Sclareolide

The herbs of Perilla frutescens

Target: NpABC1

IC50: NA

Sclareolide (Norambreinolide) is a sesquiterpene lactone natural product derived from various plant sources including Salvia yosgadensis, Salvia sclarea, and cigar tobacco [1]. Sclareolide is a close analog of sclareol, an antifungal diterpene produced at the leaf surface of Nicotiana spp. Moreover, Sclareolide is used as a fragrance in cosmetics and has been more recently marketed as a weight loss supplement.

In vitro: Sclareolide (20, 100, and 500 μM) dose-dependently induced NpABC1 expression of a plasma membrane protein in Nicotiana plumbaginifolia cells [1]. Sclareolide (20 μM) had no effect on Nicotiana plumbaginifolia cell growth although the induction of NpABC1 expression. In addition, NpABC1 transcript levels were high 3 hr after sclareolide addition and then decreased. However, the level of NpABC1 protein expression remained fairly stable for up to 12 hr [1]. The 160-kD NpABC1 protein is localized in the plasma membrane and is involved in the secretion of a secondary metabolite which plays an important role in plant defense [1].

In vivo: N/A

Reference:
1.  Jasinski M, Stukkens Y, Degand H, Purnelle B, Marchand-Brynaert J, Boutry M. A plant plasma membrane ATP binding cassette-type transporter is involved in antifungal terpenoid secretion. Plant Cell. 2001;13(5):1095-107.

Genes Encoding Cucumber Full-Size ABCG Proteins Show Different Responses to Plant Growth Regulators and Sclareolide.[Pubmed:27429510]

Plant Mol Biol Report. 2016;34:720-736.

Full-size members of the ABCG (ATP-binding cassette, subfamily G) subfamily of ABC transporters have been found only in plants and fungi. The plant genes encoding full-size ABCGs identified so far appeared to be differentially regulated under various environmental constraints, plant growth regulators, and microbial elicitors, indicating a broad functional role of these proteins in plant responses to abiotic and biotic stress. Nevertheless, the structure and physiological function of full-size ABCGs in many plant species are still unknown. We have recently identified 16 genes encoding full-size ABCG proteins in cucumber and found that the transcripts of two of them, CsABCG36 (CsPDR8) and CsABCG40 (CsPDR12), are most abundant in roots and are significantly affected by phytohormones and auxin herbicide. In this study, we analyzed the structure and phylogeny of all the full-size cucumber ABCG transporters and studied the organ expression profiles of the remaining 14 CsABCG genes. In addition, we investigated the effect of different plant growth regulators and the diterpene Sclareolide on CsABCG expression in cucumber roots. Until now, the full-size plant ABCG transporters have been grouped into five different clusters. The new phylogenetic analysis of full-size ABCGs from model plants and cucumber clustered these proteins into six different subgroups. Interestingly, the expression profiles of cucumber ABCG genes assigned to the same clusters were not correlated, suggesting functional diversification or different regulatory mechanisms of the full-size cucumber ABCG proteins.

Sclareolide enhances gemcitabineinduced cell death through mediating the NICD and Gli1 pathways in gemcitabineresistant human pancreatic cancer.[Pubmed:28259943]

Mol Med Rep. 2017 Apr;15(4):1461-1470.

Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc1 and ASPC1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabineresistant cells (GRHPCCs). The anticancer effect of gemcitabine combined with Sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GRHPCCs, and the mechanisms were investigated. Sclareolide resensitized the GRHPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GRHPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabineinduced EMT through the TWIST1/Slug pathway in the GRHPCCs. In addition, Sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/gliomaassociated oncogene 1 (Gli1) pathway, which triggered TWIST1/SlughENT1/RRM1 signaling and resensitized GRHPCCs to gemcitabine. Finally, Sclareolide resensitized GRHPCCs to gemcitabine through inducing apoptosis; in vivo, the coadministraion of Sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabineresistant pancreatic cancer, which resensitizes GRHPCCs to gemcitabine through mediating NICD and Gli1.

Biohydroxylation of (-)-ambrox(R), (-)-sclareol, and (+)-sclareolide by whole cells of Brazilian marine-derived fungi.[Pubmed:25634054]

Mar Biotechnol (NY). 2015 Apr;17(2):211-8.

A screening was performed using nine marine-derived fungi as biocatalysts and the natural products (-)-ambrox(R) (1), (-)-sclareol (2), and (+)-Sclareolide (3) in order to select the microorganisms able to catalyze the biooxidation of these compounds. It was observed that only the Aspergillus sydowii CBMAI 934, Botryosphaeria sp., Eutypella sp., and Xylaria sp. presented active oxidoreductases and catalyzed the regioselective hydroxylation in the natural products. The hydroxylated metabolites obtained were 1beta-hydroxy-ambrox (1a) (14%, A. sydowii CBMAI 934); 3beta-hydroxy-ambrox (1b) (17%, Botryosphaeria sp.; 11%, Eutypella sp.); 3beta-hydroxy-sclareol (2a) (31%, Xylaria sp.; 69%, Botryosphaeria sp.; 55%, Eutypella sp.); 18-hydroxy-sclareol (2b) (10%, Xylaria sp.); and 3beta-hydroxy-Sclareolide (3a) (34%, Botryosphaeria sp.; 7%, Eutypella sp.). This is the first report of biohydroxylation of (-)-ambrox(R) (1), (-)-sclareol (2), and (+)-Sclareolide (3) by whole mycelia of marine-derived fungi.

Expanding Diversity without Protecting Groups: (+)-Sclareolide to Indolosesquiterpene Alkaloid Mycoleptodiscin A and Analogues.[Pubmed:27181938]

Org Lett. 2016 Jun 3;18(11):2684-7.

Short and scalable synthesis of the complex pentacyclic indolosesquiterpene natural product mycoleptodiscin A has been achieved from commercially available diterpenoid (+)-Sclareolide in 19% overall yield. This approach allows one to prepare various analogues of mycoleptodiscin using McMurry cyclization as a key reaction with just three chromatographic purifications.

Sclareolide(Norambreinolide) is a sesquiterpene lactone natural product derived from various plant sources including Salvia sclarea, Salvia yosgadensis, and cigar tobacco.

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