Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes
by
, , , , and
Rubria Marlen Martínez-Casares
1
,
Liliana Hernández-Vázquez
1,
Angelica Mandujano
2,
Leonor Sánchez-Pérez
2
,
Salud Pérez-Gutiérrez
1 and
Julia Pérez-Ramos
1,* 1
Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Coyoacán 04960, CDMX, Mexico
2
Departamento de Atención a la Salud, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Coyoacán 04960, CDMX, Mexico
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(12), 4744; https://doi.org/10.3390/molecules28124744
Submission received: 9 May 2023
/
Revised: 2 June 2023
/
Accepted: 9 June 2023
/
Published: 13 June 2023
(This article belongs to the Special Issue Advances in Isolation, Identification and Biological Activity of Natural Products)
Abstract
:The secondary metabolites of clerodane diterpenoids have been found in several plant species from various families and in other organisms. In this review, we included articles on clerodanes and neo-clerodanes with cytotoxic or anti-inflammatory activity from 2015 to February 2023. A search was conducted in the following databases: PubMed, Google Scholar and Science Direct, using the keywords clerodanes or neo-clerodanes with cytotoxicity or anti-inflammatory activity. In this work, we present studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belonging to 9 families. These plants are mostly from the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. In summary, clerodane diterpenes have activity against different cell cancer lines. Specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some of which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. Furthermore, some diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way.
1. Introduction
Diterpenes are metabolites that come from isoprene units; these compounds can be classified according to their structure [1]. One type of diterpene is clerodanes, which are found in a wide range of plant species, especially those from the Labiatae, Euphorbiaceae and Verbenaceae families [2,3]; they have also been found in bacteria, fungi and marine sponges. This type of diterpene has been extensively studied due to many of them having biological activity [1,2,3,4]. For example, clerodin has anthelminthic activity [5]; salvinorin A is an agonist of κ-opioid receptor-serotonin-2A [6] with potential for use as a treatment in neuropsychiatric disorders [7]; tinosinenosides A–C show cytotoxicity effects against HeLa [8]; and columbin has anti-inflammatory and anticancer efficacy [4].
Clerodanes are secondary metabolites; when these compounds are obtained from plants, they are biosynthesized in the chloroplasts from geranylgeranyl pyrophosphate, producing a labdane-type precursor skeleton, which can be transformed to a halimane-type intermediate, and then converted to either cis- or trans- clerodanes [3] (Figure 1a).
Clerodanes are bicyclic diterpenoids with a fused ring of decalin structure (C1–C10) and a side chain of six carbons at C9. They are classified according to the configuration at the ring fusion and the substituents in C8 and C9 into four types: trans-cis, trans-trans, cis-cis and cis-trans (Figure 1b). About 25% have a cis ring fusion, and 75% have 5:10 trans ring fusion [9].
In this review, we have included clerodanes and neo-clerodanes and their enantiomers ent-neo-clerodanes (Figure 2). Additionally, carbons 12 to 16 are usually oxidized to diene, furan, lactone or hydrofurofuran, which give structural characteristics to clerodane [10].
Cancer is a global health problem and is currently one of the main causes contributing to premature death worldwide [11]. At the present time, even with the great advances in medicine in our understanding and treatment of cancer with multimodal therapies including immunotherapy, gene-targeted therapy, chemotherapy, hormonal therapy and cancer vaccines [12] against specific cell targets, there are needs that have not been covered. These include more effective therapies, with fewer adverse effects, but also therapies at a more affordable cost. Thus, there is still a need to investigate more effective and less toxic compounds. Most of the chemotherapeutic drugs (nearly 65%) that are used in current cancer treatment regimens were originally isolated from natural products or their derivatives such as plants or microorganisms [13]. For instance, paclitaxel, a diterpene isolated from Taxus brevifolia (yew trees), classified as a taxane, is used in the therapy of various types of cancers [14]. Other examples include anthracyclines derived from Streptomyces strains, among them being doxorubicin, bleomycin and many others [13]. The cytotoxic activity of several clerodanes in different cancer cell lines has been described [1].
On the other hand, inflammation is an immune response to different stimuli, such as pathogens such as viruses and bacteria, traumas and chemical irritants [15]; that is to say, inflammation is a protective response of the body against harmful stimuli. Additionally, long-term inflammation could lead to several symptoms, such as pain, fatigue, insomnia, depression and gastrointestinal problems [16]. Chronic inflammation is associated with diseases such as cancer, diabetes and arthritis [17]. The inflammatory response leads to the production of pro-inflammatory mediators, such as cytokines, serotonin, leukotrienes and histamine [18]. These mediators promote vascular permeability, leukocyte migration, blood vessel dilatation and pain. The anti-inflammatory activity of terpenes, such as carvacrol, some carotenes and diterpenes, such as clerodanes, and triterpenes, has been studied [2,19].
In this review, 158 clerodanes and 70 neo-clerodanes (1, 56, 57, 71–73, 94–132, 141–158, 184–187, 196, 197 and 207–210) with cytotoxic and anti-inflammatory activities reported from 2015 to February of 2023 were included. A total of 56 articles were found; in Table 1, the plants, family, collection place and part of the plants from which the clerodanes and neo-clerodanes were isolated are shown.
2. Discussion
This review discusses research from the last 8 years on clerodane and neo-clerodane diterpenes that exhibit cytotoxic and anti-inflammatory activities. It presents studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belong to 9 families. These plants mostly belong to the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. They include 228 clerodanes and neo-clerodanes, of which, 140 have cytotoxic activity, 88 have anti-inflammatory activity and crassifolin Q-U (49–53), compounds 74–77 and (-)-hardwickiic acid (91) have both activities. Compound 75 and 77 were alone in including acute toxicity, but they did not indicate LD50.
2.1. Cytotoxic Activity
All clerodanes included in this review are oxygenated; 58% of them have at least one acetate group, 47% a hydroxyl group, 49% a ring of lactone and 22% a ring of furan as substituents. Additionally, it was found that three diterpenes isolated from Sheareria nana (125–127) have -OSO3H.
We found that 82 compounds out of 140 were evaluated using the MTT assay, which is broadly used to measure the cytotoxic effects of drugs on cancer cell lines, and it is considered a quantitative cytotoxicity analysis; the assay is used more often because in itself, it is relatively straightforward and provides benefits due to the ease of its utility.
Compared to standard cancer therapies, in vitro studies have shown the cytotoxic and antiproliferative properties of different clerodane compounds. The mechanisms involved include growth inhibition, apoptosis, interference with DNA synthesis and driving DNA fragmentation in many cancer cell lines of mesenchymal, epithelial and hematopoietic origin [1,3].
Some clerodane compounds inhibit growth in cancer cell lines. Anacolosins A–F (3–8) and corymbulosins X and Y (9–10) isolated from Anacolosa clarkii exhibit cytotoxic properties in four paediatric cancer types [21]. Caseakurzin B (29) and caseakurzin J (34) from Casearia kurzii were investigated in a lung epithelial carcinoma cell line; the former arrested the cell cycle at the G2/M phase and the second at the S phase. Obtained from the same plant, corymbulosin M (25), caseamembrin B (26) and caseamembrin U (27) were also cytotoxic in three types of cancer cell lines. Of note, corymbulosin M (25) was the most potent of them and apparently even more active than etoposide, and it was shown that it affects the cell cycle at the G0/G1 stage [28]. Kurzipene D (38), also obtained from C. kurzii, has a potent antiproliferative effect compared to other kurzipenes and affects proliferation at the S stage. Further, one in vivo study used a xenograft tumor model in zebra fish embryos; this compound suppressed tumor proliferation and migration comparable to etoposide [26]. Crassifolins Q-U (49–53) from Croton crassifolius inhibited angiogenesis in HUVECs, and crassifolin U (53) had the strongest activity in this model [32]. Notably, the antitumor properties of casearins have been shown using in vivo and ex vivo methods [30]. Epoxy clerodane diterpene (139) isolated from Tinospora cordifolia had cytotoxic activity, inhibiting MCF7 growth by regulating the expression of the functional genes Rb1 and Mdm2 [55].
Several specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. However, it is important to mention that clinical studies are required to demonstrate their efficacy in the therapy of the current cancer pandemic, and demonstrating their safety is also of great importance.
2.2. Anti-Inflammatory Activity
A total of 45% of the clerodanes with anti-inflammatory activity have at least one hydroxyl, 69% compounds contain a ring of lactones, 50% a ring of furans and 26% an acetate group as substituents.
We found that 63 compounds reported to have anti-inflammatory activity were evaluated for nitric oxide inhibition with the Griess assay on RAW264.7 macrophages or BV-2-cell-stimulated-LPS, and the clerodanes 157, 158, 185, 186 and 207 showed the best activity in this test with IC50 values of less than 2 µM. In this review, we found that in vivo studies have only been performed for hautriwaic acid (196) and nepetolide (204).
The anti-inflammatory activity of clerodane diterpenoids mediated by different mechanisms has been demonstrated in in vitro and in vivo animal models. Compounds 154, 155, 157 and 158 from Callicarpa arborea showed potent inhibitory effects against the NLRP3 inflammasome by inhibiting Casp-1 activation and IL-1β in reticulum cell sarcoma cells [59].
Clerodane 74–77 and 206 from extracts of Polyalthia longifolia seeds inhibit inflammation, blocking the synthesis of prostaglandins and leukotrienes through highly selective binding to cyclooxygenases (COX) 1 and 2 and 5-lipooxygenase (5-LOX), respectively, compared to the nonsteroidal anti-inflammatory drugs diclofenac and indomethacin [71]. In 2008, clerodane 206 was associated with the suppression of neutrophil respiratory burst and degranulation, and it is thought that it is mediated at least in part by the inhibition of calcium mobilization, AKT (protein kinase B) and p38 mitogen-activated protein kinase pathways [77]. Hautriwaic acid (196) from Dodonaea viscosa leaves, used for rheumatism, exhibited anti-inflammatory activity in a mouse ear edema model [66]. Clerodane compounds 164–175 from Callicarpa hypoleucophylla suppress superoxide anion generation and elastase release, inhibiting the function of human neutrophils [61]. Trans-crotonin inhibits dextran- and histamine-induced oedema [2].
Compounds derived from the Scutellaria genus have strong interactions with inducible nitric oxide synthase, and because of that, they inhibit nitric oxide production [72]. Five clerodane diterpenoids from Croton crassifolius roots, named crassifolins Q–U (49–53), reduced the levels of IL-6 and TNF-α in lipopolysaccharide-stimulated RAW 264.7 cells [32]. Compounds 211–213 from Tinospora crispa diminish the production of pro-inflammatory mediators (IL-1β, IL-6, TNF-α, iNOs, CCL12 and COX-2) [74].
3. Conclusions
In summary, clerodane diterpenes have activity against different cell cancer lines. Furthermore, some of the diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way, but the discovery of new compounds and new mechanisms remains to be seen. Anyway, the study of possible new therapies for inflammation continues to be important in order to expand the options for the treatment of inflammatory diseases that afflict the world.
More than 50% of clerodanes included in this review with cytotoxic activity contain acetate groups; on the other hand, 69% of the compounds with anti-inflammatory effects have a ring of lactone.
Author Contributions
Conceptualization, J.P.-R. and S.P.-G.; methodology, R.M.M.-C., L.H.-V., A.M., L.S.-P., S.P.-G. and J.P.-R.; validation R.M.M.-C., L.H.-V., A.M., L.S.-P., S.P.-G. and J.P.-R.; formal analysis, R.M.M.-C., L.H.-V., A.M., L.S.-P., S.P.-G. and J.P.-R.; data curation, R.M.M.-C., L.H.-V., A.M., L.S.-P., S.P.-G. and J.P.-R.; writing—original draft preparation, S.P.-G. and A.M.; writing—review and editing, R.M.M.-C., L.H.-V., A.M., L.S.-P., S.P.-G. and J.P.-R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Acquaviva, R.; Malfa, G.A.; Loizzo, M.R.; Xiao, J.; Bianchi, S.; Tundis, R. Advances on Natural Abietane, Labdane and Clerodane Diterpenes as Anti-Cancer Agents: Sources and Mechanisms of Action. Molecules 2022, 27, 4791. [Google Scholar] [CrossRef] [PubMed]
- Feng, Z.; Cao, J.; Zhang, Q.; Lin, L. The Drug Likeness Analysis of Anti-Inflammatory Clerodane Diterpenoids. Chin. Med. 2020, 15, 126. [Google Scholar] [CrossRef] [PubMed]
- Li, R.; Morris-Natschke, S.L.; Lee, K.-H. Clerodane Diterpenes: Sources, Structures, and Biological Activities. Nat. Prod. Rep. 2016, 33, 1166–1226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- dos Lima, J.; Marinho, E.M.; Alencar de Menezes, J.E.; Mendes, F.R.S.; da Silva Antonio, W.; Maria, K.A.F.; Emmanuel, S.M.; Marinho, M.M.; Bandeira, P.N.; dos Santos, H.S. Biological Properties of Clerodane-Type Diterpenes. J. Anal. Pharm. Res. 2022, 11, 56–64. [Google Scholar] [CrossRef]
- Kumar, A.; Shukla, R.; Chaudhary, A. Evaluation of Antiulcerogenic Activity of Clerodendron Infortunatum Extract on Albino Rat Gastric Ulceration. J. Drug Deliv. Ther. 2019, 9, 57–62. [Google Scholar] [CrossRef]
- Ranganathan, M.; Schnakenberg, A.; Skosnik, P.D.; Cohen, B.M.; Pittman, B.; Sewell, R.A.; D’Souza, D.C. Dose-Related Behavioral, Subjective, Endocrine, and Psychophysiological Effects of the κ Opioid Agonist Salvinorin A in Humans. Biol. Psychiatry 2012, 72, 871–879. [Google Scholar] [CrossRef] [Green Version]
- Cichon, J.; Liu, R.; Le, H.V. Therapeutic Potential of Salvinorin A and Its Analogues in Various Neurological Disorders. Transl. Perioper. Pain Med. 2022, 9, 452–457. [Google Scholar]
- Jiang, H.; Zhang, G.-J.; Liu, Y.-F.; Wang, H.-S.; Liang, D. Clerodane Diterpenoid Glucosides from the Stems of Tinospora sinensis. J. Nat. Prod. 2017, 80, 975–982. [Google Scholar] [CrossRef]
- Tokoroyama, T. Synthesis of Clerodane Diterpenoids and Related Compounds—Stereoselective Construction of the Decalin Skeleton with Multiple Contiguous Stereogenic Centers. Synthesis 2000, 2000, 611–633. [Google Scholar] [CrossRef]
- Hagiwara, H. Total Syntheses of Clerodane Diterpenoids—A Review. Nat. Prod. Commun. 2019, 14, 1934578X19843613. [Google Scholar] [CrossRef]
- Soerjomataram, I.; Bray, F. Planning for Tomorrow: Global Cancer Incidence and the Role of Prevention 2020–2070. Nat. Rev. Clin. Oncol. 2021, 18, 663–672. [Google Scholar] [CrossRef] [PubMed]
- Tsimberidou, A.M.; Fountzilas, E.; Nikanjam, M.; Kurzrock, R. Review of Precision Cancer Medicine: Evolution of the Treatment Paradigm. Cancer Treat. Rev. 2020, 86, 102019. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; He, Y.; Jian, M.; Fu, X.; Cheng, Y.; He, Y.; Fang, J.; Li, L.; Zhang, D. Breaking the Bottleneck in Anticancer Drug Development: Efficient Utilization of Synthetic Biology. Molecules 2022, 27, 7480. [Google Scholar] [CrossRef] [PubMed]
- Gallego-Jara, J.; Lozano-Terol, G.; Sola-Martínez, R.A.; Cánovas-Díaz, M.; de Diego Puente, T. A Compressive Review about Taxol®: History and Future Challenges. Molecules 2020, 25, 5986. [Google Scholar] [CrossRef]
- Li, D.; Xue, M.; Geng, Z.; Chen, P. The Suppressive Effects of Bursopentine (BP5) on Oxidative Stress and NF-ĸB Activation in Lipopolysaccharide-Activated Murine Peritoneal Macrophages. Cell Physiol. Biochem. 2012, 29, 9–20. [Google Scholar] [CrossRef] [PubMed]
- Pahwa, R.; Goyal, A.; Jialal, I. Chronic Inflammation; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Nathan, C.; Ding, A. Nonresolving Inflammation. Cell 2010, 140, 871–882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fuller, B. Role of PGE-2 and Other Inflammatory Mediators in Skin Aging and Their Inhibition by Topical Natural Anti-Inflammatories. Cosmetics 2019, 6, 6. [Google Scholar] [CrossRef] [Green Version]
- Araruna, M.E.; Serafim, C.; Alves Júnior, E.; Hiruma-Lima, C.; Diniz, M.; Batista, L. Intestinal Anti-Inflammatory Activity of Terpenes in Experimental Models (2010–2020): A Review. Molecules 2020, 25, 5430. [Google Scholar] [CrossRef]
- Olatunde, O.Z.; Yong, J.; Lu, C. New Neo-Clerodane Diterpenoids Isolated from Ajuga decumbens Thunb., Planted at Pingtan Island of Fujian Province with the Potent Anticancer Activity. Anti-Cancer Agents Med. Chem. 2023, 23, 237–244. [Google Scholar]
- Cai, S.; Risinger, A.L.; Petersen, C.L.; Grkovic, T.; O’Keefe, B.R.; Mooberry, S.L.; Cichewicz, R.H. Anacolosins A-F and Corymbulosins X and Y, Clerodane Diterpenes from Anacolosa clarkii Exhibiting Cytotoxicity toward Pediatric Cancer Cell Lines. J. Nat. Prod. 2019, 82, 928–936. [Google Scholar] [CrossRef]
- Vila-Luna, M.L.; Moo-Puc, R.E.; Torres-Tapia, L.W.; Peraza-Sánchez, S.R. Cytotoxic Activity of Casearborin c Isolated from Casearia corymbosa. J. Mex. Chem Soc. 2018, 62, 24–28. [Google Scholar] [CrossRef]
- Meesakul, P.; Ritthiwigrom, T.; Cheenpracha, S.; Sripisut, T.; Maneerat, W.; Machan, T.; Laphookhieo, S. A New Cytotoxic Clerodane Diterpene from Casearia graveolens Twigs. Nat. Prod. Commun. 2016, 11, 13–15. [Google Scholar] [CrossRef] [Green Version]
- Nuanyai, T.; Chailap, B.; Buakeaw, A.; Puthong, S. Cytotoxicity of Clerodane Diterpenoids from Fresh Ripe Fruits of Casearia grewiifolia. J. Sci. Technol. 2017, 39, 517–521. [Google Scholar] [CrossRef]
- Nguyen, H.T.T.; Truong, N.B.; Doan, H.T.M.; Litaudon, M.; Retailleau, P.; Do, T.T.; Nguyen, H.V.; Chau, M.V.; Pham, C.V. Cytotoxic Clerodane Diterpenoids from the Leaves of Casearia grewiifolia. J. Nat. Prod. 2015, 78, 2726–2730. [Google Scholar] [CrossRef]
- Liang, Y.; Zhang, Q.; Yang, X.; Li, Y.; Zhang, X.; Li, Y.; Du, Q.; Jin, D.-Q.; Cui, J.; Lall, N.; et al. Diterpenoids from the Leaves of Casearia kurzii Showing Cytotoxic Activities. Bioorg. Chem. 2020, 98, 103741. [Google Scholar] [CrossRef]
- Zhang, L.-T.; Wang, X.-L.; Wang, T.; Zhang, J.-S.; Huang, Z.-Q.; Shen, T.; Lou, H.-X.; Ren, D.-M.; Wang, X.-N. Dolabellane and Clerodane Diterpenoids from the Twigs and Leaves of Casearia kurzii. J. Nat. Prod. 2020, 83, 2817–2830. [Google Scholar] [CrossRef]
- Shuo, Y.; Zhang, C.; Yang, X.; Liu, F.; Zhang, Q.; Li, A.; Ma, J.; Lee, D.; Ohizumi, Y.; Guo, Y. Clerodane Diterpenoids from Casearia kurzii and Their Cytotoxic Activities. J. Nat. Med. 2019, 73, 826–833. [Google Scholar] [CrossRef]
- Liu, F.; Zhang, Q.; Yang, X.; Xi, Y.; Zhang, X.; Wang, H.; Zhang, J.; Tuerhong, M.; Jin, D.-Q.; Lee, D.; et al. Cytotoxic Diterpenoids as Potential Anticancer Agents from the Twigs of Casearia kurzii. Bioorg. Chem. 2019, 89, 102995. [Google Scholar] [CrossRef]
- Ferreira, P.M.P.; Bezerra, D.P.; do Nascimento Silva, J.; da Costa, M.P.; de Oliveira Ferreira, J.R.; Alencar, N.M.N.; de Figueiredo, I.S.T.; Cavalheiro, A.J.; Machado, C.M.L.; Chammas, R.; et al. Preclinical Anticancer Effectiveness of a Fraction from Casearia Sylvestris and Its Component Casearin X: In Vivo and Ex Vivo Methods and Microscopy Examinations. J. Ethnopharmacol. 2016, 186, 270–279. [Google Scholar] [CrossRef]
- Zou, M.-F.; Pan, Y.-H.; Hu, R.; Yuan, F.-Y.; Huang, D.; Tang, G.-H.; Li, W.; Yin, S. Highly Modified Nor-Clerodane Diterpenoids from Croton yanhuii. Fitoterapia 2021, 153, 104979. [Google Scholar] [CrossRef]
- Li, C.; Sun, X.; Yin, W.; Zhan, Z.; Tang, Q.; Wang, W.; Zhuo, X.; Wu, Z.; Zhang, H.; Li, Y.; et al. Crassifolins Q−W: Clerodane Diterpenoids From Croton crassifolius With Anti-Inflammatory and Anti-Angiogenesis Activities. Front. Chem. 2021, 9, 733350. [Google Scholar] [CrossRef]
- Tian, J.-L.; Yao, G.-D.; Wang, Y.-X.; Gao, P.-Y.; Wang, D.; Li, L.-Z.; Lin, B.; Huang, X.-X.; Song, S.-J. Cytotoxic Clerodane Diterpenoids from Croton crassifolius. Bioorg. Med. Chem. Lett. 2017, 27, 1237–1242. [Google Scholar] [CrossRef] [PubMed]
- Qiu, M.; Cao, D.; Gao, Y.; Li, S.; Zhu, J.; Yang, B.; Zhou, L.; Zhou, Y.; Jin, J.; Zhao, Z. New Clerodane Diterpenoids from Croton crassifolius. Fitoterapia 2016, 108, 81–86. [Google Scholar] [CrossRef] [PubMed]
- Vendruscolo, I.; Venturella, S.R.T.; Bressiani, P.A.; Marco, I.G.; Novello, C.R.; Almeida, I.V.; Vicentini, V.E.P.; Mello, J.C.P.; Düsman, E. Cytotoxicity of Extracts and Compounds Isolated from Croton echioides in Animal Tumor Cell (HTC). Braz. J. Biol. 2022, 82, e264356. [Google Scholar] [CrossRef] [PubMed]
- Guetchueng, S.T.; Nahar, L.; Ritchie, K.J.; Ismail, F.M.D.; Evans, A.R.; Sarker, S.D. Ent-Clerodane Diterpenes from the Bark of Croton oligandrus Pierre Ex Hutch. and Assessment of Their Cytotoxicity against Human Cancer Cell Lines. Molecules 2018, 23, 410. [Google Scholar] [CrossRef] [Green Version]
- Ng, S.-Y.; Kamada, T.; Suleiman, M.; Vairappan, C.S. Two New Clerodane-Type Diterpenoids from Bornean Liverwort Gottschelia schizopleura and Their Cytotoxic Activity. Nat. Prod. Res. 2018, 32, 1832–1837. [Google Scholar] [CrossRef]
- Aimaiti, S.; Suzuki, A.; Saito, Y.; Fukuyoshi, S.; Goto, M.; Miyake, K.; Newman, D.J.; O’Keefe, B.R.; Lee, K.-H.; Nakagawa-Goto, K. Corymbulosins I–W, Cytotoxic Clerodane Diterpenes from the Bark of Laetia corymbulosa. J. Org. Chem. 2018, 83, 951–963. [Google Scholar] [CrossRef] [PubMed]
- Widyowati, R.; Sugimoto, S.; Yamano, Y.; Sukardiman; Otsuka, H.; Matsunami, K. New Cis-Ent-Clerodanes from Linaria japonica. Phytochem. Lett. 2015, 14, 56–62. [Google Scholar] [CrossRef]
- Tatipamula, V.B.; Thonangi, C.V.; Dakal, T.C.; Vedula, G.S.; Dhabhai, B.; Polimati, H.; Akula, A.; Nguyen, H.T. Potential Anti-Hepatocellular Carcinoma Properties and Mechanisms of Action of Clerodane Diterpenes Isolated from Polyalthia longifolia Seeds. Sci. Rep. 2022, 12, 9267. [Google Scholar] [CrossRef]
- Yu, Z.-X.; Fu, Y.-H.; Chen, G.-Y.; Song, X.-P.; Han, C.-R.; Li, X.-B.; Song, X.-M.; Wu, A.-Z.; Chen, S.-C. New Clerodane Diterpenoids from the Roots of Polyalthia laui. Fitoterapia 2016, 111, 36–41. [Google Scholar] [CrossRef]
- Bautista, E.; Fragoso-Serrano, M.; Ortiz-Pastrana, N.; Toscano, R.A.; Ortega, A. Structural Elucidation and Evaluation of Multidrug-Resistance Modulatory Capability of Amarissinins A–C, Diterpenes Derived from Salvia amarissima. Fitoterapia 2016, 114, 1–6. [Google Scholar] [CrossRef] [PubMed]
- Fragoso-Serrano, M.; Ortiz-Pastrana, N.; Luna-Cruz, N.; Toscano, R.A.; Alpuche-Solís, A.G.; Ortega, A.; Bautista, E. Amarisolide F, an Acylated Diterpenoid Glucoside and Related Terpenoids from Salvia amarissima. J. Nat. Prod. 2019, 82, 631–635. [Google Scholar] [CrossRef]
- Bautista, E.; Fragoso-Serrano, M.; Toscano, R.A.; García-Peña, M.d.R.; Ortega, A. Teotihuacanin, a Diterpene with an Unusual Spiro-10/6 System from Salvia amarissima with Potent Modulatory Activity of Multidrug Resistance in Cancer Cells. Org. Lett. 2015, 17, 3280–3282. [Google Scholar] [CrossRef] [PubMed]
- Bustos-Brito, C.; Pérez-Juanchi, D.; Rivera-Chávez, J.; Hernández-Herrera, A.D.; Bedolla-García, B.Y.; Zamudio, S.; Ramírez-Apan, T.; Quijano, L.; Esquivel, B. Clerodane and 5 10-Seco-Clerodane-Type Diterpenoids from Salvia involucrata. J. Mol. Struct. 2021, 1237, 130367. [Google Scholar] [CrossRef]
- Jiang, Y.-J.; Su, J.; Shi, X.; Wu, X.-D.; Chen, X.-Q.; He, J.; Shao, L.-D.; Li, X.-N.; Peng, L.-Y.; Li, R.-T.; et al. Neo-Clerodanes from the Aerial Parts of Salvia leucantha. Tetrahedron 2016, 72, 5507–5514. [Google Scholar] [CrossRef]
- Wang, M.; Chen, Y.; Hu, P.; Ji, J.; Li, X.; Chen, J. Neoclerodane Diterpenoids from Scutellaria barbata with Cytotoxic Activities. Nat. Prod. Res. 2020, 34, 1345–1351. [Google Scholar] [CrossRef]
- Yang, G.-C.; Hu, J.-H.; Li, B.-L.; Liu, H.; Wang, J.-Y.; Sun, L.-X. Six New Neo-Clerodane Diterpenoids from Aerial Parts of Scutellaria barbata and Their Cytotoxic Activities. Planta Med. 2018, 84, 1292–1299. [Google Scholar] [CrossRef]
- Yuan, Q.-Q.; Song, W.-B.; Wang, W.-Q.; Xuan, L.-J. Scubatines A–F, New Cytotoxic Neo-Clerodane Diterpenoids from Scutellaria barbata D. Don. Fitoterapia 2017, 119, 40–44. [Google Scholar] [CrossRef]
- Wang, M.; Ma, C.; Chen, Y.; Li, X.; Chen, J. Cytotoxic Neo-Clerodane Diterpenoids from Scutellaria barbata D.Don. Chem. Biodivers. 2019, 16, e1800499. [Google Scholar] [CrossRef]
- Dai, S.-J.; Xiao, K.; Zhang, L.; Han, Q.-T. New Neo-Clerodane Diterpenoids from Scutellaria strigillosa with Cytotoxic Activities. J. Asian Nat. Prod. Res. 2016, 18, 456–461. [Google Scholar] [CrossRef]
- Dai, S.-J.; Zhang, L.; Xiao, K.; Han, Q.-T. New Cytotoxic Neo-Clerodane Diterpenoids from Scutellaria strigillosa. Bioorg. Med. Chem. Lett. 2016, 26, 1750–1753. [Google Scholar] [CrossRef] [PubMed]
- Tang, Z.; Shen, J.; Zhang, F.; Liang, J.; Xia, Z. Sulfated Neo-Clerodane Diterpenoids and Triterpenoid Saponins from Sheareria nana S. Moore. Fitoterapia 2018, 124, 12–16. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.; Zhang, P.-L.; Zhou, M.-X.; Shen, T.; Zou, Y.-X.; Lou, H.-X.; Wang, X.-N. New Nor-Clerodane-Type Furanoditerpenoids from the Rhizomes of Tinospora capillipes. Phytochem. Lett. 2016, 15, 225–229. [Google Scholar] [CrossRef]
- Subash-Babu, P.; Alshammari, G.M.; Ignacimuthu, S.; Alshatwi, A.A. Epoxy Clerodane Diterpene Inhibits MCF-7 Human Breast Cancer Cell Growth by Regulating the Expression of the Functional Apoptotic Genes Cdkn2A, Rb1, Mdm2 and P53. Biomed. Pharmacother. 2017, 87, 388–396. [Google Scholar] [CrossRef]
- Qin, N.; Wang, A.; Li, D.; Wang, K.; Lin, B.; Li, Z.; Hua, H. Cytotoxic Clerodane Furanoditerpenoids from the Root of Tinospora sagittata. Phytochem. Lett. 2015, 12, 173–176. [Google Scholar] [CrossRef]
- Liu, W.; Song, Z.; Wang, H.; Yang, X.; Joubert, E.; Zhang, J.; Li, S.; Tuerhong, M.; Abudukeremu, M.; Jin, J.; et al. Diterpenoids as Potential Anti-Inflammatory Agents from Ajuga pantantha. Bioorg. Chem. 2020, 101, 103966. [Google Scholar] [CrossRef]
- Dong, B.; Yang, X.; Liu, W.; An, L.; Zhang, X.; Tuerhong, M.; Du, Q.; Wang, C.; Abudukeremu, M.; Xu, J.; et al. Anti-Inflammatory Neo-Clerodane Diterpenoids from Ajuga pantantha. J. Nat. Prod. 2020, 83, 894–904. [Google Scholar] [CrossRef]
- Pu, D.-B.; Zhang, X.-J.; Bi, D.-W.; Gao, J.-B.; Yang, Y.; Li, X.-L.; Lin, J.; Li, X.-N.; Zhang, R.-H.; Xiao, W.-L. Callicarpins, Two Classes of Rearranged Ent-Clerodane Diterpenoids from Callicarpa Plants Blocking NLRP3 Inflammasome-Induced Pyroptosis. J. Nat. Prod. 2020, 83, 2191–2199. [Google Scholar] [CrossRef]
- Wang, Y.; Lin, J.; Wang, Q.; Shang, K.; Pu, D.-B.; Zhang, R.-H.; Li, X.-L.; Dai, X.-C.; Zhang, X.-J.; Xiao, W.-L. Clerodane Diterpenoids with Potential Anti-Inflammatory Activity from the Leaves and Twigs of Callicarpa cathayana. Chin. J. Nat. Med. 2019, 17, 953–962. [Google Scholar] [CrossRef]
- Lin, Y.-C.; Lin, J.-J.; Chen, S.-R.; Hwang, T.-L.; Fang, S.-Y.; Korinek, M.; Chen, C.-Y.; Lin, Y.-S.; Wu, T.-Y.; Yen, M.-H.; et al. Clerodane Diterpenoids from Callicarpa hypoleucophylla and Their Anti-Inflammatory Activity. Molecules 2020, 25, 2288. [Google Scholar] [CrossRef]
- Ye, G.-H.; Xue, J.-J.; Liang, W.-L.; Yang, S.-J. Three New Bioactive Diterpenoids from the Roots of Croton crassifolius. Nat. Prod. Res. 2021, 35, 1421–1427. [Google Scholar] [CrossRef] [PubMed]
- Queiroz, S.A.S.; Pinto, M.E.F.; Bobey, A.F.; Russo, H.M.; Batista, A.N.L.; Batista, J.M.; Codo, A.C.; Medeiros, A.I.; Bolzani, V.S. Diterpenoids with Inhibitory Activity of Nitrite Production from Croton floribundus. J. Ethnopharmacol. 2020, 249, 112320. [Google Scholar] [CrossRef]
- Li, F.; Zhang, D.-B.; Li, J.-T.; He, F.-J.; Zhu, H.-L.; Li, N.; Xiao, X.-C.; Ren, L.; Zheng, W. Bioactive Terpenoids from Croton laui. Nat. Prod. Res. 2021, 35, 2849–2857. [Google Scholar] [CrossRef]
- 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. 2021, 35, 2722–2729. [Google Scholar] [CrossRef]
- Salinas-Sánchez, D.O.; Zamilpa, A.; Pérez, S.; Herrera-Ruiz, M.; Tortoriello, J.; González-Cortazar, M.; Jiménez-Ferrer, E. Effect of Hautriwaic Acid Isolated from Dodonaea viscosa in a Model of Kaolin/Carrageenan-Induced Monoarthritis. Planta Med. 2015, 81, 1240–1247. [Google Scholar] [CrossRef] [Green Version]
- Zhang, P.-Z.; Zhang, Y.-M.; Lin, Y.; Wang, F.; Zhang, G.-L. Three New Diterpenes from Dysoxylum lukii and Their NO Production Inhibitory Activity. J. Asian Nat. Prod. Res. 2020, 22, 531–536. [Google Scholar] [CrossRef]
- Li, Y.; Zhu, R.; Zhang, J.; Wu, X.; Shen, T.; Zhou, J.; Qiao, Y.; Gao, Y.; Lou, H. Clerodane Diterpenoids from the Chinese Liverwort Jamesoniella autumnalis and Their Anti-Inflammatory Activity. Phytochemistry 2018, 154, 85–93. [Google Scholar] [CrossRef]
- Polbuppha, I.; Suthiphasilp, V.; Maneerat, T.; Charoensup, R.; Limtharakul, T.; Cheenpracha, S.; Pyne, S.G.; Laphookhieo, S. Nitric Oxide Production Inhibitory Activity of Clerodane Diterpenes from Monoon membranifolium. Nat. Prod. Res. 2022, 36, 2513–2517. [Google Scholar] [CrossRef]
- ur Rehman, T.; Khan, A.; Abbas, A.; Hussain, J.; Khan, F.U.; Stieglitz, K.; Ali, S. 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, 422–429. [Google Scholar] [CrossRef]
- Nguyen, H.T.; Vu, T.-Y.; Chandi, V.; Polimati, H.; Tatipamula, V.B. Dual COX and 5-LOX Inhibition by Clerodane Diterpenes from Seeds of Polyalthia longifolia (Sonn.) Thwaites. Sci. Rep. 2020, 10, 15965. [Google Scholar] [CrossRef]
- Feng, X.-S.; Yan, W.; Bai, L.-H.; Wang, K.; Chen, X.-Q. Neo-Clerodane Diterpenoids from the Aerial Parts of Scutellaria barbata with Anti-Inflammatory Activity. Chem. Biodivers. 2021, 18, e2100693. [Google Scholar] [CrossRef] [PubMed]
- Lv, H.-W.; Luo, J.-G.; Zhu, M.-D.; Zhao, H.-J.; Kong, L.-Y. Neo-Clerodane Diterpenoids from the Aerial Parts of Teucrium fruticans Cultivated in China. Phytochemistry 2015, 119, 26–31. [Google Scholar] [CrossRef] [PubMed]
- You, J.-Q.; Liu, Y.-N.; Zhou, J.-S.; Sun, X.-Y.; Lei, C.; Mu, Q.; Li, J.-Y.; Hou, A.-J. Cis-Clerodane Diterpenoids with Structural Diversity and Anti-Inflammatory Activity from Tinospora crispa. Chin. J. Chem. 2022, 40, 2882–2892. [Google Scholar] [CrossRef]
- Zhu, Y.-L.; Deng, L.; Song, J.-Q.; Zhu, Y.; Yuan, R.-W.; Fan, X.-Z.; Zhou, H.; Huang, Y.-S.; Zhang, L.-J.; Liao, H.-B. Clerodane Diterpenoids with Anti-Inflammatory and Synergistic Antibacterial Activities from Tinospora crispa. Org. Chem. Front. 2022, 9, 6945–6957. [Google Scholar] [CrossRef]
- Zhang, G.; Ma, H.; Hu, S.; Xu, H.; Yang, B.; Yang, Q.; Xue, Y.; Cheng, L.; Jiang, J.; Zhang, J.; et al. Clerodane-Type Diterpenoids from Tuberous Roots of Tinospora sagittata (Oliv.) Gagnep. Fitoterapia 2016, 110, 59–65. [Google Scholar] [CrossRef]
- Chang, H.-L.; Chang, F.-R.; Chen, J.-S.; Wang, H.-P.; Wu, Y.-H.; Wang, C.-C.; Wu, Y.-C.; Hwang, T.-L. 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, 332–339. [Google Scholar] [CrossRef]
Figure 1.
(a) Biosynthesis of clerodanes and (b) general structure of clerodanes.
Figure 2.
Absolute clerodane configuration.
Figure 3.
Isolated compound of Ajuga decumbens and Anacolosa clarkii.
Figure 4.
Isolated compounds of different species of Casearia.
Figure 5.
Isolated compounds of different species of Casearia (continued).
Figure 6.
Isolated compounds of different species of Croton.
Figure 7.
Isolated compounds of Gottschelia schizopleura and Laetia corymbulosa.
Figure 8.
Isolated compounds of Linaria japonica and Polyalthia longifolia.
Figure 9.
Isolated compounds of different species of Salvia.
Figure 10.
Isolated compounds of Scutellaria barbata (continued).
Figure 11.
Isolated compounds of Scutellaria barbata.
Figure 12.
Isolated compounds of Scutellaria strigillosa.
Figure 13.
Isolated compounds of Sheareria nana, Tinospora capillipes, Tinospora cordifolia and Tinospora sagittata.
Figure 13.
Isolated compounds of Sheareria nana, Tinospora capillipes, Tinospora cordifolia and Tinospora sagittata.
Figure 14.
Compounds of Ajuga pantantha and Callicarpa arborea with anti-inflammatory activity.
Figure 15.
Compounds of Callicarpa cathayana and Callicarpa hypoleucophylla with anti-inflammatory activity.
Figure 15.
Compounds of Callicarpa cathayana and Callicarpa hypoleucophylla with anti-inflammatory activity.
Figure 16.
Compounds of different species of Croton with anti-inflammatory activity.
Figure 17.
Compounds of different species of Croton with anti-inflammatory activity (continued).
Figure 18.
Compounds of Dodonaea viscosa, Dysoxylum lukii, Jamesoniella autumnalis, Monon membranifolium, Nepeta suavis, Polyalthia longifolia and Scutellaria barbata with anti-inflammatory activity.
Figure 18.
Compounds of Dodonaea viscosa, Dysoxylum lukii, Jamesoniella autumnalis, Monon membranifolium, Nepeta suavis, Polyalthia longifolia and Scutellaria barbata with anti-inflammatory activity.
Figure 19.
Compounds of different species of Teucrium fructicans, Tinospora crispa and Tinospora sagittata with anti-inflammatory activity.
Figure 19.
Compounds of different species of Teucrium fructicans, Tinospora crispa and Tinospora sagittata with anti-inflammatory activity.
Table 1.
Part of plant, family and collection place of plants that contained clerodanes or neo-cleordanes.
Table 1.
Part of plant, family and collection place of plants that contained clerodanes or neo-cleordanes.
| Plant | Family | Part of Plant | Collection Place |
|---|---|---|---|
| Ajuga decumbens [20] | Lamiaceae | Aerial parts | Pingtan island of Fujian Province. |
| Anacolosa clarkia [21] | Olacaceae | Fruit, leaves and twigs of the plant | Bana Forest Preserve in Danang. NCI Natural Products Repository. |
| Casearia corymbosa [22] | Salicaceae | Stem bark | Othón P. Blanco, Quintana Roo, Mexico. |
| Casearia graveolens [23] | Salicaceae | Twigs | Chiang Rai Province, northern Thailand. |
| Casearia grewiifolia [24,25] | Salicaceae | Fresh fruits | Khon Kaen University campus. |
| Leaves | Phu Loc–Thua Thien Hue, Vietnam. | ||
| Casearia kurzii [26,27,28,29] | Salicaceae | Fruit, leaves and twigs | Bana Forest Preserve in Danang, Vietnam. |
| Twigs and leaves | Xishuangbanna County, Yunn an Province, P. R. China. | ||
| Casearia sylvestris [30] | Salicaceae | Leaves | Parque Estadual Carlos Botelho (São Miguel Arcanjo, São Paulo State.) |
| Croton caudatus [31] | Euphorbiaceae | Leaves and twigs | Xishuangbanna Prefecture, Yunnan Province, P. R. China. |
| Croton crassifolius [32,33,34] | Euphorbiaceae | Roots | Yulin City, Guangxi Province, China. |
| Southeast China, Thailand, Vietnam, and Laos. | |||
| Fujian Province, People’s Republic of China. | |||
| Croton echioides [35] | Euphorbiaceae | Stems | Brazil |
| Croton oligandrus [36] | Euphorbiaceae | Bark | Mount Eloundem, Central Region, Cameroon. |
| Gottschelia schizopleura [37] | Cephaloziellaceae | Aerial parts | Mount Alab, Sabah, North Borneo, Malaysia. |
| Laetia corymbulosa [38] | Salicaceae | Bark | The plant was provided by NCI/NIH (Frederick, MD, U.S.). |
| Linaria japonica [39] | Plantaginaceae | Whole plants | Hiroshima, Japan. |
| Polyalthia longifolia [40] | Annonaceae | Seeds | Tirupati, India. |
| Polyalthia laui [41] | Annonaceae | Roots | Hainan Province, China. |
| Salvia amarissima [42,43,44] | Lamiaceae | Leaves and flowers | Teotihuacan, State of Mexico. |
| Aerial portions | Teotihuacan Valley | ||
| Salvia involucrata [45] | Lamiaceae | Aerial parts | Municipality of Xilitla, State of San Luis Potosí, Mexico. |
| Salvia leucantha [46] | Lamiaceae | Aerial parts | Yunnan Province, China. |
| Scutellaria barbata [47,48,49,50] | Lamiaceae | Whole plant | Linyi district, Shandong Province, China. |
| Aerial parts | Purchased in a drugstore of Liaoning Guodayizhi Pharmaceutical Co., Ltd. China. | ||
| Aerial parts | Purchased from Bozhou Herbal Market in Anhui Province, China | ||
| Scutellaria strigillosa [51,52] | Lamiaceae | Whole plants | Yantai district, Shandong Province, China. |
| Whole plants | Hebei, Shandong, Zhejiang and Jilin Provinces, China | ||
| Sheareria nana [53] | Asteraceae | Whole herb | Jishou, Hunan Province, China. |
| Tinospora capillipes [54] | Menispermaceae | Whole herb | Xishuangbanna County, Yunnan Province, China. |
| Tinospora cordifolia [55] | Menispermaceae | Stems | India |
| Tinospora sagittata [56] | Menispermaceae | Roots | Anguo Medicine market in Hebei Province, China. |
| Ajuga pantantha [57,58] | Lamiaceae | Aerial parts | Yunnan Province, China. |
| Aerial parts | Purchased from Anhui Province, China. | ||
| Callicarpa arborea [59] | Lamiaceae | Twigs | Xishuangbanna and Yuanyang Prefectures. |
| Callicarpa cathayana [60] | Lamiaceae | Dried aerial parts | Bozhou Herbal Market in Anhui Province, China. |
| Callicarpa hypoleucophylla [61] | Lamiaceae | Leaves and twigs | Kaohsiung city, Taiwan. |
| Croton crassifolius [32,62] | Euphorbiaceae | Roots | Guangxi Province, China. |
| Croton floribundus [63] | Euphorbiaceae | Roots | Provided by the company Mudas Nativas e Exóticas. LTDA of CNPJ, Araraquara Brazil. |
| Croton laui [64] | Euphorbiaceae | Leaves | Hainan Province, China. |
| Croton poomae [65] | Euphorbiaceae | Leaves and stems | Bung Kan Province, Thailand. |
| Dodonaea viscosa [66] | Sapindaceae | Leaves | Sierra de Huautla, Morelos State, Mexico. |
| Dysoxylum lukii. [67] | Meliaceae | Twigs and leaves | Xishuangbanna County, Yunnan Province, China. |
| Jamesoniella autumnalis [68] | Adelanthaceae | Whole plant | Wangtiane park, Changbaishan City, Jilin Province, China. |
| Monoon membranifolium [69] | Annonaceae | Twig extract | Thailand and Peninsula Malaysia. |
| Nepeta suavis [70] | Lamiaceae | Roots | Found in central and southern Europe, North Africa and southern Asia. |
| Polyalthia longifolia [71] | Annonaceae | Seeds | Seshachalam hills, Tirupati, India. |
| Scutellaria barbata [72] | Lamiaceae | Aerial parts | Baise city, Guangxi Province, China. |
| Teucrium fructicans [73] | Lamiaceae | Aerial parts | Jiansu Province, China. |
| Tinospora crispa [74,75] | Menispermaceae | Stems | Mengla County, Yunnan Province, China. |
| Vines and leaves | Longzhou County, Guangxi Province, China. | ||
| Tinospora sagittata [76] | Menispermaceae | Tuberous roots | Shiyan city of Hubei Province, China. |
Table 2.
Clerodane diterpenes with cytotoxic activity.
| Plant Source | Compound Name | Methods | Results | References |
|---|---|---|---|---|
| Ajuga decumbens | Compound 1 | CCK8 method A549 HeLa | IC50 µM 71.4 71.6 | [20] |
| Ajugamarin A1 (2) | A549 HeLa | 76.7 5.39 × 10−7 | ||
| Anacolosa clarkii | Anacolosin A (3) | SRB assay A-673 SJCRH30 D283 Hep293TT | TGI μM 1.10 0.52 0.70 1.00 | [21] |
| Anacolosin B (4) | A-673 SJCRH30 D283 Hep293TT | 1.00 0.50 0.60 0.90 | ||
| Anacolosin C (5) | A-673 SJCRH30 D283 Hep293TT | 1.10 0.67 0.66 1.00 | ||
| Anacolosin D (6) | A-673 SJCRH30 D283 Hep293TT | 1.20 0.73 0.66 0.80 | ||
| Anacolosin E (7) | A-673 SJCRH30 D283 Hep293TT | 3.10 1.90 2.00 1.80 | ||
| Anacolosin F (8) | A-673 SJCRH30 D283 Hep293TT | 4.10 2.30 2.30 3.20 | ||
| Corymbulosin X (9) | A-673 SJCRH30 D283 Hep293TT | 0.70 0.34 0.36 0.22 | ||
| Corymbulosin Y (10) | A-673 SJCRH30 D283 Hep293TT | 1.00 0.44 0.70 0.28 | ||
| Compound 11 | A-673 SJCRH30 D283 Hep293TT | 1.70 0.80 1.10 0.60 | ||
| Caseamembrin S (12) | A-673 SJCRH30 D283 Hep293TT | 0.90 0.36 0.50 0.30 | ||
| Casearia corymbosa | Casearborin c (13) | SRB assay HeLa SiHa Vero | CC50µM (SI) 13.44 77.36 50.26 | [22] |
| Casearia graveolens | Caseariagraveolin (14) | REMA assay KB MCF-7 | IC50 μM 2.48 6.63 | [23] |
| Casearia grewiifolia | Caseargrewiin M (15) | MTT assay BT474 Chago-K1 Hep-G2 KATO-III SW620 | IC50 µg/mL 6.30 6.10 4.64 5.50 5.50 | [24,25] |
| Caseargrewiin G (16) | BT474 Chago-K1 Hep-G2 KATO-III SW620 | 5.67 6.10 0.90 5.46 3.85 | ||
| Caseagrewiifolin B (17) | WST-1 assay KB Hep-G2 | IC50 μM 6.2 7.0 | ||
| Caseanigrescen D (18) | KB Hep-G2 LU-1 MCF-7 NIH-3T3 | 0.5 0.3 0.9 0.8 0.3 | ||
| Casearia kurzii | Kurziterpene A (19) | MTT assay A549, HeLa HepG2 | IC50 μM 40.8 >60 >60 | [26,27,28,29] |
| Kurziterpene B (20) | A549 HeLa Hep-G2 | 19.7 12.1 49.3 | ||
| Kurziterpene C (21) | A549, HeLa Hep-G2 | >60 49.4 >60 | ||
| Kurziterpene D (22) | A549, HeLa Hep-G2 | 18.3 9.0 >60 | ||
| Kurziterpene E (23) | A549, HeLa Hep-G2 | 10.2 5.3 10.7 | ||
| Analysis via flow cytometry | Apoptosis of HeLa | |||
| (2R,5S,6S,8R,9R,10S,18S,19S)-2,19-diacetoyloxy-6,18-dimethoxy-18,19-epoxycleroda-3,13(16),14-triene (24) | MTT assay A549 HeLa Hep-G2 | IC50 μM >60 17.9 >60 | ||
| Corymbulosin M (25) | A549 HeLa Hep-G2 | 5.5 4.1 9.3 | ||
| Analysis via flow cytometry | Apoptosis of HeLa | |||
| Caseamembrin B (26) | MTT assay A549 HeLa Hep-G2 | IC50 μM 36.1 18.8 >60 | ||
| Caseamembrin U (27) | A549 HeLa Hep-G2 | 33.2 15.6 >60 | ||
| Caseakurzin A (28) | QIR assay A549 | IC50 μM 10.8 | ||
| Caseakurzin B (29) | QIR assay A549 | IC50 μM 4.4 | ||
| Cell apoptosis assay | Apoptosis of A549 | |||
| Caseakurzin C (30) | QIR assay A549 | IC50 μM 30.3 | ||
| Caseakurzin D (31) | 27.8 | |||
| Caseakurzin E (32) | 32.7 | |||
| Caseakurzin F (33) | 26.8 | |||
| Caseakurzin J (34) | QIR assay A549 | IC50 μM 4.6 | ||
| Cell apoptosis assay | Apoptosis of A549 | |||
| Kurzipene A (35) | MTT assay Hep-G2 A549 HeLa K562 | IC50 μM >60 >60 >60 >60 | ||
| Kurzipene B (36) | Hep-G2 A549 HeLa K562 | >60 32.6 54.6 >60 | ||
| Kurzipene C (37) | Hep-G2 A549 HeLa K562 | >60 >60 >60 >60 | ||
| Kurzipene D (38) | Hep-G2 A549 HeLa K562 | 9.7 10.9 12.4 7.2 | ||
| Flow cytometry | Apoptosis of Hep-G2 | |||
| Anti-tumor assay using zebrafish model | It blocked tumor cell invasion and metastasis | |||
| Kurzipene E (39) | Hep-G2 A549 HeLa K562 | >60 >60 >60 >60 | ||
| Kurzipene F (40) | Hep-G2 A549 HeLa K562 | >60 >60 33.1 >60 | ||
| Corymbulosin V (41) | Hep-G2 A549 HeLa K562 | 16.8 11.2 14.2 10.3 | ||
| Corymbulosin M (25) | Hep-G2 A549 HeLa K562 | 20.6 18.4 17.5 16.5 | ||
| Casearia sylvestris | Casearin X (42) | Induced sarcoma tumor 25 mg/kg/day | Tumor inhibition % 90.0 | [30] |
| Croton caudatus | Crocleropene A (43) | MTT assay MCF-7 | IC50 μM 35.8 | [31] |
| Crocleropene B (44) | MCF-7 | 40.2 | ||
| Croton crassifolius | Crassifolius A (45) | Morphology | Induced apoptosis | [32,33,34] |
| Western blot | Caspase activation | |||
| MTT assay Hep3B Hep-G2 | IC50 µM 17.91 42.04 | |||
| Crassifolin C (46) | Hep-G2 | 51.63 | ||
| Compound 47 | Hep-G2 | 45.22 | ||
| Crassifolin B (48) | CT26.WT | 96.6 | ||
| Crassifolin Q (49) | HUVEC assay | Compounds 49–51 and 53 inhibited angiogenesis | ||
| Crassifolin R (50) | ||||
| Crassifolin S (51) | ||||
| Crassifolin T (52) | HUVEC assay | Anti-angiogenesis effect | ||
| Crassifolin U (53) | HUVEC assay Junction densities Vessel areas Vessel lengths | IC50 μM 7.20 48.27 8.62 | ||
| Croton echioides | CEH-1 (54) | MTT assay HTC | Compound 54 diminished 67% cell viability and 55 < 76%. | [35] |
| CEH-4 (55) | ||||
| Croton oligandrus | Megalocarpoidolide D (56) | MTT assay A549 MCF-7 | IC50 µM 63.8 136.2. | [36] |
| 12-epi-megalocarpodolide D (57) | A549 MCF-7 | 138.6 171.3 | ||
| Gottschelia schizopleura | Schizopleurolide A (58) | MTT assay HL-60 B16-F10 | IC50 µM 38.47 47.25 | [37] |
| Schizopleurolide B (59) | HL-60 B16-F10 | 36.13 44.33 | ||
| Laetia corymbulosa | Corymbulosin I (60) | Flow cytometry | Compounds 60, 61, 12 and 11 induced apoptosis in MDA-MB-231 | [38] |
| SRB assay A549 MDA-MB-231 MCF-7 KB KB-VIN | IC50 µM 0.66 0.48 0.68 0.56 0.98 | |||
| Corymbulosin K (61) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 0.47 0.49 0.50 0.45 0.49 | ||
| Corymbulosin L (62) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 4.60 4.95 4.94 5.19 4.92 | ||
| Corymbulosin N (63) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 5.04 4.90 5.82 5.23 5.19 | ||
| Corymbulosin O (64) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 4.75 3.31 4.65 4.25 4.76 | ||
| Corymbulosin P (65) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 5.98 4.93 6.39 5.16 5.03 | ||
| Corymbulosin Q (66) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 40.2 20.5 31.7 19.8 39.2 | ||
| Corymbulosin S (67) | A549 MDA-MB-231 MCF-7 KB KB-VIN | >40 22.9 26.2 25.1 26.6 | ||
| Corymbulosin T (68) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 2.29 0.49 0.69 0.56 0.61 | ||
| Corymbulosin V (41) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 4.76 4.73 5.19 4.74 4.88 | ||
| Caseamembrin S (12) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 0.58 0.45 0.66 0.53 0.90 | ||
| Caseamembrin E (69) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 0.53 0.40 0.55 0.43 0.51 | ||
| Corymbulosin A (70) | A549 MDA-MB-231 MCF-7 KB KB-VIN | 0.45 0.43 0.44 0.42 0.45 | ||
| Compound 11 | A549 MDA-MB-231 MCF-7 KB KB-VIN | 4.15 0.54 0.89 0.73 4.07 | ||
| Linaria japonica | Linarenone C (71) | MTT assay A549 | IC50 µM 51.2 | [39] |
| Linarenone E (72) | 86.5 | |||
| Linarienone (73) | 79.0 | |||
| Polyalthia longifolia | 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (74) | Evaluation of morphometric liver and biochemical parameters in (NDEA+PB)-induced HCC rats | Compound 75 and 77 restored the parameters’ biochemical and liver morphology | [40] |
| MTT assay Hep-G2 | IC50 µg/mL 34.33 | |||
| 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (75) | Hep-G2 HuH-7 | 14.34 47.32 | ||
| 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (76) | Hep-G2 | 29.21 | ||
| 3β-16a-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (77) | Hep-G2 HuH-7 | 24.91 48.57 | ||
| Polyalthia laui | Polylauiester A (78) | MTT assay HeLa MCF-7 A549 | IC50 μM 34.84 33.21 35.65 | [41] |
| (4→2)-abeo-2,13-diformyl-cleroda-2,12E-dien-14-oic acid (79) | HeLa MCF-7 A549 | 39.31 37.35 37.82 | ||
| Polylauiamide B (80) | HeLa MCF-7 A549 | 28.09 29.16 29.25 | ||
| Polylauiamide C (81) | HeLa MCF-7 A549 | 25.01 30.30 28.65 | ||
| Polylauiamide D (82) | HeLa MCF-7 A549 | 26.73 27.03 28.88 | ||
| Salvia amarissima | Teotihuacanin (83) | SRB assay MDA-MB-231 HeLa HCT-15 HCT-116 MCF-7 | IC50 μM 12.3 13.7 12.9 10.9 >20 | [42,43,44] |
| Amarissinin A (84) | MCF-7 MCF-7/Vin+ MDA-MB-231 HeLa | 18.2 0.27 19.3 14.0 | ||
| Amarissinin B (85) | SRB assay | 83, 84, 85, 86 and 87 exhibited MDR modulatory effects in mammalian cancer cells | ||
| Amarissinin C (86) | ||||
| Amarisolide F (87) | SRB assay MCF-7 HeLa HCT-15 HCT-116 MDA-MB-231 | IC50 μM 42.1 >42 >42 >42 >42 | ||
| Salvia involucrata | Involucratin A (88) | U251 PC-3 K562 SKLU-1 | 49.6 14.7 24.8 12.6 | [45] |
| Involucratin B (89) | U251 PC-3 K562 HCT-15 MCF-7 SKLU-1 COS-7 | 5.1 23.5 34.7 11.8 0.5 36.7 21.6 | ||
| Involucratin C (90) | PC-3 K562 HCT-15 SKLU-1 COS-7 | 11.0 19.4 9.7 16.8 11.9 | ||
| (-)-Hardwickiic acid (91) | U251 PC-3 K562 HCT-15 MCF-7 SKLU-1 COS-7 | 22.4 1.8 45.5 10.4 1.4 11.5 19.8 | ||
| 7α-hydroxybacchotricuneatin A (92) | U251 PC-3 K562 HCT-15 SKLU-1 COS-7 | 3.8 12.8 20.2 13.3 33.0 14.2 | ||
| Kingidiol (93) | SRB assay U251 PC-3 K562 HCT-15 MCF-7 SKLU-1 COS-7 | IC50 μM 22.4 13.0 51.6 15.5 0.8 22.9 19.7 | ||
| Salvia leucantha | Salvileucantholide (94) | MTT assay HCT-116 BT474 HepG2 Hsp90 | IC50 µM 32.61 25.02 37.35 6.78 | [46] |
| Scutellaria barbata | Scubatine A (95) | MTT assay HL-60 A549 | IC50 µM >20 >20 | [47,48,49,50] |
| Scubatine B (96) | HL-60 A549 | >20 >20 | ||
| Scubatine C (97) | HL-60 A549 | >20 >20 | ||
| Scubatine D (98) | HL-60 A549 | >20 >20 | ||
| Scubatine E (99) | HL-60 A549 | >20 >20 | ||
| Scubatine F (100) | HL-60 A549 | 15.3 10.4 | ||
| Scutebata E (101) | MTT assay HL-60 A549 LoVo | IC50 µM >20 >20 61.23 | ||
| Scutolide K (102) | HL-60 A549 | >20 >20 | ||
| Scutebata X (103) | SGC-7901 MCF-7 A549 | >40 37.2 >40 | ||
| Scutebata Y (104) | SGC-7901 MCF-7 A549 | >40 >40 >40 | ||
| Scutebata Z (105) | SGC-7901 MCF-7 A549 | >40 >40 >40 | ||
| Scutebata A1 (106) | SGC-7901 MCF-7 A549 | >40 >40 35.5 | ||
| Scutebata B1 (107) | SGC-7901 MCF-7 A549 | >40 >40 >40 | ||
| Scutebata C1 (108) | SGC-7901 MCF-7 A549 | 17.9 29.9 35.7 | ||
| Barbatin H. (109) | LoVo MCF-7 SMMC-7721 HCT-116 | 32.44 49.86 48.75 44.24 | ||
| Scuterbarbatine F (110) | LoVo MCF-7 SMMC-7721 HCT-116 | 23.32 49.19 58.12 78.83 | ||
| 6-O-nicotinoylscutebarbatine G (111) | LoVo SMMC-7721 HCT-116 | 29.44 65.51 54.44 | ||
| Scutebata G (112) | LoVo MCF-7 SMMC-7721 HCT-116 | 22.56 31.33 32.49 28.29 | ||
| Scutebata D (113) | LoVo MCF-7 SMMC-7721 HCT-116 | 20.75 31.42 29.24 62.66 | ||
| Barbatin C (114) | LoVo MCF-7 SMMC-7721 HCT-116 | 37.99 28.06 72.69 32.94 | ||
| Scutebarbatine A (115) | LoVo | 67.77 | ||
| Scutebarbatine G (116) | LoVo SMMC-7721 HCT-116 | 56.46 70.16 44.25 | ||
| 6,7-di-O-acetoxybarbatin A (117) | LoVo MCF-7 SMMC-7721 HCT-116 | 60.33 37.31 77.93 32.28 | ||
| Scutebarbatine X (118) | LoVo MCF-7 SMMC-7721 HCT-116 | 43.21 74.83 46.14 62.11 | ||
| Barbatin F (119) | LoVo HCT-116 | 56.46 44.25 | ||
| Barbatin G (120) | LoVo SMMC-7721 MCF-7 HCT-116 | 60.33 37.31 77.93 32.28 | ||
| Scutebata A (121) | LoVo SMMC-7721 MCF-7 HCT-116 HL-60 A549 | 4.57 7.68 5.31 6.23 >20 >20 | ||
| Scutebata B (122) | LoVo SMMC-7721 MCF-7 HCT-116 | 10.73 18.96 10.27 28.48 | ||
| Scutebata C (123) | LoVo SMMC-7721 MCF-7 | 47.15 33.18 38.79 | ||
| Scutebata P (124) | LoVo SMMC-7721 MCF-7 HCT-116 HL-60 A549 HCT-116 | 15.17 42.63 32.49 23.97 5.6 21.7 23.97 | ||
| Scutellaria strigillosa | Scutestrigillosin A (125) | REMA assay P-388 HONE-1, HT-29 MCF-7 | IC50 μM 5.8 3.5 4.7 5.7 | [51,52] |
| Scutestrigillosin B (126) | P-388 HONE-1 HT-29 MCF-7 | 5.2 4.2 4.1 6.0 | ||
| Scutestrigillosin C (127) | P-388 HONE-1, HT-29 MCF-7 | 7.1 3.9 6.4 7.7 | ||
| Scutestrigillosin D (128) | P388 HONE 1 HT-29 MCF-7 | 5.6 3.4 4.7 5.2 | ||
| Scutestrigillosin E (129) | P388 HONE 1 HT-29 MCF-7 | 8.9 7.3 8.1 7.4 | ||
| Sheareria nana | Sheareria A (130) | CCK8 assay HeLa PANC-1 A549 | IC50 µM 11.6 7.1 9.3 | [53] |
| Sheareria B (131) | HeLa PANC-1 A549 | 9.4 5.6 6.8 | ||
| Sheareria C (132) | HeLa PANC-1 A549 | 17.2 9.8 12.5 | ||
| Tinospora cordifolia | Tinocapillin A (133) | MTT assay A549 HepG2 HeLa OS-RC-2 | IC50 µM 14.0 9.9 9.7 10.6 | [54] |
| Tinocapillin B (134) | A549 HepG2 HeLa OS-RC-2 | 9.6 10.1 12.0 19.1 | ||
| Tinocapillin C (135) | A549 HeLa | 53.2 67.5 | ||
| Tinocallone A (136) | A549 HepG2 HeLa | 67.8 68.4 79.3 | ||
| Tinocallone C (137) | A549 HepG2 HeLa OS-RC-2 | 16.3 13.8 17.5 12.8 | ||
| Columbin (138) | A549 HeLa | 77.3 58.4 | ||
| Tinospora capillipes | ECD (epoxy clerodane diterpene) (139) | MTT assay V79 MCF-7 Vero | IC50 µM 52.7 3.2 45.8 | [55] |
| qPCR analysis | Inhibited MCF-7 grow by regulation the expression of genes such Cdkn2A, Rb1, Mdm2 y p53 | |||
| Tinospora sagittata | Tinosporin A (140) | MTT assay HL-60 MCF-7 | IC50 µM 18.63 23.58 | [56] |
Compound 1 (1S,4aS,5R,6S,8R,8aS)-8-acetoxy-5-((R)-2-acetoxy-2-(5-oxo-2,5-dihydrofuran-3-yl)ethyl)-2-hydroxy-5,6-dimethyloctahydro-8aH-spiro[naphthalene-1,2′-oxiran]-8a-yl)methyl (E)-2-methylbut-2-enoate; Compound 11 (2R,5S,6S,8R,9R,10S,18R,19S)-18,19-di-O-acetyl-18,19-epoxy-6-hydroxy-2-(2′-methylbutanoyloxy)cleroda-3,13-(16),14triene; Compound 47 6-[2-(furan-3-yl)-2-oxoethyl]-1,5,6-trimethyl-10-oxatricyclo[7.2.1.02,7] dodec-2(7)-en-11-one. 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT); sulforhodamine B (SRB); N-nitrosodiethylamine and phenobarbital sodium (NDEA+PB); cell counting kit 8 assay (CCK8); resazurin microplate assay (REMA); protein 90 kDa of family of chaperones (Hsp90); concentration cytotoxic at 50% (CC50); quinone reductase assay (QIR); selective index (SI); total growth inhibitory (TGI); breast cancer (MCF-7); breast cancer resistant at vinblastine (MCF-7/Vin); breast ductal carcinoma (BT474); cervix adenocarcinoma (HeLa); cervix squamous carcinoma (SiHa); colon adenocarcinoma (SW620, HCT-15, HCT-116 and HT-29) colon cancer (LoVo); chronic myeloid leukemia (K562); epidermoid carcinoma of the nasopharynx (KB); Ewing sarcoma (A-673); gastric carcinoma (KATO-III, SGC-7901); glioblastoma (U251); hepatocarcinoma (Hep293TT, Hep3B, Hep-G2, SMMC-7721, HCC, HuH-7); human umbilical vein endothelial cells (HUVEC); liver tumor cells of Rattus norvegicus (HTC); lymphoma cells (P388); lung adenocarcinoma (LU-1, SKLU-1, A549); medulloblastoma (D283); mouse colon adenocarcinoma (CT26.WT); mouse embryonic fibroblast cell line (NIH-3T3); musculus skin melanoma (B16-F10); normal green monkey kidney cell line (Vero); normal monkey kidney (COS-7); normal prostate epithelium (PNT2); promyelocytic leukemia (HL-60); prostate cancer (PC-3); P-gp-overexpressing MDR subline of KB (KB-VIN); pancreatic carcinoma (PANC-1); renal carcinoma (OS-RC-2); rhabdomyosarcoma (SJCRH30); triple-negative breast cancer (MDA-MB-231); two epithelial tumor cell lines (HNE-1 and HONE-1; undifferentiated lung carcinoma (Chago-K1).
Table 3.
Clerodane diterpenes with anti-inflammatory activity.
| Plant Source | Compound Name | Methods | Results | References |
|---|---|---|---|---|
| Ajuga pantantha | Ajugapantin C (141) | Western Blot Analysis | Compounds 141, 142 and 146 downregulated iNOS and COX-2 protein levels | [57,58] |
| Docking Analysis | Compounds 141, 142 and 146 have strong interactions with the iNOS and COX-2 proteins | |||
| Griess assay BV-2 cells stimulated LPS | IC50 µM 20.2 | |||
| Ajugapantin E (142) | Griess assay BV-2 cells stimulated LPS | IC50 µM 45.5. | ||
| Ajugapantin F (143) | 34.0 | |||
| Ajugapantin G (144) | 27.0 | |||
| Ajugapantin H (145) | 45.0 | |||
| Ajugapantin I (146) | 25.8 | |||
| Pantanpene α (147) | Griess assay BV-2 cells stimulated LPS | IC50 μM 65.7 | ||
| Pantanpene B (148) | 37.7 | |||
| Pantanpene C (149) | 61.7 | |||
| Pantanpene d (150) | >50% inhibition at 30 μM | |||
| Pantanpene E (151) | Griess assay BV-2 cells stimulated LPS | IC50 μM 21.7 | ||
| Anti-inflammatory assay in zebrafish model | The anti-inflammatory effect was confirmed | |||
| Docking Analysis | Compounds 148 and 151 have strong interactions with the iNOS and COX-2 proteins | |||
| Callicarpa arborea | Callicarpin A (152) | NLRP3 Inflammasome activation assay J774A.1 cells were primed with LPS | IC50 μM 16.6 | [59] |
| Callicarpin B (153) | 4.0 | |||
| Callicarpin C (154) | 25.4 | |||
| (16S)-Tris-O-Acetylcallicarpin C (155) | 5.3 | |||
| Callicarpin E (156) | 24.7 | |||
| Callicarpin F (157) | 1.5 | |||
| Callicarpin G (158) | NLRP3 Inflammasome activation assay J774A.1 cells were primed with LPS | IC50 μM 1.4 | ||
| Pyroptosis fluorescence microscopy | The compound 153 inhibited pyroptosis and blocked NLRP3 inflammasome activation by hampering Casp-1 cleavage and IL-1β secretion | |||
| Callicarpa cathayana | Cathayanalactone A (159) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 22.92 | [60] |
| Cathayanalactone B (160) | 13.25 | |||
| Cathayanalactone C (161) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 82.82 | ||
| 15-methoxypatagonic acid (162) | 35.35 | |||
| 16-hydroxycleroda-3, 13-dien-16, 15-olide-18-oic acid (163) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 17.49 | ||
| ELISA assay Quantification of TNF-α, IL-6 and IL-1β | Compounds 161–163 inhibited IL-1β, IL-6 and TNF-α | |||
| Callicarpa hypoleucophylla | Callihypolin A (164) | Inhibitory activities in - superoxide anion generation and - elastase release in formyl-methionyl-leucyl-phenylalanine (fMLF)/cytochalasin (CB)-induced human neutrophils | % of inhibition 20.28 8.26 | [61] |
| Callihypolin B (165) | 32.19 17.55 | |||
| Compound 166 | 31.19 12.15 | |||
| Patagonic acid (167) | 32.88 13.57 | |||
| Limbatolide F (168) | 23.65 7.33 | |||
| Limbatolide A (169) | 8.44 10.50 | |||
| Compound 170 | 7.93 9.30 | |||
| Clerodermic acid (171) | 15.23 11.80 | |||
| Visclerodol acid (172) | 18.80 16.30 | |||
| Croton crassifolius | Crassifolin Q (49) | ELISA assay IL-6 TNF-α | % of production 72.23 89.38 | [32,62] |
| Crassifolin R (50) | 77.88 77.73 | |||
| Crassifolin S (51) | 73.36 79.23 | |||
| Crassifolin T (52) | 35.48 54.14 | |||
| Crassifolin U (53) | 32.78 12.53 | |||
| Compound 173 | Griess assay RAW264.7 macrophages stimulated LPS | IC50 μM 25.8 | ||
| Compound 174 | 173 at 178 < 50% inhibition at 50 µM | |||
| C-6 epimer of crotoeuricin C (175) | ||||
| Crotocaudin (176) | ||||
| Teucvin (177) | ||||
| Crassifolin F (178) | ||||
| Croton floribundus | Croflorin A (179) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 μM 28.52 | [63] |
| Croflorin B (180) | 40.26 | |||
| Croflorin C (181) | 25.47 | |||
| Croflorin D (182) | 35.78 | |||
| 3α-hydroxy-5,10-didehydrochiliolide (183) | 40.58 | |||
| Croton laui | 3S-acetoxyl-mollotucin D dilactone ester (184) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM weak activity | [64] |
| 6S-crotoeurin C (185) | 1.2 | |||
| Crotoeurin C (186) | 1.6 | |||
| Mollotucin D dilactone ester (187) | weak activity | |||
| Crassifolin F compound 178 | weak activity | |||
| Croton poomae | Crotonolide K (188) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 46.43 | [65] |
| Furocrotinsulolide A acetate (189) | 31.99 | |||
| Furocrotinsulolide A (190) | 81.97 | |||
| Compound 191 | 86.98 | |||
| Compound 192 | 48.85 | |||
| Crotonolide E (193) | 74.78 | |||
| Crotonolide F (194) | 42.04 | |||
| Compound 195 | 32.19 | |||
| Dodonaea viscosa | Hautriwaic acid (196) | Arthritis in mice induced by caolin/carrageenan Doses mg/kg 5 10 20 | % inflammation of edema after 15 days 27 20 13 | [66] |
| ELISA assay Quantification of IL-10, TNF-α, IL-6 and IL-1β | Compound 196 diminished TNF-α, IL-6 and IL-1β and increased IL-10 | |||
| Dysoxylum lukii. | neoclerod-13Z-ene-3α, 4β, 15-triol (197) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM. 25.5 | [67] |
| Jamesoniella autumnalis | Jamesoniellide Q (198) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 45.10 | [68] |
| Jamesoniellide R (199) | 82.98 | |||
| Monoon membranifolium | 2β-Methoxyhardwickiic acid (200) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 µM 65.4 | [69] |
| (-)-hardwickiic acid (91) | 38.9 | |||
| 2β-acetoxyhardwickiic acid (201) | 16.1 | |||
| 2β-hydroxyhardwickiic acid (202) | 82.4 | |||
| 15-methoxypatagonic acid (203) | 28.9 | |||
| Nepeta suavis. | Nepetolide (204) | Carrageenan-induced hind paw edema Docking Analysis In silico evaluation | Compound 204 inhibited hind paw edema Target Cox-2 EGFR and Lox-2 | [70] |
| Polyalthia longifolia | 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (205) | Cyclooxygenase inhibitory assay 5-LOX kit COX-1 COX-2 5-LOX | IC50 µM 8.00 8.41 8.41 | [40,71] |
| 16-hydroxy-cleroda-3,13-dien-15-oic acid (206) | COX-1 COX-2 5-LOX | 9.75 4.07 9.78 | ||
| 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (74) | COX-1 COX-2 5-LOX | 3.77 2.71 4.06 | ||
| 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (75) | COX-1 COX-2 5-LOX | 3.63 4.29 5.67 | ||
| 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (76) | COX-1 COX-2 5-LOX | 3.01 3.29 4.58 | ||
| Docking Analysis In silico evaluation | Compounds 74–76 have interactions with COX-1/2 and LOX enzymes | |||
| 3β-16a-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (77) | ELISA assay Quantification of cytokines such as TNF-α, TGF-β, IL-6, IL-10 and IL-1β | Compounds 74 and 77 inhibited production of proinfammatory cytokines and increased IL-10 and TGF-β | ||
| Docking Analysis In silico evaluation | Compound 74 docked into the active sites of MDM2, TNF-α, FAK and IL-6 Compound 77 docked into the active sites of MDM2, TNF-α, TGF-β and FAK | |||
| Scutellaria barbata | Scuttenline C (207) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 μM 1.9 | [72] |
| Barbatin A (208) | 12.6 | |||
| Scutebarbatine F (209) | 3.7 | |||
| Teucrium fructicans | 11-hidroxyfruticolone (210) | Griess assay RAW264.7 macrophages stimulated LPS | IC50 μM 39.3 | [73] |
| Tinospora crispa | Crispinoid D (211) | qPCR assay IL-1β, IL-6, TNF-α, iNOs, CCL12 and COX-2 | Compounds 211–213 diminish the production of pro-inflammatory mediators | [74,75] |
| Luciferase assay: Inhibition of NF-κB | IC50 μM 5.94 | |||
| Tinosporol C (212) | Inhibition of NF-κB | 6.32 | ||
| marrubiagenin-methylester (213) | Inhibition of NF-κB | 25.20 | ||
| Tinopanoid A (214) | Griess assay BV-2 cells stimulated LPS | IC50 μM >60 | ||
| Tinopanoid B (215) | >60 | |||
| Tinopanoid C (216) | 24.1 | |||
| Tinopanoid D (217) | 41.1 | |||
| Tinopanoid E (218) | 7.5 | |||
| Tinopanoid F (219) | 50.8 | |||
| Tinopanoid G (220) | 10.6 | |||
| Tinopanoid H (221) | 39.4 | |||
| Tinopanoid I (222) | 59.1 | |||
| Tinopanoid J (223) | 45.9 | |||
| Tinospin C (224) | >60 | |||
| borapetol B (225) | >60 | |||
| Tinotufolin D (226) | 14.5 | |||
| Tinospora sagittata | Fibaruretin H (227) | Griess assay RAW264.7 macrophages stimulated LPS | % inhibition at 24 µM 27.0% | [76] |
| Fibaruretin I (228) | 33.1% |
Compound 166 (4aR,5S,6R,8aR)-5-[2-(2,5-dihydro-5-methoxy-2-oxofuran-3-yl)ethyl]-3,4,4a,5,6,7,8,8a-octahydro-5,6,8a-trimethylnaphthalene-1-carboxylic acid); Compound 170 (methyl (4aR,5S,6R,8S,8aR)-3,4,4a,5,6,7,8,8a-octahydro-8-hydroxy-5,6,8a-trimethyl-5-[2-(2-oxo-2,5-dihydrofuran-3-yl)ethyl]naphthalene-1-carboxylate); Compound 173 (3S,4S,6S,8R,9R,12S)-3-acetoxy-18-methoxycarbonyl-6,19:15,16-diepoxy-halim-5(10),13(16),14-triene-20,12-olide; Compound 174 (3S,4S,6S,8R,9R,12S)-3,19-diacetoxy-18-methoxycar-bonyl-15,16-epoxy-6-hydroxyhalim-5(10),13(16),14-triene-20,12-olide; Compound 191 (3,4,15,16-diepoxycleroda-13(16),14-diene-12,17-olide); Compound 192 (15,16-epoxy-3β-hydroxy-5(10),13(16),14-dien-12,17-olide; Compound 195 (3β,4β:15,16-diepoxy-13(16),14-clerodadiene; Compound 226 (2aβ,3α,5aβ,6β,7α,8aα)-6-[2-(3-furanyl)ethyl]-2a,3,4,5,5a,6,7,8,8a,8b-decahydro-2a,3-dihydroxy-6,7,8b-trimethyl-2H-naphtho[1,8-bc]furan-2-one). Cells are immortalized by v-raf/v-myc carrying J2 retrovirus (BV-2); inducible nitric oxide synthase (iNOS); cyclooxygenase 2 (COX-2); key sensor molecule in the inflammasome activity (NLRP3); protein found on the surface of some cells that binds epidermal growth factor (EGFR); 5-lipoxigenasa (5-LOX); tumor necrosis factor-α (TNF-α); interleukin-6 (IL-6); interleukin 1β (IL-1β); proinflammatory–chemokine (C-C motif) ligand 12 (CCL12).
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Martínez-Casares, R.M.; Hernández-Vázquez, L.; Mandujano, A.; Sánchez-Pérez, L.; Pérez-Gutiérrez, S.; Pérez-Ramos, J. Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes. Molecules 2023, 28, 4744. https://doi.org/10.3390/molecules28124744
AMA Style
Martínez-Casares RM, Hernández-Vázquez L, Mandujano A, Sánchez-Pérez L, Pérez-Gutiérrez S, Pérez-Ramos J. Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes. Molecules. 2023; 28(12):4744. https://doi.org/10.3390/molecules28124744
Chicago/Turabian StyleMartínez-Casares, Rubria Marlen, Liliana Hernández-Vázquez, Angelica Mandujano, Leonor Sánchez-Pérez, Salud Pérez-Gutiérrez, and Julia Pérez-Ramos. 2023. "Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes" Molecules 28, no. 12: 4744. https://doi.org/10.3390/molecules28124744
APA StyleMartínez-Casares, R. M., Hernández-Vázquez, L., Mandujano, A., Sánchez-Pérez, L., Pérez-Gutiérrez, S., & Pérez-Ramos, J. (2023). Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes. Molecules, 28(12), 4744. https://doi.org/10.3390/molecules28124744
