Search

Eight previously undescribed diterpenoids, caesamins A-H (1-8), were separated and identified from the seeds of Caesalpinia minax Hance. Their structures were characterized by extensive spectroscopic data and X-ray crystallographic analysis. Structurally, caesamin A (1) is the first cassane-type diterpenoid with a C23 carbon skeleton containing an unusual isopropyl. Caesamin F (6) represents the first example of cleistanthane diterpenoid from the genus Caesalpinia. Caesamins B (2) and F (6) exhibited inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages with IC 50 values of 45.67 ± 0.92 and 42.99 ± 0.24 μM, comparable to positive control 43.69 ± 2.62 μM of NG-Monomethyl-L-arginine. Furthermore, the chemotaxonomic significance of the isolates was discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC 50 value of 18.13 ± 0.63 μM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The phytochemical investigation of the pericarps of Caesalpinia bonduc led to the isolation and identification of five new cassane-type alkaloids: caesalminines C - G (1-5) and six new diterpenoids: caesalbonducin K - P (6-11), along with seven known compounds (12-18). Compounds 1-5 were identified as a group of rare alkaloids possessing a tetracyclic cassane-type diterpenoid skeleton with a lactam D-ring instead of a typical furan or lactone moiety. The structures of 1-11 were elucidated on the basis of 1D and 2D NMR including HSQC, HMBC, COSY and NOESY, and other spectroscopic analyses. The cytotoxic activities of the isolated compounds were evaluated in the A431, A549 and U87MG cancer cell lines., Competing Interests: Declaration of competing interest The authors of the present manuscript have declared that no competing interests exist., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Caesalpinia minax Hance, whose seeds are known as "Ku-shi-lian" in China, have been used in Chinese folk medicine for treatment of rheumatism, dysentery, and skin itching. However, the anti-neuroinflammatory constituents of its leaves and their mechanism are rarely reported., Aim of the Study: To search for new anti-neuro-inflammatory compounds from the leaves of C. minax and elucidate their mechanism on anti-neuroinflammatory effect., Materials and Methods: The main metabolites of the ethyl acetate fraction from C. minax were analyzed and purified via HPLC and various column chromatography techniques. Their structures were elucidated on the basis of 1D and 2D NMR, HR-ESI-MS, and single crystal X-ray diffraction analysis. Anti-neuroinflammatory activity was evaluated in BV-2 microglia cells induced by LPS. The expression levels of molecules in NF-κB and MAPK signaling pathways were analyzed through western blotting. Meanwhile, the time- and dose-dependent expression of associated proteins such as iNOS and COX-2 were detected by western blotting. Furthermore, Compounds 1 and 3 were performed on the NF-κB p65 active site using molecular docking simulation to elucidate the molecular level inhibition mechanism., Results: 20 cassane diterpenoids, including two novel ones (caeminaxins A and B) were isolated from the leaves of C. minax Hance. Caeminaxins A and B possessed a rare unsaturated carbonyl moiety in their structures. Most of the metabolites exhibited potent inhibition effects with IC 50 values ranging from 10.86 ± 0.82 to 32.55 ± 0.47 μM. Among them, caeminaxin A inhibited seriously the expression of iNOS and COX-2 proteins and restrained the phosphorylation of MAPK and the activation of NF-κB signaling pathways in BV-2 cells. The anti-neuro-inflammatory mechanism of caeminaxin A has been studied systematically for the first time. Furthermore, biosynthesis pathways for compounds 1-20 were discussed., Conclusions: The new cassane diterpenoid, caeminaxin A, alleviated the expression of iNOS and COX-2 protein and down-regulated of intracellular MAPK and NF-κB signaling pathways. The results implied that cassane diterpenoids had potential to be developed into therapeutic agents for neurodegenerative disorders such as Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Natural products play a significant role in the development of novel bactericide candidates. Caesalpinia pulcherrima, a traditional medicine, had anti-inflammatory, antimicrobial, and antifeedant activities, therefore the previous bioassay results of C. pulcherrima implied that its main active ingredients may have potential to be used as botanical bactericides., Results: Bio-guided isolation of C. pulcherrima was conducted to obtain 11 novel cassane diterpenoids (capulchemins A-K) and 10 known sesquiterpenes. Their structures were established by extensive spectroscopic methods and single-crystal X-ray diffraction analyses. Capulchemins A-F possess a rare aromatic C ring, while capulchemin K with a 15,16-degradative carbon skeleton represents a rare group of cassane diterpenes. Capulchemin A exhibited remarkable antibacterial activity against four phytopathogenic bacteria, particularly against Pseudomonas syringae pv. actinidae and Bacillus cereus, with minimal inhibitory concentration values of 3.13 μM. Meanwhile, capulchemin A showed significant control effect on kiwifruit canker in vivo. Further investigation of its mechanism of antibacterial activity revealed that compound 1 was closely related to destroy cell membrane to cause cell death. Additionally, some of those cassane diterpenoids showed potential antifeedant against Mythimna separate walker and Plutella xylostella. Consequently, capulchemin A could have the potential to be used as a template for the development for new eco-friendly NP-based bactericides., Conclusion: These data contribute to a better understanding of the antibacterial activity of cassane diterpenes. Cassane diterpenes have been discovered to be leading to broad application prospects in the development as novel botanical bactericides. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Guided by an MS/MS-based molecular networking, six undescribed cassane diterpenoids and three known ones were isolated and identified from the seeds of Caesalpinia sappan. Their structures were unequivocally elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Cytotoxic evaluation showed that phanginin JA exhibited significant antiproliferative activities against human non-small cell lung cancer (A549) cells with IC 50 values of 16.79±0.83 μM. Further flow cytometry analysis revealed that phanginin JA could exert apoptotic effect of A549 cells by arresting cell cycle in G0/G1 phase., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Three new cassane-type diterpenoids, namely, (4 S )-6 β ,12 α ,19-trihydroxy-cass-13(15)-en-16,12-olide ( 1 ), cass-13(15)-en-​16,12-olide ( 2 ), and 12 α -hydroxy-cass-13(15)-en-16,12-olide ( 3 ), were isolated from the seeds of Caesalpinia sinensis. The structures of 1 - 3 were established by extensive spectroscopic analysis, and their absolute configurations were assigned by electronic circular dichroism (ECD) calculations. The inhibitory activities against PTP1B of the isolated compounds were evaluated. The results showed that compound 2 possessed PTP1B inhibitory activity with an IC 50 value of 217.45 ± 36.4 μM.

Five compounds were isolated from the methanolic extract of Caesalpinia sinensis stems and leaves including a new cassane-type butenolide norditerpenoid compound ( 1 ) and a new type of biphenyl compound ( 2 ); the compounds were identified as Norcaesalpin-one ( 1 ), 4'-hexyl 3-methyl 6-methoxy-[1,1'-biphenyl]-3,4'-dicarboxylate ( 2 ), rhapontigenin ( 3 ), 3-deoxysappanchalcone ( 4 ), isoliquiritigenin ( 5 ). Compounds 1 - 5 were first isolated from C. sinensis . Their structures were elucidaded on the basis of MS, IR, NMR spectroscopic, X-ray diffraction data analyses. The NGF-induced PC12 differentiation assay was performed on compound 1 , and the results showed that compound 1 had a promotive effect on PC12 cell differentiation, with a differentiation rate of 12.32%. In addition, compounds 1 - 5 were evaluated for their cytotoxic activities against four human cancer cell lines (including A-549, BGC-823, MDA-MB-231, HepG2), and the results showed that compounds 3 - 5 showed inhibitory activity against these cancer cell lines with IC 50 values ranging from 22.96 to 74.92 μmol/L, compound 4 showing the best activity against human malignant melanoma cells A375 with an IC 50 value of 22.96 μmol/L.

Two new cassane-type derivatives ( 1 - 2 ), together with three known compounds ( 3 - 5 ), were isolated from the seed kernels of Caesalpinia sinensis . Their structures were elucidated on the basis of interpretation of comprehensive spectroscopic data, including HRESIMS and 1D/2D NMR spectroscopy, and the absolute configuration were established by means of ECD calculation. Compound 2 , possessing a 16-degradative cassane skeleton, was rarely encountered in cassane diterpenoids isolated from the genus Caesalpinia . All compounds were evaluated for their anti-inflammatory activities against the overproduction of NO in LPS-stimulated RAW 264.7 macrophages, and compounds 1-5 could inhibit production of NO at the concentration of 50 μM.

The first investigation of chemical composition in seed kernels of Caesalpinia cucullata Roxb. resulted in the separation of four new cassane diterpenes, including three furanoditerpenes ( 1 , 2 and 4 ) and one tricyclic type ( 3 ). It was the first found cassane diterpenoids from this plant. Their gross structures were elucidated by means of comprehensive spectroscopic analysis (UV, IR, NMR, HRESIMS) as well as electronic circular dichroism (ECD) calculation. The compound 1 possess a rare isomerized dihydrofuran ring in structure framework. In bioassay, compounds 1 - 4 exhibited moderate anti-inflammatory activity by inhibiting production of NO in LPS-induced RAW 264.7 cells.

Three undescribed cassane-type diterpenoids (CAs), caesalpulcherrins K-M ( 1 - 3 ), together with three known ones ( 4 - 6 ) were isolated from the aerial parts of Caesalpinia pulcherrima (L.) Sw (Fabaceae). Their structures were elucidated via analysis of NMR (1 D and 2 D) and HRESIMS data. The character for caesalpulcherrin K possessing the olefin bond at C-11 and C-12 in its cassane skeleton was observed, which belonged to a small group among more than 450 CAs. That is, only fifteen derivatives have been reported up to now, to our knowledge. Biological evaluation revealed that compounds 1 - 6 exhibited moderate anti-inflammatory activity, with an IC 50 value from 6.04 ± 0.34 to 8.92 ± 0.65 μM. Furthermore, compounds 5 and 6 exhibited significant α -glucosidase inhibitory activity at 10 μM.

In this study, phytochemical investigation on the chloroform soluble fraction of seed kernels of Caesalpinia bonduc led to the isolation of two new cassane-type diterpenoids, norcaesalpinin Q ( 1 ) and caesalpinin MR ( 2 ), together with seven known compounds ( 3 - 9 ). The structures of the new compounds were elucidated on the basis of extensive NMR spectroscopic and mass spectrometric analyses, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. All compounds were evaluated for inhibitory effects against NO production of RAW264.7 cells induced by LPS, and compounds 5 , 7 and 8 could inhibited the production of NO at the concentration of 50 µM.

Two undescribed nitrogen bridged cassane alkaloids (caesanamides A-B) and five undescribed oxygen bridged cassane diterpenoids (caesalpinins JA-JE), together with six known analogs, were isolated and identified from the seeds of Caesalpinia sappan. Their structures, including the absolute configurations, were unequivocally elucidated by the analysis of comprehensive spectroscopic data, ECD calculations, single-crystal X-ray diffraction and the CASE algorithm. Among them, caesanamides A and B represent the first examples of cassane alkaloids bearing unique ring systems of an amide bridge between C-19/C-20 incorporating a 1,3-oxazolidine (6/6/6/5/6/5) or a 7-one-1,3-oxazepine (6/6/6/5/6/7). Caesalpinin JA is an A/B cis-20-norcassane diterpenoid with a rare five-membered oxygen bridge between C-10/C-18. Biological evaluation showed that cassane alkaloids exhibited significant cytotoxicity against HepG2 cells with IC 50 values of 13.48 ± 1.07 μM (caesanamide A), 18.91 ± 0.98 μM (caesanamide B), and 7.82 ± 0.65 μM (caesanine B). Further flow cytometry analysis revealed that caesanine B could cause G0G1 cell cycle arrest and promote apoptosis in a dose- and time-dependent manner in HepG2 cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A new cassane diterpenoid, caesappine A ( 1 ), and a new natural cassane diterpenoid, caesappine B ( 2 ) were isolated from the seeds of Caesalpinia sappan . The new structures of compounds 1 and 2 were elucidated by analysing their 1D NMR, 2D NMR and HR-ESI-MS spectra. Compounds 1 and 2 were evaluated for the cytotoxic activities on Hela and HepG-2 human cancer cell lines.

Eight undescribed cassane diterpenes, pterolobirins C-J, together with two known analogs, were isolated from the roots of Pterolobium macropterum. Their structures were characterized by extensive spectroscopic techniques including NMR, MS, ECD and X-ray crystallographic spectroscopy. The absolute configuration of pterolobirin J was confirmed by single-crystal X-ray diffraction data. The compounds were screened for their anti-inflammatory activity on the lipopolysaccharide (LPS) induced nitric oxide (NO) production in J774. A1 macrophage cells. Pterolobirin E and sucutinirane C displayed good NO inhibition with IC 50 values of 24.44 ± 1.34 and 19.16 ± 1.22 μM, respectively., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sixteen cassane diterpenoids (CAs), including four undescribed lactam-type, four unreported lactone-type, along with eight known ones, were isolated from the aerial parts of Caesalpinia pulcherrima (L.) Sw. Their structures were characterized by comprehensive spectroscopic analyses (including NMR and HRESIMS). The absolute configuration of pulcherritam A was finally established by single-crystal X-ray diffraction with Cu Kα radiation. Notably, pulcherritam s A-D were elucidated as a group of rare CAs bearing an α, β-unsaturated γ-lactam ring rather than a typical lactone moiety. Almost all compounds were examined for their antibacterial. The results reveal that pulcherritam H exhibited significant antibacterial activities against Bacillus cereus, Staphylococcus aureus, as well as Pseudomonas syringae pv. actinidae (Psa) with the MIC from 6.25 to 12.5 μM, while pulcherritams A and C displayed potent antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA). Then, all isolates were evaluated for their anti-glioblastoma activities. Pulcherritam A and Pulcherrimin G illustrated moderate inhibitory activity against glioblastoma multiforme (GBM) U87MG cell, and the other compounds did not show obvious inhibitory activity against GBM U87MG cell. Furthermore, the preliminary structure-activity relationship and their biosynthetic pathway were also discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The seeds of Caesalpinia minax Hance have shown anti-tumor potential, while the chemical principle is still unknown. In a search for anti-tumor compounds, six new cassane-type diterpenoids, 12-demethylcaesalpin G ( 1 ), caesalpinolide H ( 2 ), 12-demethylcaesalpin H ( 3 ), caesalpinolide J ( 4 ), 12- O -ethyl neocaesalpin B ( 5 ), and 3-deacetyldecapetpene B ( 6 ), were isolated from the seeds of C. minax Hance, along with fifteen known analogues. The structures of the new compounds were established by means of spectroscopic techniques (NMR, HRESIMS and IR). The absolute configurations of the new compounds were determined by their ECD spectra. All of the new compounds were tested for their anti-proliferative activity against human lung cancer A549 cells, breast cancer MCF-7 cells, and ovarian cancer HEY cells. The results indicated that only compound 6 displayed moderate cytotoxicity against three cancer cell lines. Thus, the opening of furan ring in cassane-type diterpenoids might enhance the cytotoxic activity.

Ten new cassane-type diterpenoids were isolated from the seeds of Caesalpinia bonduc (L.) Roxb., including 6α-hydroxycaesalpinin P (1), 14-epi-caesalpinin E1 (2), 6-deacetylcaesalmin Z (3), 14-epi-caesalmin Z (4), caesalpinolides I (5), K (6), L (7), M (9) and N (10), and 14-epi-neocaesalpin L (8). Their planar structures and absolute configurations were fully determined by comprehensive spectroscopic methods, including 2D NMR and electronic circular dichroism spectra. Compounds 1-4 are tetracyclic cassane diterpenoids possessing a furan ring, and compounds 5-10 are tetracyclic cassane diterpenoids possessing a fused butenolide moiety. The anti-inflammatory and cytotoxic activities of the isolates were evaluated, while none of them showed obvious effects. The current study identified ten new cassane-type diterpenoids from the seeds of C. bonduc (L.) Roxb., which enriched the chemical diversity of the titled herbal medicine., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

The first investigation of phytochemistry on the seed kernels of Caesalpinia sinensis led to the isolation and characterization of six new compounds including three tricyclic-type cassane diterpenoids (1--3) and three norcassane-type diterpenoids (4-6), together with three know compounds (7-9). Compounds 1-9 represented the first discovery of cassane-type diterpenoids from C. sinensis. Their structures were elucidated by a combination of spectroscopic analysis, single-crystal X-ray diffraction experiment and ECD calculation. The characters for compounds 4 and 5 possessing the 15,16-degradative cassane skeleton were observed, which was extremely rare structural type in the genus Caesalpinia. The anti-inflammatory activities of all isolates were evaluated via examining their inhibitory effects against NO production in LPS-simulated RAW 264.7 cells. The results demonstrated that compound 1 exhibited the most significantly inhibitory efficacy with inhibition rate 67.3% at 10 μM. The iNOS enzyme activity assay further revealed that compound 1 showed potent NO inhibitory effect by reducing the enzymatic activity of iNOS., (Copyright © 2021. Published by Elsevier B.V.)

Eighteen cassane diterpenoids, including five new lactam-type ( 4 - 8 ), 12 new lactone-type ( 1 - 3 and 9 - 17 ), and one known compound ( 18 ), were isolated from Caesalpinia sinensis . To our knowledge, this is the first study on the seed kernels of C. sinensis , and cassane derivatives were discovered in this plant for the first time. Their structures including absolute configurations were established by extensive spectroscopic methods complemented with single-crystal X-ray diffraction analyses and ECD calculations. Compounds 4 - 8 were identified as a group of rare cassane diterpenoids possessing a lactam D-ring instead of a typical lactone moiety. Biological evaluation revealed that compounds 4 - 6 exhibited effective inhibitory effects on NO production in the LPS-induced RAW 264.7 macrophages, with IC 50 values in the range 8.2-11.2 μM. Compound 4 suppressed the excessive production of NO by down-regulating the expression of inducible nitric oxide synthase enzymes (iNOS) and reducing the enzymatic activity of iNOS. Moreover, the intermolecular interaction and binding mode between compound 4 and iNOS were elaborated by conducting a molecular docking study.

Two dimeric cassane diterpenoids with an unprecedented 6/6/6/6/6/5/6/6/6 nonacyclic framework, pterolobirins A and B ( 1 and 2 ), were isolated from the fruits of Pterolobium macropterum . Their structures were assigned by interpreting the spectroscopic data. The absolute configuration of 1 was unequivocally confirmed by single-crystal X-ray diffraction data. A putative biosynthetic pathway is proposed based on a regular intermolecular Diels-Alder reaction and an intramolecular nucleophilic addition.

Three dimeric cassane diterpenoids, caesalpanins A-C, were isolated from the seeds of Caesalpinia sappan L., as well as three known compounds. Their structures were determined via analysis of 1D-, 2D-NMR, and HR-ESI-MS data. Caesalpanins A and B were the second and third compounds that presented a nitrogen-containing cassane diterpenoid dimer linked through one ether bond between C-19 and C-20'. Caesalpanin B exhibited moderate cytotoxic activity against MCF-7 cell lines with IC 50 value of 29.98 μm. Caesalpanins A and B had weak inhibitory effects against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages at 50 μm with inhibitory rate of 36.01 % and 32.93 %, respectively., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)

Ten new cassane diterpenoids, caesalpulcherrins A-J ( 1 - 10 ), together with 11 known analogues ( 11 - 21 ) were isolated from the aerial parts of Caesalpinia pulcherrima . Their structures and relative stereochemistry were elucidated by spectrometric and spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and single-crystal X-ray diffraction analysis. Compounds 1 - 4 represent the first examples of 2,5-dimethoxyfuranocassane diterpenoids. Results of the antifeedant activity indicated that isovouacapenol C ( 12 ) and pulcherrin N ( 14 ) exhibited remarkable antifeedant activity against Mythimna separate with EC 50 values of 3.43 and 4.20 μg/cm 2 , respectively. Meanwhile, pulcherrimin C ( 13 ) and 12-demethyl neocaesalpin F ( 18 ) exerted significant antifeedant activity against Plutella xylostella with an EC 50 data of 4.00 and 3.05 μg/cm 2 , respectively. Some of the compounds showed obvious toxic activity against the plant-feeding generalist insect herbivores, M. separate and P. xylostella , at 0.8 mg/mL (800 ppm). Furthermore, the structure-activity relationships of antifeedant and insecticidal activities are also discussed in the article.

In this paper, chemical investigation on the chloroform soluble fraction of seed kernels of Caesalpinia bonduc resulted in the isolation of five new cassane diterpenoids: norcaesalpinin O (1), norcaesalpinin P (2), caesalpinin MQ (3), caesall O/P (4/5) and seven known compounds (6-12). Compounds structures were elucidated by 1 H NMR, 13 C NMR, 2D NMR, HR-MS and ECD (electronic circular dichroism) spectral analysis. The characters for new compounds with the presence of an aromatized C ring or demethyl group at C-17 position in the structures were found. By means of bioactive screenings, the inhibitory effect on type-4 phosphodiesterase (PDE4, the target protein of asthma disease) and nuclear factor-kappa B (NF-κB) expression were valued. Compound 1 was found to exhibit moderate inhibitory activity on PDE4 and much better binding affinity than other structures by docking studies for interaction analyzing. Compounds 6, 10 and 11 displayed considerable inhibitory strength against NF-κB expression with inhibitory ratio 48.6%, 42.9% and 37.1% at 10 µM, respectively. The isolation of cassane-type diterpenoids with anti-inflammation activity from C. bonduc implied that this plant might be a good source for anti-inflammation agents finding., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cassane diterpenoids (CAs), recognized as main constituents of many medical plants of the genus Caesalpinia, exhibit diverse bioactivities, including anti-inflammatory and immunomodulatory activity, and also showed a therapeutic effect on rheumatoid arthritis (RA) according to previous work, including ours. In this study, 102 CA compounds were selected to explore the possible molecular mechanism of this class of natural products on anti-inflammatory and immunomodulatory activity using RA as a disease model through a series of in silico methods: chemical-similarity-based target prediction, molecular docking, and molecular dynamics (MD) simulation. As a consequence, four signaling pathways (TCR signaling pathway, TLR signaling pathway, VEGF signaling pathway, and osteoclast differentiation pathway) by which CAs exert their effect on inflammation and immunomodulation were identified. Furthermore, the binding modes of CAs complexing with several crucial targets, which were picked out by credible docking results and took part in these signaling pathways, were explored by MD simulations. This is the first time that the molecular mechanism of the anti-RA activity of natural CAs has been investigated with in silico methods, and these findings might explain the activity of CAs on anti-inflammation and immunomodulation, which could supply a valuable reference for drug design research on CAs.

Natural products, especially diterpenoids, are enriched with numerous compounds with a broad spectrum of therapeutic indications, suggesting that functional moieties serve as a core pharmacophore. Cassane diterpenoids (CAs), as the main and characteristic constituents of medical plants in the Caesalpinia genus, have been widely studied due to their bioactivities, and >450 compounds have been reported since the 1960s, including 283 compounds that have been reported in the past decade. There are five main types of structures for these compounds: tricyclic cassane diterpenoids with a fused furan ring (I) or butanolide lactone (II), tricyclic cassane diterpenoids (III), norcassane diterpenoids (IV), and other types (V). CAs derivatives have a wide range of biological properties, including anti-inflammatory, antimalarial, antitumour, antiviral, antimicrobial, antinociceptive, and antioxidant effects. This review highlights the role of the biosynthetic pathway, including those with abnormal skeletons, as well as advances in structure, pharmacological activities and primarily mechanisms of CAs obtained from the Caesalpinia genus. The findings herein provide new insights into the development of this kind of natural diterpenoids., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Six previously undescribed cassane diterpenoids, named caesalminaxins O-T (1-6), together with 28 known compounds (7-34), were isolated from the seeds of Caesalpinia minax Hance. Their structures, including their absolute configurations were elucidated by extensive spectroscopic analysis, X-ray diffraction, and quantum chemical calculations. Among the undescribed diterpenoids, compound 6 that possessed an unusual enol group at C-7 with a highly deshielded 1 H NMR signal was the first example in cassane diterpenoids. All of the isolates were evaluated for their inhibitory activity against lipopolysaccharide-activated NO production in RAW264.7 cells. Compound 16 showed moderate inhibitory activity with an IC 50 value of 17.3 μM, which was more potent than the positive control (indomethacin, IC 50  = 29.7 μM)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI 50 value of 2.45 and 0.71 µM, mean TGI value of 9.77 and 2.29 µM, and a mean LC 50 of 26.92 and 11.48 µM for 1 and 2 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03 µg/mL., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Seven undescribed hydroxylated cassane-type furanoditerpenoids were isolated from pupal cases formed from the secretion/excretion of the larvae of the wild bruchid seed beetle Sulcobruchus sauteri in infested Caesalpinia decapetala seeds, and their structures were elucidated by interpreting their spectra. The hydroxylated furanoditerpenoids found in the pupal cases were not present in the seeds of the host plant. Caesalacetal and caesaljapin obtained from the intact seeds exhibited larvicidal activity against the larvae of Aedes albopictus, while the hydroxylated furanoditerpenoids isolated from the pupal cases were inactive. The larvae of S. sauteri are proposed to detoxify larvicidal diterpenoids that occur in the seeds of the host plant by regiospecific hydroxylation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Two new cassane ditepenoid lactams, caesmimotam A (1) and B (2), along with eight known compounds (3-10) were isolated from the fruits of Caesalpinia mimosoides Lam. Their structures were identified by 1D and 2D NMR spectral data. Compounds 1 and 2 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, but they were inactive.

Four fractions were prepared from the crude extract of Caesalpinia minax Hance and the inhibitory activity of nitric oxide (NO) production release of RAW 264.7 cells stimulated by lipopolysaccharide (LPS) was evaluated. The ethyl acetate (EtOAc) fraction showed obvious inhibitory effect. Bioassay-guided fractionation led to the isolation of three new cassane diterpenes, caesalmin X (1), caesalmin Y (2) and caesalmin Z (3), together with 19 known cassane diterpenoids (4-22). Their structures were mainly characterised on the basis of extensive spectroscopic analyses and comparison with reported data. Moreover, three compounds (20-22) which possessed furanditerpenoid 7,17-lactone structures, displayed moderate activities, with IC 50 value of 29.85, 27.38 and 25.40 μM, respectively.

One new cassane diterpene possessing an unusual N bridge between C-19 and C-20 named caesalsappanin R ( 1 ), as well as another new diterpene caesalsappanin S ( 2 ), were isolated from the seeds of Caesalpinia sappan with methanol extract. Their structures were determined by spectroscopic analysis and examined alongside existing data from prior studies. Their biological activities were profiled by their antiplasmodial activity., Competing Interests: There is no conflict of interest associated with the authors of this paper.

Plant-derived natural products have been the highly significant sources of novel antitumor agents. The cassane-type diterpenes of genus Caesalpinia have been reported to bear antiproliferative activities toward different types of cancer cells. In this study, we evaluated the antineoplasmic activities of 16 natural origin cassane-type diterpenes isolated from the CHCl 3 extract of the seeds of C. minax in pituitary adenomas cells and identified caesalpin G (CAG) showed the strongest cytotoxicity. Moreover, we further investigated the structure-activity relationship and molecular mechanism of these derivatives systematically. The results confirmed the unsaturated lactone-type ring, hydroxyl at C-7, and alkenyl at C-11 or C-14 functionality as critical for anticancer activity in this family of natural products. In addition, the mechanism experiments also demonstrated unfolded protein response and ER stress and Wnt/β-catenin pathway were involved in the CAG-induced apoptosis.

Five cassane diterpenes were isolated from the 95% ethanol extract of the seeds of Caesalpinia bonduc (Leguminosea) by a combination of various chromatographic methods, including silica gel, Sephadex LH-20, and semi-preparative HPLC. On the basis of spectroscopic techniques, their structures were identified as 3β-acetoxy-cassa-12,14(17),15-trien-7β-ol (1), caesalmin C (2), caesall E (3), caesalpinin MJ (4), and 1-deacetylcaesalmin C (5). Among them, compound 1 is a new compound and 2, 4, 5 were isolated from the plant for the first time.

A phytochemical investigation on the chloroform extract of Caesalpinia pulcherrima roots led to the isolation of ten known furanocassane diterpenoids, vouacapen-5 α -ol ( 1 ), 8,9,11,14-didehydrovouacapen-5 α -ol ( 2 ), 6 β -cinnamoyl-7 β -hydroxyvouacapen-5 α -ol ( 3 ), pulcherrin A ( 4 ), pulcherrin B ( 5 ), pulcherrin J ( 6 ), pulcherrimin A ( 7 ), pulcherrimin B ( 8 ), pulcherrimin C ( 9 ), and pulcherrimin E ( 10 ). Chemical transformation of 3 and 7 gave compounds 6 β -hydroxyisovouacapenol C ( 11 ), 6 β -cinnamoyl-7 β -acetoxyvouacapen-5 α -ol ( 12 ), and pulcherrimin D ( 13 ). Cytotoxicity of compounds 1 - 13 was evaluated against three cancer cell lines (MCF-7, HeLa, and PC-3). Anti-inflammatory potential of the compounds was evaluated via the oxidative burst assay using a luminol-amplified chemiluminescence technique. Leishmanicidal activity was tested against promastigotes of Leishmania major in vitro . Compounds 3, 4, 8, 9 , and 10 were found active against all three cancer cell lines with IC 50 s ranging from 7.02 ± 0.31 to 36.49 ± 1.39 µM. Compounds 8 and 13 exhibited a potent inhibitory effect on reactive oxygen species generated from human whole blood phagocytes (IC 50  = 15.30 ± 1.10 µM and 8.00 ± 0.80 µM, respectively). Compounds 3, 9 , and 13 showed significant activity against promastigotes of L. major (IC 50  = 65.30 ± 3.20, 58.70 ± 2.80, and 55.90 ± 2.40 µM, respectively)., (Georg Thieme Verlag KG Stuttgart · New York.)

Eighteen compounds, including eight new cassane-type furanoditerpenoids, 3β-hydroxyphanginin H (1), 3β-acetoxyphanginin H (2), 7β-acetoxyphanginin H (3), 7β-hydroxyphanginin H (4), 4-epi-3β-hydroxycaesalpinilinn (5), 4-epi-3β-acetoxycaesalpinilinn (6), 20-acetoxytaepeenin D (7), and tomocin E (8), along with 10 known compounds (9-18) were isolated from the roots of Caesalpinia decapetala. Compounds 1-13 were isolated from C. decapetala for the first time. The new compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1, 4, 5, 7, and 11 exhibited inhibitory activities against the SW1990 human pancreatic cancer cell line with IC 50 values ranging from 2.9 to 8.9 μM.

Four casssane diterpenes were isolated from the ethanol extract of the seeds of Caesalpinia decapetala (Fabaceae), with a combination of various chromatographic approaches, including silica gel, Sephadex LH-20, reverse phase C18 and so on. On the basis of spectroscopic data analysis, they were identified as caesalpinin MQ (1), neocaesalpin N(2), caesalmin F (3) and α-caesalpin (4). Among them, compound 1 is a new diterpene, compounds 2-4 were isolated for the first time from the plant of C. decapetala.

Caesalpinia decapetala is a versatile medicinal plant belonging to the Fabaceae plant family. In our survey on plant secondary metabolites to obtain bioactive substances for the development of new agricultural anti-TMV agents, the chemical constituents of C. decapetala were investigated. This investigation led to the isolation of three new and ten known diterpenoids. Their structures including absolute configurations were elucidated based on the extensive NMR spectroscopic data analyses and the time-dependent density functional theory calculations. The following biological screenings revealed that most of these diterpenoids possessed anti-TMV activities., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Caesalpinone A (1), a new type of gorgonane sesquiterpenoid containing an unprecedented 1,15-bridge, along with ten known sesquiterpenoids (2-11) were isolated from the pods of Caesalpinia spinosa Kuntze (Tara). The structure of caesalpinone A was elucidated based on its 1D and 2D NMR spectra. The absolute configuration of 1 was assigned by the comparison of the experimental and calculated electronic circular dichroism spectra. Compound 1 was evaluated for the inhibitory activities against five human tumor cell lines. The sesquiterpenoids of isodaucane skeleton and caryolane skeleton were isolated from Caesalpinia genus for the first time. Compounds 5-9 were firstly reported from Tara., (Copyright © 2016. Published by Elsevier B.V.)

The seeds of the medicinal plant Caesalpinia sappan yielded fourteen cassane-type diterpenes, including six new rearranged ones named as caesalppans A-F (1-6). Their structures were elucidated by spectroscopic analysis and comparison with literature data. The isolated new compounds 1-6 possess lactone-type cassane diterpenoid skeleton with an oxygen bridge between C-19 and C-20, and were tested cytotoxic activity against four cancer cell lines using the MTT method., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The chemical study on the seeds of Caesalpinia sappan led to the isolation of five new cassane diterpenoids, phanginins R‒T (1-3) and caesalsappanins M and N (4 and 5), together with seven known compounds 6-12. Their structures were elucidated on the basis of NMR and HRESIMS analyses. The absolute configurations of compounds 1 and 4 were determined by the corresponding CD spectra. All the isolated compounds were tested for their cytotoxicity against ovarian cancer A2780 and HEY, gastric cancer AGS, and non-small cell lung cancer A549 cells. Compound 1 displayed significant toxicity against the four cell lines with the IC50 values of 9.9 ± 1.6 µM, 12.2 ± 6.5 µM, 5.3 ± 1.9 µM, and 12.3 ± 3.1 µM, respectively. Compound 1 induced G1 phase cell cycle arrest in A2780 cells. Furthermore, compound 1 dose-dependently induced A2780 cells apoptosis as evidenced by Hoechst 33342 staining, Annexin V positive cells, the up-regulated cleaved-PARP and the enhanced Bax/Bcl-2 ratio. What's more, compound 1 also promoted the expression of the tumor suppressor p53 protein. These findings indicate that cassane diterpenoids might have potential as anti-cancer agents, and further in vivo animal studies and structural modification investigation are needed.

Eight structurally diverse cassane diterpenes named tomocins A-H were isolated from the seed kernels of Vietnamese Caesalpinia sappan Linn. Their structures were determined by extensive NMR and CD spectroscopic analysis. Among the isolated compounds, tomocin A, phanginin A, F, and H exhibited mild preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived condition without causing toxicity in normal nutrient-rich conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ten new cassane-type diterpenoids, caesalbonducins D-F (1-3), 6-deacetoxybonducellpin B (4), 3-acetoxy-α-caesalpin (5), 2(3)-en-α-caesalpin (6), 1α-hydroxycaesalpinin J (7), 1α-hydroxy-6-decaetoxysalpinin J (8), 6α-hydroxycaesall M (9), and 6α-hydroxy-14(17)-dehydrocaesalpin F (10), along with eight known compounds (11-18), were isolated from the pericarps of Caesalpinia bonduc. Compounds 1-3 and 11 are methyl-migrated cassane-type diterpenoids with a 19(4→3)-cassane skeleton. The structures of 1-10 were elucidated on the basis of 1D and 2D NMR methods and other spectroscopic analysis. The neuroprotective effects of the isolated compounds were evaluated.

Phytochemical investigation on the seeds of Caesalpinia decapetala led to the isolation of a new cassane diterpenoid with an unusual O bridge between C-19 and C-20, named phanginin Q (1), together with three known cassane diterpenoids, caesaljapin (2), caesaldekarin A (3), and caesaldekarin B (4). The structure of the new compound was elucidated by spectroscopic methods, including (1)H NMR, (13)C NMR, HSQC, (1)H - (1)H COSY, HMBC, NOESY, and HR-ESI-MS.

Two cassane-type furanoditerpenoids, designated caesalacetal and caesalpinetate, and a norditerpenoid designated caesalpinone were isolated from the roots of Caesalpinia decapetala var. japonica along with seven known diterpenoids. Structures were elucidated by interpretation of their spectroscopic data, and the absolute structure of caesalacetal was confirmed by X-ray crystallographic analysis. Furthermore, the structure of a previously reported furanoditerpenoid, caesaljapin, was revised as its C-4 epimer on the basis of detailed NMR spectroscopic data as well as X-ray crystallographic analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cassane diterpenoids were successfully and simultaneously identified in Caesalpinia minax Hance by high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. A total of 59 peaks were detected, and among them 51 compounds, including 41 furanocassane diterpenoids, 10 furanolactone cassane diterpenoids were simultaneously identified and characterized on the basis of the protonated molecule, retention behavior, and fragments in MS(2) . Ten compounds, including seven novel compounds, were identified or tentatively identified for the first time in C. minax. In a positive ion mode, the fragmentation pathways of cassane diterpenoids were also analyzed for the first time. The relative amounts of the five main diterpenoids (caesalpinin L, caesalpinin F2 , bondcellpin C, caesalpinin E, and ξ-caesalmin) were simultaneously quantified by high-performance liquid chromatography. Results showed that the newly discovered and known components of C. minax can be used to determine the material basis of bioactivity; this method can also be applied to analyze cassane diterpenoids in herbal medicines from the genus Caesalpinia belonging to the family Fabaceae., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bioassay-guided fractionation of a methanol extract of the seeds of Caesalpinia sappan led to the isolation of 12 new cassane-type diterpenes, caesalsappanins A-L (1-12). Their structures were elucidated on the basis of NMR and HRESIMS analysis, and the absolute configuration of compound 1 was determined by single-crystal X-ray crystallography. All isolated compounds were tested against a chloroquine-resistant Plasmodium falciparum strain for antiplasmodial activities and against a small panel of human cancer cell lines for antiproliferative activities. Compounds 7 and 8 displayed antimalarial activity against the chloroquine-resistant K1 strain of P. falciparum with IC50 values of 0.78 and 0.52 μM and selectivity indices of 17.6 and 16.4, respectively. Compound 10 showed antiproliferative activity against the KB cancer cell line with an IC50 value of 7.4 μM.

Six new cassane diterpenes, isoneocaesalpin H (1), caespinosin A (2), caespinosin B (3), a cassane diterpene with unique 6/6/7 carbon rings, and caespinosins C-E (4-6) were isolated from the twigs and leaves of Tara (Caesalpinia spinosa Kuntze). The absolute configuration of isoneocaesalpin H (1) was determined by single-crystal X-ray crystallographic analysis. Compound 3 represents a class of rare natural cassane diterpene bearing unique 6/6/7 carbon rings. Their structures were identified by 1D and 2D NMR spectral data. Cassane diterpenes were firstly reported from Tara. Compounds 1-5 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, but they were inactive., (Copyright © 2015. Published by Elsevier B.V.)