Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from Salvia ballotiflora

Esquivel, Baldomero; Bustos-Brito, Celia; Sánchez-Castellanos, Mariano; Nieto‐Camacho, Antonio; Ramírez‐Ápan, Teresa; Joseph‐Nathan, Pedro; Quijano, Leovigildo

doi:10.3390/molecules22101690

Cited by 28 publications

(41 citation statements)

References 51 publications

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Section: Resultsmentioning

confidence: 99%

“…Their structures were established by spectroscopic means, mainly 1 H-and 13 C-NMR, while the AC of 110, 111, and 112 (Figure 28) was determined by X-ray diffraction analysis and VCD. 65 The aerial parts of Salvia clinopodioides gave abietanes 113, 115, and 117, together with icetexane 118 (Figure 29). The AC of 113 and 115 was verified by VCD of their acetates 114 and 116.…”

Section: Terpenoidsmentioning

confidence: 99%

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Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

Río

Joseph‐Nathan

2021

Natural Product Communications

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Although demonstrated in 1975, vibrational circular dichroism (VCD) finally started to popularize during this century as a reliable tool to determine the absolute configuration (AC) of organic molecules. This research field continues to be a very dynamic one, in particular for the study of natural products which are a unlimited source of chiral molecules. It therefore turns of interest to summarize the accomplishments published in recent years and to comment on some eventual difficulties that emerged in rare cases to complete the AC determination task. Therefore the aim of this review is to update VCD results for the AC assignment of natural products published from 2015 to 2019, a period in which VCD was reported in some 126 publications involving almost 300 molecules. They are organized according the type of studied metabolite allowing an easily search. The molecules correspond to 28 monoterpenes concerning 17 papers, to 42 sesquiterpenes in 14 papers, to 51 diterpenes in 19 publications, to 5 other terpenoids in three papers, to 48 aromatic molecules in 15 reports, to 20 polyketides in 10 publications, to 27 miscellaneous formulas also in 10 papers, and to 76 nitrogen containing compounds, which include alkaloids and their synthetic analogs, in 38 articles. The landscape of reviewed molecules is quite wide as it goes from simple monoterpenes, like borneol or camphor, to very relevant biological molecules like the alkaloid cocaine or tadalafil samples to distinguish genuine and counterfeit Cialis®. In addition, 5 natural products and a simple derivative published outside the reviewed period, were used to illustrate some aspects of density functional theory calculations.

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Section: Resultsmentioning

confidence: 99%

Section: Terpenoidsmentioning

confidence: 99%

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

Río

Joseph‐Nathan

2021

Natural Product Communications

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“…Abietane diterpenes (ADs), extracted from a variety of plant sources, display a wide variety of biological activities, including antibacterial, antioxidant, anti-inflammatory, and antifungal activities, amongst others (Çadirci et al, 2012;Wu et al, 2012;Hanson, 2013;Gonzalez, 2015). In particular, the antiproliferative activity of both phenolic-type (carnosic acid and ferruginol) and quinone-type (aethiopinone, salvipisone, and 1oxoaethiopinone) ADs has been reported in different cancer cell lines (Gonzalez, 2015;Akaberi et al, 2015;Esquivel et al, 2017). Aethiopinone and salvipisone from S. sclarea induce caspase-3 mediated apoptosis in a time-and concentration-dependent manner in leukemia cells (Rozalski et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Boosting the Synthesis of Pharmaceutically Active Abietane Diterpenes in S. sclarea Hairy Roots by Engineering the GGPPS and CPPS Genes

et al. 2020

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Abietane diterpenoids (ADs), synthesized in the roots of different Salvia species, such as aethiopinone, 1-oxoaethiopinone, salvipisone, and ferruginol, have a variety of known biological activities. We have shown that aethiopinone has promising cytotoxic activity against several human tumor cell lines, including the breast adenocarcinoma MCF7, HeLa, epithelial carcinoma, prostate adenocarcinoma PC3, and human melanoma A375. The low content of these compounds in natural sources, and the limited possibility to synthesize them chemically at low cost, prompted us to optimize the production of abietane diterpenoids by targeting genes of the methylerythritol phosphate (MEP) pathway, from which they are derived. Here, we report our current and ongoing efforts to boost the metabolic flux towards this interesting class of compounds in Salvia sclarea hairy roots (HRs). Silencing the gene encoding the ent-copalyldiphosphate synthase gene (entCPPS), acting at the lateral geranylgeranyl pyrophosphate (GGPP) competitive gibberellin route, enhanced the content of aethiopinone and other ADs in S. sclarea HRs, indicating indirectly that the GGPP pool is a metabolic constraint to the accumulation of ADs. This was confirmed by overexpressing the GGPPS gene (geranyl-geranyl diphosphate synthase) which triggered also a significant 8-fold increase of abietane diterpene content above the basal constitutive level, with a major boosting effect on aethiopinone accumulation in S. sclarea HRs. A significant accumulation of aethiopinone and other AD compounds was also achieved by overexpressing the CPPS gene (copalyl diphosphate synthase) pointing to this biosynthetic step as another potential metabolic target for optimizing the biosynthesis of this class of compounds. However, by co-expressing of GGPPS and CPPS genes, albeit significant, the increase of abietane diterpenoids was less effective than that obtained by overexpressing the two genes individually. Taken together, the results presented here add novel and instrumental knowledge to a rational design of a hairy rootbased platform to yield reliable amounts of aethiopinone and other ADs for a deeper understanding of their molecular pharmacological targets and potential future commercialization.

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“…We found that the yield of DAM, ICT, and DEOX was lower than 0.005% [ 6 ], and as a result, only few experiments with these compounds were performed [ 9 ]. Therefore, the in vivo models, quantitation of IL-1β and IL-10 in LPS-stimulated macrophages, anti-arthritic activity, membrane stabilization assay, the apoptosis and the antitumor assay were assessed only with ECL standardized with DEOX as the phytochemical marker.…”

Section: Discussionmentioning

confidence: 99%

“…From this plant species, two diterpene quinones have been isolated, icetexone (ICT) and conacytone [7] as well as other diterpenes, such as 19-deoxyicetexone (DEOX), 19-deoxyisocetexone (DIC), and 7,20-dihydroanastomosine (DAM), among others [8]. Other isolated compounds from Salvia ballotiflora include 7α-acetoxy-6,7-dihydroicetexone, and anastomosine, these two compounds have shown cytotoxic activity against the cancer cell lines U251 and SKLU-1, and an anti-inflammatory effect on acute ear edema induced by TPA in mice [9]. Additional, some studies have found that different diterpenes exhibited an important anti-inflammatory effect [10].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory and antitumor activities of the chloroform extract and anti-inflammatory effect of the three diterpenes isolated from Salvia ballotiflora Benth

Campos-Xolalpa

Alonso-Castro

Ortíz‐Sánchez

et al. 2021

BMC Complement Med Ther

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Background Drugs used for the treatment of diseases associated with chronic inflammation, such as cancer and rheumatoid arthritis have the potential to cause undesirable side-effects, which might result in patients ending treatment prematurely. However, plants are a viable option for the treatment of inflammatory diseases. In this study, we assessed the in vivo and in vitro anti-inflammatory activity, and the antitumor effects of the chloroform extract of Salvia ballotiflora (ECL). The pro-apoptotic effects of ECL in CT26 cells were also determined. Methods The chloroform extract of Salvia ballotiflora (ECL) was standardized using 19-deoxyicetexone (DEOX) as a phytochemical marker. The anti-inflammatory activity of ECL was determined on acute and chronic inflammatory models using the TPA-induced mouse ear edema assay. The antitumor activity of ECL was evaluated by the subcutaneous inoculation of CT26 cells on the back of Balb/c mice. In vitro CT26 cell death induced by ECL was determined by Annexin V/propidium iodide staining assay using flow cytometry. ECL and the diterpenes isolated from the chloroform extract included 19-deoxyicetexone (DEOX), icetexone (ICT), and 7,20-dihydroanastomosine (DAM), which were tested in LPS-stimulated J774A.1 macrophages to quantify pro-inflammatory cytokine levels. The in vitro anti-arthritic activity of ECL was determined using the bovine serum protein (BSP) denaturation assay. Results ECL exerted anti-inflammatory activities in acute (84% of inhibition, 2 mg/ear) and chronic models (62.71%, at 100 mg/kg). ECL showed antitumor activity at 200 mg/kg and 300 mg/kg, reducing tumor volume by 30 and 40%, respectively. ECL (9.5 μg/mL) induced in vitro apoptosis in CT26 cells by 29.1% (48 h of treatment) and 93.9% (72 h of treatment). ECL (10 μg/ml) decreased levels of NO (53.7%), pro-inflammatory cytokines IL-6 (44.9%), IL-1β (71.9%), and TNF-α (40.1%), but increased the production of the anti-inflammatory cytokine IL-10 (44%). The diterpenes DEOX, ICT, and DAM decreased levels of NO (38.34, 47.63, 67.15%), IL-6 (57.84, 60.45, 44.26%), and TNF-α (38.90, 31.30, 32.83%), respectively. ECL showed in vitro antiarthritic activity (IC50 = 482.65 μg/mL). Conclusions ECL exhibited anti-inflammatory and anti-tumor activities. Furthermore, the diterpenes DEOX, DAM, and ICT showed anti-inflammatory activity by reducing levels of NO, TNF-α, and IL-6.

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Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from Salvia ballotiflora

Cited by 28 publications

References 51 publications

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

Boosting the Synthesis of Pharmaceutically Active Abietane Diterpenes in S. sclarea Hairy Roots by Engineering the GGPPS and CPPS Genes

Anti-inflammatory and antitumor activities of the chloroform extract and anti-inflammatory effect of the three diterpenes isolated from Salvia ballotiflora Benth

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