Acidic and hepatic derivatives of bioactive clerodane diterpenes casearins J and O

Oda, Fernando Bombarda; Crevelin, Eduardo José; Crotti, Antônio Eduardo Miller; Orlando, Allan Botinhon; Medeiros, Alexandra Ivo de; Resende, Flávia Aparecida; Santos, André Gonzaga dos

doi:10.1016/j.fitote.2019.104197

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…The dried ethyl acetate fraction was submitted to silica gel column chromatography (20 × 5 cm, 40–60 μm) eluted with a gradient of hexane/ethyl acetate/isopropanol. Casearins B, J, O, X and caseargrewiin F were purified by preparative HPLC‐PDA (C18 column, 250 × 21.20 mm, 10 μm) using methanol/water mixtures as the mobile phase 8,21,33 …”

Section: Methodsmentioning

confidence: 99%

Fragmentation study of clerodane diterpenes from Casearia species by tandem mass spectrometry (quadrupole time‐of‐flight and ion trap)

Danuello

Castro

Pilon

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Clerodane‐type diterpenes from Casearia species show important pharmacological activites such as antitumor, antimicrobial and anti‐inflamatory. There are several mass spectrometry (MS)‐based methods for identification of diterpenes; however, there is still a lack of MS procedures capable of providing characteristic fragmentation pathways for a rapid and unambiguous elucidation of casearin‐like compounds. Methods Casearin‐like compounds were investigated by electrospray ionization tandem mass spectrometry (ESI‐MS/MS). The fragmentation studies were carried out by tandem mass spectrometry in space (quadrupole time‐of‐flight (QTOF)) using different collision energies and also by tandem mass spectrometry in time (QIT) by selective isolation of product ions. Results Casearin‐like compounds presented a predominance of sodium‐ and potassium‐cationized precursor ions. Both QIT and QTOF techniques provided sequential neutral losses of esters related to the R1 to R5 substituents linked to the nucleus of the clerodane diterpenes. The fragmentation pathway is initiated with a cleavage of the ester moieties R2 followed by the elimination of the ester groups R3, both losing neutral carboxylic acids. Using QIT, it was also possible to observe the cleavage of the ester groups R1 or R5 by MS4 experiments. Conclusions Through a rational analysis of the fragmentation mechanisms of Casearia diterpenes it was possible to suggest an annotation strategy based on the sequential cleavages of the ester groups related to the R2, R3 and R5 substituents. These results will assist studies of the dereplication and metabolomics involving casearin‐like compounds present in complex extracts of Casearia species.

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Section: Methodsmentioning

confidence: 99%

Fragmentation study of clerodane diterpenes from Casearia species by tandem mass spectrometry (quadrupole time‐of‐flight and ion trap)

Danuello

Castro

Pilon

et al. 2020

Rapid Comm Mass Spectrometry

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“…In vitro immunoassays for cas J and O showed no inhibition activity in oxide nitric oxide in macrophages or COX-I and II enzyme. Given the traditional oral use of C. sylvestris and its derivatives containing casearins, in vivo biological activity seems to be related to the acid degradation products of casearins [18].…”

Section: Resultsmentioning

confidence: 99%

“…Full-scan analysis was performed in the mass range of 300 to 700 mass units ( m/z ). The data acquisition and analysis were carried out using MassLynx version 4.1 (Waters) 18 , 39 .…”

Section: Methodsmentioning

confidence: 99%

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Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

et al. 2023

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Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory and antiulcerogenic activities. The clerodane diterpenes casearin B (cas B) and caseargrewiin F (casg F) are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of cas B and casg F were not previously investigated. We aimed to assess the stability of cas B and casg F in physiological conditions and their metabolism in human liver microsomes (HLM). The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of cas B and casg F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism is not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed log P in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 μM and 66.4 μM and Vmax values of 327 and 648 nmol/min/mg of protein for cas B and casg F, respectively. Metabolism parameters in HLM were extrapolated to predict human hepatic clearance and suggest that casg F and cas B have a high hepatic extraction ratio. In conclusion, our data suggest that casg F and cas B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.

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“…These compounds were identified as clerodane diterpenes by NMR and MS techniques ( Figure 1 ). Previous studies reported that clerodane diterpenes from the Casearia genus, such as those from C. grewiifolia [ 25 ], C. graveolens [ 17 ], C. rupestris [ 26 ], C. sylvestris [ 27 ], and many others [ 13 ] are the most active constituents of the genus Casearia . They display antiplasmodial, antifungal, antimicrobial, and cytotoxic properties.…”

Section: Resultsmentioning

confidence: 99%

Bioactive Clerodane Diterpenoids from the Leaves of Casearia coriacea Vent

et al. 2023

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Casearia coriacea Vent., an endemic plant from the Mascarene Islands, was investigated following its antiplasmodial potentialities highlighted during a previous screening. Three clerodane diterpene compounds were isolated and identified as being responsible for the antiplasmodial activity of the leaves of the plant: caseamembrin T (1), corybulosin I (2), and isocaseamembrin E (3), which exhibited half maximal inhibitory concentrations (IC50) of 0.25 to 0.51 µg/mL. These compounds were tested on two other parasites, Leishmania mexicana mexicana and Trypanosoma brucei brucei, to identify possible selectivity in one of them. Although these products possess both antileishmanial and antitrypanosomal properties, they displayed selectivity for the malaria parasite, with a selectivity index between 6 and 12 regarding antitrypanosomal activity and between 25 and 100 regarding antileishmanial activity. These compounds were tested on three cell lines, breast cancer cells MDA-MB-231, pulmonary adenocarcinoma cells A549, and pancreatic carcinoma cells PANC-1, to evaluate their selectivity towards Plasmodium. This has not enabled us to establish selectivity for Plasmodium, but has revealed the promising activity of compounds 1–3 (IC50 < 2 µg/mL), particularly against pancreatic carcinoma cells (IC50 < 1 µg/mL). The toxicity of the main compound, caseamembrin T (1), was then evaluated on zebrafish embryos to extend our cytotoxicity study to normal, non-cancerous cells. This highlighted the non-negligible toxicity of caseamembrin T (1).

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Acidic and hepatic derivatives of bioactive clerodane diterpenes casearins J and O

Cited by 6 publications

References 23 publications

Fragmentation study of clerodane diterpenes from Casearia species by tandem mass spectrometry (quadrupole time‐of‐flight and ion trap)

Fragmentation study of clerodane diterpenes from Casearia species by tandem mass spectrometry (quadrupole time‐of‐flight and ion trap)

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F

Bioactive Clerodane Diterpenoids from the Leaves of Casearia coriacea Vent

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