products (black), natural derivatives (light grey), natural product type macrocyte (light blue), natural products polycyclic (yellow)

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Size: molecular weight

Lopinski’s rule of five defined the suitable traditional therapeutic agents [101], including less than 500 Da molecular mass, no more than 10 HBA, no more than 5 HBD, and an octanol–water partition coefficient LogP not great than 5. According to the SwissADME results, the mean MW for the anti-inflammatory clerodane diterpenoids was 452.4 Da (Fig. 3a). Most NSAIDs [102], and 61% of clerodane diterpenoids are with the MW less than 500 Da, which match to Lopinski’s rule of five.

Chirality: number of stereogenic centers

The number of stereocenters has an important impact on the chiral structure and self-assembly of molecular aggregates. The number of stereogenic centers in clerodane diterpenoids was 6, which was comparable with those of natural products, natural products derivatives,natural product type macrocycles, polycyclic compounds, synthetic compounds, and assumed synthetic compounds (Fig. 3b). The natural product type macrocycle have the highest value of the stereogenic center, 12. For the synthesis of chemical compounds, more chiral centers causes more difficulty and higher cost of synthesis [99]. The number of stereogenic centers in the anti-inflammatory clerodane diterpenoid derivatives meets the standards for new drug development.

Polarity: PSA and HBD/HBA

A major challenge in drug discovery is the prediction of permeability, which, along with solubility, governs the skill of drugs and candidates transport across the gastrointestinal membrane and thus contributes to the overall exposure in systemic circulation and brain penetration. PSA, a descriptor defined as the sum of surfaces of nitrogen or oxygen atoms, plus hydrogen atoms attached to oxygen or nitrogen atoms in a molecule, has been widely used with a discrete success to model permeability and other ADME-related properties [103]. The topological PSA (TPSA) is often implemented in the drug-discovery pipeline [104]. However, the limitation of PSA should be considered. PSA does not take into account the contribution of polarity arising from electronegative atoms in drugs besides nitrogen and oxygen. And the different electronegativity of the atoms of the molecule produces a redistribution of the electron density that in principle involves the entire molecule. PSA is highly correlated with hydrogen bonding (HB. In principle, quantum mechanics calculations could also improve the description of HBA and HBD properties and the polarity of the molecules [105].

The PSA mean values were 96.1 Å2 for clerodane diterpenoids, 86.9 Å2 for polycyclic drugs, and 105.3 Å2 for natural products. Additionally, the HBA/HBD and PSA values of anti-inflammatory clerodane diterpenoids are positively correlated with their MW (Figs. 3d–f and  4). According to the rule of 5, most of the anti-inflammatory clerodane diterpene derivatives might have good oral absorption.

Fig. 4
figure 4

PSA values of the anti-inflammatory clerodane diterpenoid derivatives vs molecular weight (MW)

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Molecular flexibility: rotatable bonds and aromatic character

RBs are the number of bonds that allow free rotation, excluding those adjacent to triple bonds, connect hydrogen or halogen atoms, or in rings containing less than five single bonds [106]. The amide C-N bond is excluded due to its high rotational energy barrier. Reduced molecular flexibility (less RBs), and low PSA or total HB imply good oral bioavailability [107]. The number and percentage of RBs are descriptors for the biological effect of molecules. Compounds with less than 7 RBs exhibited oral bioavailability of more than 20% [108]. The increased RBs number interrupts the permeation rate to reduce oral bioavailability.

The mean numbers of RBs for the summarized clerodane diterpenoids, the polycyclic compounds, natural products, natural product derivatives, and synthetic drugs were 5.92, 7.4, 9.4, 7.4, and 5.4, respectively (Fig. 3g). The less RBs for the clerodane diterpenoids indicated a good permeation rate. The summarized clerodane diterpenoids have a mean Fsp3 of 0.64 because they possess an aromatic character.

Lipophilicity: LogP

LogP is normally determined in the hit to lead stage of drug discovery [109]. Lipophilicity of a drug is the ratio between its concentrations at the equilibrium in 1-octanol and water, commonly described as LogD [110]. The partition coefficient (P) is the specific distribution coefficient (D) at any given pH (typically neutral) [111].

The logP values of the anti-inflammatory clerodane diterpenoids are different by using different predicted method on Swiss ADME. Among all logP index, MLOGP is the most discrepant one (Fig. 5). Compare to the synthetic compounds, assumed synthetic compounds, natural products, natural derivatives, natural product macrocycles, and natural products polycyclic, the logP value of the clerodane diterpenoids (3.0) is higher, indicating lower oral bioavailability.

Fig. 5
figure 5

Mean LogP values of the anti-inflammatory clerodane diterpenoids calculated by different methods

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Solubility: LogS

If the solubility and rate of dissolution are low, an enterally administered drug will mostly be excreted [112]. Solubility of a compound is commonly expressed as logS, where S is the concentration of the compound in a saturated aqueous solution (mol/L). 85% of drugs have logS values between −1 and −5 and virtually none has value below -6 [113].

The aqueous solubility of clerodane diterpenoids is negatively correlated with MW (Fig. 6). Most of the anti-inflammatory clerodane diterpenoids have poor water solubility. Only a few examples showed the Log S values greater than -4, such as casearin B (65) and isocajucarinolide (32), which might have great potential to be developed as drugs.

Fig. 6
figure 6

LogS (SILICON-IT) of the anti-inflammatory clerodane diterpenoids vs Molecular weight (top); Log S (SILICON-IT) of the anti-inflammatory clerodane diterpenoids vs LogP (SILICON-IT) (bottom)

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Compliance of clerodane diterpenoids with the rules of drug-likeness

The “5 Rules” has been widely used as the first filter to eliminate potential drug candidates with poor oral bioavailability [107]. According to different compliance rules, the biophysical and chemical properties and molecular descriptors of the anti-inflammatory clerodane diterpenoids were evaluated. Most of them possess good drug-likeness (green in Additional file 1: Table S3).

Trends on the PK behavior of clerodane diterpenoids

Besides efficacy and toxicity, poor pharmacokinetics and bioavailability always cause drug development failures. The two pharmacokinetic behaviors, gastrointestinal absorption and brain entry, are critical at different stages of the drug discovery process. BOILED Egg, an accurate predictive model, was developed by calculating the lipophilicity and polarity of small molecules [114]. It is widely used in the filtering of chemical libraries and the evaluation of drug candidates [115].

Based on the predicted results, about 80% of anti-inflammatory clerodane diterpenoids are more likely to be absorbed in the gastrointestinal (GI), mainly due to their lower MW (Fig. 7a). Among them, 53 clerodane diterpenoids have higher GI absorption, and 34 ones have a high probability as P-gp substrates (Fig. 7a).

Fig. 7
figure 7

a GI absorption for the identified anti-inflammatory clerodane diterpenoids (left pie chart). Anti-inflammatory clerodane diterpenoids with high GI absorption were classified accordingly to its P-gp substrate (right pie chart). (B) BBB permeability of the identified clerodane diterpenoids

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The brain capillary endothelium for the blood–brain barrier (BBB) to exclude 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drug. BBB is the key issue in brain drug development [116]. Most of the anti-inflammatory clerodane diterpenoids have a low probability to cross the BBB (Fig. 7b). Among them, ten compounds are with potential ability to be P-gp substrates (Additional file 1: Table S5).

The possibility of clerodane diterpenoids as inhibitors of one of the five major isoforms of CYP450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was predicted by SwissADME (Additional file 1: Table S4) [117, 118]. The anti-inflammatory clerodane diterpenoids are potent CYP450 enzyme inhibitors, especially for the CYP3A4 (Fig. 8).

Fig. 8
figure 8

CYP450 enzyme inhibitors of the identified anti-inflammatory clerodane diterpenoid derivatives

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Conclusions

Clerodane diterpenoids are secondary metabolites widely distributed in plants, fungi, bacteria, and marine sponges. In this review, 65 anti-inflammatory clerodane diterpenoids were reviewed based on their chemical structures and pharmacological models. The knowledge system of chemistry and bioactivity of clerodane diterpenoids continues to grow rapidly in recent years. Based on the current review, ent-clerodane diterpenoids always possess better anti-inflammatory activity than clerodane diterpenoids. And a lactone ring between C-18 and C-19 is essential for the anti-inflammation activity of clerodane diterpenoids. Although lots of evidence suggested the anti-inflammatory property of clerodane diterpenoids, the clinical application of these molecules as anti-inflammatory therapy is still far away. Till now, only evidence from in vitro cellular models or in vivo animal models was available. Clinical trials are necessary to authenticate the therapeutic effect of clerodane diterpenoids in alleviating inflammatory responses. The efficacy of these clerodane diterpenoids is not potent enough; thus, further phytochemical isolation and structural optimization are needed to enhance activity, improve specificity and reduce toxicity. Moreover, virtual docking and/or chemical biology studies should be carried out to identify the potential targets for the anti-inflammatory clerodane diterpenoids. The underlying mechanisms involved in the anti-inflammatory activity should be disclosed by pharmacological investigation.

Online bioinformatics tool SwissADME provides a lot of predicted data of a compound, such as molecular descriptors, the biophysiochemical properties, and the PK parameters. A serious of drug-likeness analyses could be performed to better understand its properties, such as MW, logP, logS, PSA, HBA, HBD, RBs, and number of stereogenic centers. For natural medicine investigation, the combination of bench research and bioinformatics prediction tools could be an effective and economical approach to discover new anti-inflammatory drugs. Regarding to the anti-inflammatory clerodane diterpenoids, future chemical and biological researches will be very bright and challenging, and they have a huge therapeutic application prospect.

Availability of data and materials

All available data and material can be accessed.

Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

BBB:

Blood-brain barrier

ECD:

Epoxy clerodane diterpene

fMLP:

N-formylmethionyl-leucyl-phenylalanine

COX:

Cyclooxygenase

DSS:

Dextran sulfate sodium

GI:

Gastrointestinal

HBA, HBD:

Hydrogen bond acceptors and donors

HA:

Hautriwaic acid

IBD:

Inflammatory bowel disease

IL-1β:

Interleukin-1β

LTs:

Leukotrienes

LTB4:

Leukotriene B4

LTC4:

Leukotriene C4

LPS:

Lipopolysaccharide

MW:

Molecular weight

MPO:

Myeloperoxidase

NOS:

Nitric oxide synthase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NSAID and SAID:

Nonsteroidal anti-inflammatory drugs (NSAID) and glucocorticoids

PM:

Peritoneal macrophages

PGE2:

Prostaglandin E2

PSA:

Polar surface area

RBs:

Rotatable bonds

TNF-α:

Tumor necrosis factor-α

TPA:

12-O-tetradecanoylphorbol-13-acetate

Th1:

T helper type 1

TPSA:

Topological polar surface area

UI:

Ulcer index

References

  1. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Amor S, Puentes F, Baker D, Van Der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129(2):154–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev. 2009;8(1):18–30.

    Article  CAS  PubMed  Google Scholar 

  4. Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology. 2010;49(9):1618–31.

    Article  CAS  PubMed  Google Scholar 

  5. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321(7255):199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Candore G, Caruso C, Jirillo E, Magrone T, Vasto S. Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievement. Curr Pharm Des. 2010;16(6):584–96.

    Article  CAS  PubMed  Google Scholar 

  7. Lin LG, Jee JH, Buras ED, Yu KJ, Wang RT, Smith CW, et al. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging. 2016;8(1):178–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci. 2004;20(2):467–73.

    Article  PubMed  Google Scholar 

  9. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hotamisligil GS, Shargill NS, Speigelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91.

    Article  CAS  PubMed  Google Scholar 

  11. Ruddle NH. Tumor necrosis factor (TNF-α) and lymphotoxin (TNF-β). Curr Opin Immunol. 1992;4(3):327–32.

    Article  CAS  PubMed  Google Scholar 

  12. Defer N, Azroyan A, Pecker F, Pavoine C. TNFR1 and TNFR2 signaling interplay in cardiac myocytes. J Biol Chem. 2007;282(49):35564–73.

    Article  CAS  PubMed  Google Scholar 

  13. Lukens JR, Gross JM, Kanneganti TD. IL-1 family cytokines trigger sterile inflammatory disease. Front Immunol. 2012;3:315.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Banerjee M, Saxena M. Interleukin-1 (IL-1) family of cytokines: role in type 2 diabetes. Clin Chim Acta. 2012;413(15–16):1163–70.

    Article  CAS  PubMed  Google Scholar 

  15. Jones LL, Vignali DA. Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. Immunol Res. 2011;51(1):5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fiorentino DF, Zlotnik A, Mosmann T, Howard M, O’garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147(11):3815‒22.

  17. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180(9):5771–7.

    Article  CAS  PubMed  Google Scholar 

  18. Faist E, Mewes A, Baker C, Strasser T, Alkan S, Rieber P, et al. Prostaglandin E2 (PGE2)-dependent suppression of interleukin alpha (IL-2) production in patients with major trauma. J Trauma. 1987;27(8):837–48.

    Article  CAS  PubMed  Google Scholar 

  19. Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C. Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci. 2005;25(43):9858–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993;54(2):171–8.

    Article  CAS  PubMed  Google Scholar 

  21. Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001;2(10):907–16.

    Article  CAS  PubMed  Google Scholar 

  22. Nozaki Y, Fujita K, Wada K, Yoneda M, Kessoku T, Shinohara Y, et al. Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model. BMC Gastroenterol. 2015;15(1):42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Li D, Liu QY, Sun W, Chen XP, Wang Y, Sun YX, et al. 1,3,6,7-Tetrahydroxy-8-prenylxanthone ameliorates inflammatory responses resulting from the paracrine interactoin of adipocyts and macrophages. Br J Pharmacol. 2018;175:1590–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang T, Fang ZJ, Linghu KG, Liu JX, Gan LS. Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes. Br J Pharmacol. 2020;177:4645–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li D, Liu QY, Lu XQ, Li ZQ, Wang CM, Leung CH, et al. α-Mangostin remodels visceral adipose tissue inflammation to ameliorate age-related metabolic disorders in mice. Aging. 2019;11(23):11084–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14(10):986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zheng XQ, Li K, Wei YD, Tie HT, Yi XY, Huang W. Nonsteroidal anti-inflammatory drugs versus corticosteroid for treatment of shoulder pain: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2014;95(10):1824–31.

    Article  PubMed  Google Scholar 

  29. Wolfensberger T, Herbort C. Treatment of cystoid macular edema with non-steroidal anti-inflammatory drugs and corticosteroids. In Macular Edema, Springer:2000;pp177‒82.

  30. Rodríguez LAG, Hernández-Díaz S. The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthrit Res Ther. 2001;3(2):98.

    Article  Google Scholar 

  31. Azab A, Nassar A, Azab AN. Anti-inflammatory activity of natural products. Molecules. 2016;21(10):1321.

    Article  PubMed Central  CAS  Google Scholar 

  32. Aswad M, Rayan M, Abu-Lafi S, Falah M, Raiyn J, Abdallah Z, et al. Nature is the best sourse of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity. Inflamm Res. 2018;67:67–75.

    Article  CAS  PubMed  Google Scholar 

  33. Li R, Morris-Natschke SL, Lee KH. Clerodane diterpenes: sources, structures, and biological activities. Nat Prod Rep. 2016;33(10):1166–226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Siebert DJ. Salvia divinorum and salvinorin A: new pharmacologic findings. J Ethnopharmacol. 1994;43(1):53–6.

    Article  CAS  PubMed  Google Scholar 

  35. Maqueda AE, Valle M, Addy PH, Antonijoan RM, Puntes M, Coimbra J, et al. Naltrexone but not ketanserin antagonizes the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. Int J Neuropsychopharmacol. 2016;19(7):pyw016.

  36. Addy PH. Acute and post-acute behavioral and psychological effects of salvinorin A in humans. Psychopharmacology. 2012;220(1):195–204.

    Article  CAS  PubMed  Google Scholar 

  37. Mendelson JE, Coyle JR, Lopez JC, Baggott MJ, Flower K, Everhart ET, et al. Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: a placebo-controlled trial. Psychopharmacology. 2011;214(4):933–9.

    Article  CAS  PubMed  Google Scholar 

  38. MacLean KA, Johnson MW, Reissig CJ, Prisinzano TE, Griffiths RR. Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology. 2013;226(2):381–92.

    Article  CAS  PubMed  Google Scholar 

  39. Ranganathan M, Schnakenberg A, Skosnik PD, Cohen BM, Pittman B, Sewell RA, et al. Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans. Biol Psychiatry. 2012;72(10):871–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Johnson MW, MacLean KA, Reissig CJ, Prisinzano TE, Griffiths RR. Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol Depend. 2011;115(1–2):150–5.

    Article  CAS  PubMed  Google Scholar 

  41. Lynn WA, Golenbock DT. Lipopolysaccharide antagonists. Immunol Today. 1992;13(7):271–6.

    Article  CAS  PubMed  Google Scholar 

  42. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71(1):635–700.

    Article  CAS  PubMed  Google Scholar 

  43. Wang P, Liu F, Yang X, Liang Y, Li S, Su G, et al. Clerodane diterpenoids from Scutellaria formosana with inhibitory effects on NO production and interactions with iNOS protein. Phytochemistry. 2017;144:141–50.

    Article  CAS  PubMed  Google Scholar 

  44. Lee SR, Kim MS, Kim S, Hwang KW, Park SY. Constituents from Scutellaria barbata inhibiting nitric oxide production in LPSstimulated microglial cells. Chem Biodivers. 2017;14(11):e1700231.

    Article  CAS  Google Scholar 

  45. Sun Z, Li Y, Jin DQ, Guo P, Xu J, Guo Y, et al. Structure elucidation and inhibitory effects on NO production of clerodane diterpenes from Ajuga decumbens. Planta Med. 2012;78(14):1579–93.

    Article  CAS  PubMed  Google Scholar 

  46. Sun Z, Li Y, Jin DQ, Guo P, Song H, Xu J, et al. neo-Clerodane diterpenes from Ajuga decumbens and their inhibitory activities on LPS-induced NO production. Fitoterapia. 2012;83(8):1409–14.

    Article  CAS  PubMed  Google Scholar 

  47. Dong B, Yang X, Liu W, An L, Zhang X, Tuerhong M, et al. Anti-inflammatory neo-clerodane diterpenoids from Ajuga pantantha. J Nat Prod. 2020;83(4):894–904.

    Article  CAS  PubMed  Google Scholar 

  48. Fang ZJ, Zhang T, Chen SX, Wang YL, Zhou CX, Mo JX, et al. Cycloartane triterpenoids from Actaea vaginata with anti-inflammatory effects in LPS-stimulated RAW264.7 macrophages. Phytochemistry. 2019;160:1–10.

    Article  CAS  PubMed  Google Scholar 

  49. Liu QY, Li D, Wang AQ, Dong Z, Yin S, Zhang QW, et al. Nitric oxide inhibitory xanthones from the pericarps of Garcinia mangostana. Phytochemistry. 2016;131:115–23.

    Article  CAS  PubMed  Google Scholar 

  50. Wang Y, Lin J, Wang Q, Shang K, Pu DB, Zhang RH, et al. Clerodane diterpenoids with potential anti-inflammatory activity from the leaves and twigs of Callicarpa cathayana. Chin J Nat Med. 2019;17(12):953–62.

    PubMed  Google Scholar 

  51. Li F, Zhang DB, Li JT, He FJ, Zhu HL, Li N, et al. Bioactive terpenoids from Croton laui. Nat Prod Res. 2019. https://doi.org/10.1080/14786419.2019.1675062.

    Article  PubMed  Google Scholar 

  52. Lv HW, Luo JG, Meng DZ, Shan SM, Kong LY. Teucvisins A-E, five new neo-clerodane diterpenes from Teucrium viscidum. Chem Pharm Bull. 2014;62(5):472–6.

    Article  CAS  Google Scholar 

  53. Yeon ET, Lee JW, Lee C, Jin Q, Jang H, Lee D, et al. neo-Clerodane diterpenoids from Scutellaria barbata and their inhibitory effects on LPS-induced nitric oxide production. J Nat Prod. 2015;78(9):2292–6.

    Article  CAS  PubMed  Google Scholar 

  54. Somteds A, Tantapakul C, Kanokmedhakul K, Laphookhieo S, Phukhatmuen P, Kanokmedhakul S. Inhibition of nitric oxide production by clerodane diterpenoids from leaves and stems of Croton poomae Esser. Nat Prod Res. 2019. https://doi.org/10.1080/14786419.2019.1667350.

    Article  PubMed  Google Scholar 

  55. Lv H, Lu J, Kong LY. A new neo-clerodane diterpene from Ajuga decumbens. Nat Prod Res. 2014;28(3):196–200.

    Article  CAS  PubMed  Google Scholar 

  56. Lv HW, Luo JG, Zhu MD, Zhao HJ, Kong LY. neo-Clerodane diterpenoids from the aerial parts of Teucrium fruticans cultivated in China. Phytochemistry. 2015;119:26–31.

    Article  CAS  PubMed  Google Scholar 

  57. Wu TH, Cheng YY, Chen CJ, Ng LT, Chou LC, Huang LJ, et al. Three new clerodane diterpenes from Polyalthia longifolia var pendula. Molecules. 2014;19(2):2049–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Zhang PZ, Zhang YM, Lin Y, Wang F, Zhang GL. Three new diterpenes from Dysoxylum lukii and their NO production inhibitory activity. J Asian Nat Prod Res. 2020;22(6):531–6.

    Article  PubMed  Google Scholar 

  59. Li Y, Zhu R, Zhang J, Wu X, Shen T, Zhou J, et al. Clerodane diterpenoids from the Chinese liverwort Jamesoniella autumnalis and their anti-inflammatory activity. Phytochemistry. 2018;154:85–93.

    Article  CAS  PubMed  Google Scholar 

  60. Sadik CD, Kim ND, Luster AD. Neutrophils cascading their way to inflammation. Trends Immunol. 2011;32(10):452–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Giuliani S, Santicioli P, Tramontana M, Geppetti P, Maggi CA. Peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) activates capsaicin-sensitive primary afferent nerves in guinea-pig atria and urinary bladder. Br J Pharmacol. 1991;102(3):730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Klebanoff SJ. In antimicrobial mechanisms in neutrophilic polymorphonuclear leukocytes. Semin Hematol. 1975;pp117‒42.

  63. Jaillon S, Galdiero MR, Del Prete D, Cassatella MA,Garlanda C, Mantovani A. In Neutrophils in innate and adaptive immunity. Semin Immunopathol. 2013; Springer: pp377‒94.

  64. Chang FR, Hwang TL, Yang YL, Li CE, Wu CC, Issa HH, et al. Anti-inflammatory and cytotoxic diterpenes from Polyalthia longifolia var. pendula. Planta Med. 2006;72(14):1344‒7.

  65. Lee CL, Yen MH, Hwang TL, Yang JC, Peng CY, Chen CJ, et al. Anti-inflammatory and cytotoxic components from Dichrocephala integrifolia. Phytochemistry Lett. 2015;12:237–42.

    Article  CAS  Google Scholar 

  66. Chang HL, Chang FR, Chen JS, Wang HP, Wu YH, Wang CC, et al. Inhibitory effects of 16-hydroxycleroda-3, 13 (14) E-dien-15-oic acid on superoxide anion and elastase release in human neutrophils through multiple mechanisms. Eur J Pharmacol. 2008;586(1–3):332–9.

    Article  CAS  PubMed  Google Scholar 

  67. Jang M, Pezzuto JM. Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetate-induced oxidative events and gene expression in mouse skin. Cancer Lett. 1998;134(1):81–9.

    Article  CAS  PubMed  Google Scholar 

  68. Khan AQ, Khan R, Qamar W, Lateef A, Rehman MU, Tahir M, et al. Geraniol attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in mouse skin: possible role of p38 MAP Kinase and NF-κB. Exp Mol Pathol. 2013;94(3):419–29.

    Article  CAS  PubMed  Google Scholar 

  69. Rao TS, Currie JL, Shaffer AF, Isakson PC. Comparative evaluation of arachidonic acid (AA)-and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation. 1993;17(6):723–41.

    Article  CAS  PubMed  Google Scholar 

  70. Simpson BS, Claudie DJ, Gerber JP, Pyke SM, Wang J, McKinnon RA, et al. In vivo activity of benzoyl ester clerodane diterpenoid derivatives from Dodonaea polyandra. J Nat Prod. 2011;74(4):650–7.

    Article  CAS  PubMed  Google Scholar 

  71. Salinas-Sánchez DO, Herrera-Ruiz M, Pérez S, Jiménez-Ferrer E, Zamilpa A. Anti-inflammatory activity of hautriwaic acid isolated from Dodonaea viscosa leaves. Molecules. 2012;17(4):4292–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Bautista E, Maldonado E, Ortega A. Neo-clerodane diterpenes from Salvia herbacea. J Nat Prod. 2012;75(5):951–8.

    Article  CAS  PubMed  Google Scholar 

  73. González-Chávez MM, Alonso-Castro AJ, Zapata-Morales JR, Arana-Argáez V, Torres-Romero JC, Medina-Rivera YE, et al. Anti-inflammatory and antinociceptive effects of tilifodiolide, isolated from Salvia tiliifolia Vahl (Lamiaceae). Drug Dev Res. 2018;79(4):165–72.

    Article  PubMed  CAS  Google Scholar 

  74. Necas J, Bartosikova L. Carrageenan: a review. Vet Med. 2013;58(4):187–205.

    Article  CAS  Google Scholar 

  75. Morris CJ. Carrageenan-induced paw edema in the rat and mouse. In Inflammation protocols. Springer: 2003;pp115‒21.

  76. Pierri EG, Castro RC, Vizioli EO, Ferreira CM, Cavalheiro AJ, Tininis AG, et al. Anti-inflammatory action of ethanolic extract and clerodane diterpenes from Casearia sylvestris. Rev Bras Farmacogn. 2017;27(4):495–501.

    Article  CAS  Google Scholar 

  77. Carvalho JCT, Silva MFC, Maciel MAM, da Cunha Pinto A, Nunes DS, Lima RM, et al. Investigation of anti-inflammatory and antinociceptive activities of trans-dehydrocrotonin, a 19-nor-clerodane diterpene from Croton cajucara. Part 1. Planta Med. 1996;62(5):402–4.

    Article  CAS  PubMed  Google Scholar 

  78. ur Rehman T, Khan AU, Abbas A, Hussain J, Khan FU, Stieglitz K, et al. Investigation of nepetolide as a novel lead compound: Antioxidant, antimicrobial, cytotoxic, anticancer, anti-inflammatory, analgesic activities and molecular docking evaluation. Saudi Pharm J. 2018;26(3):422‒9.

  79. Rossi A, Pace S, Tedesco F, Pagano E, Guerra G, Troisi F, et al. The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis in experimental models of inflammation. Pharmacol Res. 2016;106:64–71.

    Article  CAS  PubMed  Google Scholar 

  80. Perazzo FF, Carvalho JCT, Rodrigues M, Morais EKL, Maciel MAM. Comparative anti-inflammatory and antinociceptive effects of terpenoids and an aqueous extract obtained from Croton cajucara Benth. Rev Bras Farmacogn. 2007;17(4):521–8.

    Article  CAS  Google Scholar 

  81. Simpson BS, Luo X, Costabile M, Caughey GE, Wang J, Claudie DJ, et al. Polyandric acid A, a clerodane diterpenoid from the Australian medicinal plant Dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo. J Nat Prod. 2014;77(1):85–91.

    Article  CAS  PubMed  Google Scholar 

  82. Haenszel W, Kurihara M, Segi M, Lee RK. Stomach cancer among Japanese in Hawaii. J Natl Cancer Inst. 1972;49(4):969–88.

    CAS  PubMed  Google Scholar 

  83. Antonisamy P, Dhanasekaran M, Ignacimuthu S, Duraipandiyan V, Balthazar JD, Agastian P, et al. Gastroprotective effect of epoxy clerodane diterpene isolated from Tinospora cordifolia Miers (Guduchi) on indomethacin-induced gastric ulcer in rats. Phytomedicine. 2014;21(7):966–9.

    Article  CAS  PubMed  Google Scholar 

  84. Monsen U, Broström O, Nordenvall B, Sörstad J, Hellers G. Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis. Scand J Gastroenterol. 1987;22(2):214–8.

    Article  CAS  PubMed  Google Scholar 

  85. Zheng JH, Lin SR, Tseng FJ, Tsai MJ, Lue SI, Chia YC, et al. Clerodane diterpene ameliorates inflammatory bowel disease and potentiates cell apoptosis of colorectal cancer. Biomolecules. 2019;9(12):762.

    Article  CAS  PubMed Central  Google Scholar 

  86. Babu NP, Pandikumar P, Ignacimuthu S. Anti-inflammatory activity of Albizia lebbeck Benth., an ethnomedicinal plant, in acute and chronic animal models of inflammation. J Ethnopharmacol. 2009;125(2):356‒60.

  87. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185–96.

    Article  CAS  PubMed  Google Scholar 

  88. Amann R, Schuligoi R, Lanz I, Donnerer J. Histamine-induced edema in the rat paw—effect of capsaicin denervation and a CGRP receptor antagonist. Eur J Pharmacol. 1995;279(2–3):227–31.

    Article  CAS  PubMed  Google Scholar 

  89. Butterfield JH. Increased leukotriene E4 excretion in systemic mastocytosis. Prostag Oth Lipid M. 2010;92(1–4):73–6.

    Article  CAS  Google Scholar 

  90. Shinomiya H, Nakano M. Calcium ionophore A23187 does not stimulate lipopolysaccharide nonresponsive C3H/HeJ peritoneal macrophages to produce interleukin 1. J Immunol. 1987;139(8):2730–6.

    CAS  PubMed  Google Scholar 

  91. Zhang DB, Tang ZS, Xie P, Liang YN, Yu JG, Zhang Z, et al. A pair of new neo-clerodane diterpenoid epimers from the roots of Croton crassifolius and their anti-inflammatory. Nat Pro Res. 2019. https://doi.org/10.1080/14786419.2019.1601193.

    Article  Google Scholar 

  92. Ichihara Y, Takeya K, Hitotsuyanagi Y, Morita H, Okuyama S, Suganuma M, et al. Cajucarinolide and isocajucarinolide: anti-inflammatory diterpenes from Croton cajucara. Planta Med. 1992;58(6):549–51.

    Article  CAS  PubMed  Google Scholar 

  93. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Stinchcomb DM, Pranata J. Conformational and tautomeric equilibria of formohydroxamic acid in the gas phase and in aqueous solution. J Mol Struct. 1996;370(1):25–32.

    Article  CAS  Google Scholar 

  95. Schröder A, Klein K, Winter S, Schwab M, Bonin M, Zell A, et al. Genomics of ADME gene expression: mapping expression quantitative trait loci relevant for absorption, distribution, metabolism and excretion of drugs in human liver. Pharmacogenomics J. 2013;13(1):12–20.

    Article  PubMed  CAS  Google Scholar 

  96. Hughes LD, Palmer DS, Nigsch F, Mitchell JB. Why are some properties more difficult to predict than others? A study of QSPR models of solubility, melting point, and Log P. J Chem Inf Model. 2008;48(1):220–32.

    Article  CAS  PubMed  Google Scholar 

  97. Ebeling H, Edge A, Böhringer H, Allen S, Crawford C, Fabian A, et al. The ROSAT Brightest Cluster Sample—I. The compilation of the sample and the cluster log N—log S distribution. Mon Not R Astron Soc. 1998;301(4):881–914.

    Article  CAS  Google Scholar 

  98. McCracken KG, Barger CP, Sorenson MD. Phylogenetic and structural analysis of the HbA (αA/βA) and HbD (αD/βA) hemoglobin genes in two high-altitude waterfowl from the Himalayas and the Andes: bar-headed goose (Anser indicus) and Andean goose (Chloephaga melanoptera). Mol Phylogen Evol. 2010;56(2):649–58.

    Article  CAS  Google Scholar 

  99. Bade R, Chan HF, Reynisson J. Characteristics of known drug space. Natural products, their derivatives and synthetic drugs. Eur J Med Chem. 2010;45(12):5646–52.

    Article  CAS  PubMed  Google Scholar 

  100. Feng ZL, Lu XQ, Gan LS, Zhang QW, Lin LG. Xanthones, a promising anti-inflammatory scaffold: structure, activity, and drug likeness analysis. Molecules. 2020;25(3):598.

    Article  CAS  PubMed Central  Google Scholar 

  101. Camp D, Garavelas A, Campitelli M. Analysis of physicochemical properties for drugs of natural origin. J Nat Prod. 2015;78(6):1370–82.

    Article  CAS  PubMed  Google Scholar 

  102. Meade EA, Smith WL, Dewitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993;268(9):6610–4.

    CAS  PubMed  Google Scholar 

  103. Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. Eur J Med Chem. 2000;43(20):3714–7.

    Article  CAS  Google Scholar 

  104. Prasanna S, Doerksen R. Topological polar surface area: a useful descriptor in 2D-QSAR. Curr Med Chem. 2009;16(1):21–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kamlet MJ, Doherty RM, Abraham MH, Marcus Y, Taft RW. Linear solvation energy relationship: an improved equation for correlation and prediction of octanol/water partition coefficients of organic nonelectrolytes (including strong hydrogen bond donor solutes). J Phys Chem A. 1988;92(18):5244–55.

    Article  CAS  Google Scholar 

  106. Tarko L. Using the bond order calculated by quantum mechanics to identify the rotatable bonds. Rev Chim. 2011;62:135–8.

    CAS  Google Scholar 

  107. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. Eur J Med Chem. 2002;45(12):2615–23.

    Article  CAS  Google Scholar 

  108. Meanwell NA. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem Res Toxicol. 2011;24(9):1420–56.

    Article  CAS  PubMed  Google Scholar 

  109. Daina A, Michielin O, Zoete V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model. 2014;54(12):3284–301.

    Article  CAS  PubMed  Google Scholar 

  110. Box K, Comer J. Using measured pKa, LogP and solubility to investigate supersaturation and predict BCS class. Curr Drug Metab. 2008;9(9):869–78.

    Article  CAS  PubMed  Google Scholar 

  111. Golumbic C, Orchin M. Partition studies. V. Partition coefficients and ionization constants of methyl-substituted pyridines and quinolines. J Am Chem Soc. 1950;72(9):4145‒7.

  112. Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Del Rev. 2002;54(3):355–66.

    Article  CAS  Google Scholar 

  113. Di L, Kerns EH. Solution stability-plasma, gastrointestinal, bioassay. Curr Drug Metab. 2008;9(9):860–8.

    Article  CAS  PubMed  Google Scholar 

  114. Daina A, Zoete V. A boiledegg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016;11(11):1117–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bode H, Brendel E, Ahr G, Fuhr U, Harder S, Staib A. Investigation of nifedipine absorption in different regions of the human gastrointestinal (GI) tract after simultaneous administration of 13C-and 12C-nifedipine. Eur J Clin Pharmacol. 1996;50(3):195–201.

    Article  CAS  PubMed  Google Scholar 

  116. Wilhelm I, Krizbai IA. In vitro models of the blood–brain barrier for the study of drug delivery to the brain. Mol Pharm. 2014;11(7):1949–63.

    Article  CAS  PubMed  Google Scholar 

  117. Boulton DW, DeVane CL, Liston HL, Markowitz JS. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 2002;71(2):163–9.

    Article  CAS  PubMed  Google Scholar 

  118. Brewer CT, Chen T. Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. Int J Mol Sci. 2017;18(11):2353.

    Article  PubMed Central  CAS  Google Scholar 

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Acknowledgements

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Funding

This research was funded by the Science and Technology Development Fund, Macau SAR (File no. 0031/2019/A1), the National Natural Science Foundation of China (81872754), and University of Macau (File no. MYRG2017-00109-ICMS and MYRG2018-00037-ICMS).

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  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, 999078, People’s Republic of China

    Zheling Feng, Jun Cao, Qingwen Zhang & Ligen Lin

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  1. Zheling Feng
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  2. Jun Cao
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All authors contributed in the preparation of this manuscript. ZLF made contributions to acquisition, compiling and analysis of the data, writing this manuscript. JC and QWZ were responsible for design and revising of this manuscript. LGL is the corresponding author and the guarantor. All authors read and approved the final manuscript.

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Additional file 1: Table S1

.Molecular descriptors of anti-inflammation clerodane diterpenoids. Table S2. Biophysiochemical properties of anti-inflammation clerodane diterpenoids.Table S3, Violations of drug-likeness rules by the anti-inflammation clerodane diterpenoids. For each compound, the type of violations of each rule was described. Table S4 .Absorption and Metabolism parameters of anti-inflammation clerodane diterpenoids.

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Feng, Z., Cao, J., Zhang, Q. et al. The drug likeness analysis of anti-inflammatory clerodane diterpenoids. Chin Med 15, 126 (2020). https://doi.org/10.1186/s13020-020-00407-w

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Keywords

  • Clerodane diterpenoids
  • Anti-inflammation
  • Drug-likeness
  • SwissADME

Chinese Medicine

ISSN: 1749-8546

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