ISOSTEVIOL

Synthesis and cytotoxic activity of MOM-ether analogs of isosteviol.[Pubmed: 24444475]

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1184-7.

Lung cancer is one of the most common malignancies worldwide.
METHODS AND RESULTS:
In this Letter, novel MOM-ether analogs of Isosteviol were designed and synthesized to be tested for anticancer activities against H1299 lung cancer cell lines. The effects of these derivatives were studied in H1299 human large cell lung carcinoma cells that are null for p53 and compared to normal counterparts NL-20 normal lung epithelial cells. The initial screening of twelve MOM-ether analogs of Isosteviol derivatives on H1299 lung cancer cells by MTT assay revealed that two derivatives (an ester and a carbamate) were the most potent in reducing cell viability. The IC50 values for these derivatives were determined to be 14 and 21 μM respectively. We compared the cytotoxicity of the best derivatives in H1299 lung cancer cells and NL-20 normal lung epithelial cells.
CONCLUSIONS:
Both derivatives showed lower cytotoxic effects on NL-20 normal lung epithelial cells. Moreover, both derivatives induced apoptosis in H1299 lung cancer cells more than NL-20 normal lung epithelial cells.

In Vitro Antibacterial, Antifungal, Antibiofilm, Antioxidant, and Anticancer Properties of Isosteviol Isolated from Endangered Medicinal Plant Pittosporum tetraspermum.[Pubmed: 26101532 ]

Evid Based Complement Alternat Med. 2015;2015:164261.

This study aimed to investigate the in vitro antibacterial, antifungal, antibiofilm, antioxidant, and anticancer properties of Isosteviol isolated from endangered medicinal plant Pittosporum tetraspermum.
METHODS AND RESULTS:
Pure compound was obtained and characterized by column chromatography followed by (1)H NMR, (13)C NMR, IR, and mass spectral analysis. The antimicrobial activities of the compound were assessed by the broth microdilution method and the antioxidant properties were determined using reducing ability assay, DPPH scavenging assay, hydroxyl radical scavenging activity, and superoxide radical scavenging assay. Anticancer study was evaluated by following MTT assay. Column purification and spectrocopical analysis lead to identifying Isosteviol from the crude ethyl acetate extract. The compound exhibited significant activity against bacteria such as Staphylococcus epidermidis (125 μg/mL), Staphylococcus aureus (125 μg/mL), and Klebsiella pneumoniae (62.5 μg/mL). The MIC of the compound against Candida albicans, Aspergillus niger, and Trichophyton mentagrophytes was 62.5, 125, and 500 μg/mL, respectively. The compound showed comparatively better antibiofilm activity against E. coli, S. typhi, and P. aeruginosa. Furthermore, it exhibited good antioxidant properties. Anticancer properties of the compound against Vero and MCF7 cell lines were its advantage.
CONCLUSIONS:
Novel Isosteviol would be useful to reduce the infectious diseases caused by pathogenic microorganisms or slow the progress of various oxidative stress-related diseases.

Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.[Pubmed: 28428073 ]

Biochim Biophys Acta. 2017 Apr 18;1859(10):1872-1879.

Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of Ito is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases.
METHODS AND RESULTS:
Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells.
CONCLUSIONS:
The decrease and increase of current densities for Ito and ICaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of Ito and ICaL are correlated to the alterations of the mRNA transcription level.

Neuroprotective Effects of Isosteviol Sodium Injection on Acute Focal Cerebral Ischemia in Rats.[Pubmed: 27047634 ]

Oxid Med Cell Longev. 2016;2016:1379162.

Previous report has indicated that Isosteviol has neuroprotective effects. However, Isosteviol was administered preventively before ischemia and the inclusion criteria were limited.
METHODS AND RESULTS:
In the present study, a more soluble and injectable form of Isosteviol sodium (STVNA) was administered intravenously hours after transient or permanent middle cerebral artery occlusion (tMCAO or pMCAO) to investigate its neuroprotective effects in rats. The rats were assessed for neurobehavioral deficits 24 hours after ischemia and sacrificed for infarct volume quantification and histology evaluation. STVNA 10 mg·kg(-1) can significantly reduce the infarct volumes compared with vehicle in animals subjected to tMCAO and is twice as potent as previously reported. Additionally, the therapeutic window study showed that STVNA could reduce the infarct volume compared with the vehicle group when administered 4 hours after reperfusion. A similar effect was also observed in animals treated 4 hours after pMCAO. Assessment of neurobehavioral deficits after 24 hours showed that STVNA treatment significantly reduced neurobehavioral impairments. The number of restored NeuN-labeled neurons was increased and the number of TUNEL positive cells was reduced in animals that received STVNA treatment compared with vehicle group.
CONCLUSIONS:
All of these findings suggest that STVNA might provide therapeutic benefits against cerebral ischemia-induced injury.

Cytotoxic and apoptosis-inducing activities of steviol and isosteviol derivatives against human cancer cell lines.[Pubmed: 23418165]

Chem Biodivers. 2013 Feb;10(2):177-88.

Seventeen steviol derivatives, i.e., 2-18, and 19 Isosteviol derivatives, i.e., 19-37, were prepared from a diterpenoid glycoside, stevioside (1).
METHODS AND RESULTS:
Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, nine steviol derivatives, i.e., 5-9 and 11-14, and five Isosteviol derivatives, i.e., 28-32, exhibited activities with single-digit micromolar IC(50) values against one or more cell lines. All of these active compounds possess C(19)-O-acyl group, and among which, ent-kaur-16-ene-13,19-diol 19-O-4',4',4'-trifluorocrotonate (14) exhibited potent cytotoxicities against four cell lines with IC(50) values in the range of 1.2-4.1 μM. Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis-inducing activity by flow-cytometric analysis.
CONCLUSIONS:
These results suggested that acylation of the 19-OH group of kaurane- and beyerane-type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis-inducing activity.

The effect of isosteviol on hyperglycemia and dyslipidemia induced by lipotoxicity in rats fed with high-fat emulsion.[Pubmed: 22075495]

Life Sci. 2012 Jan 2;90(1-2):30-8.

The aim of present study was to investigate the effects of Isosteviol on hyperglycemia and hyperlipidemia in rats fed with high-fat emulsion (HFE). The effect of the supplement of palmitate in HFE on the activity of Isosteviol was investigated. Ultrastructural changes in islet β-cells and peroxisome proliferator-activated receptor α (PPARα) mRNA expression profile were determined.
METHODS AND RESULTS:
FSG, FSI, TC and LDL levels and insulin resistance index (IRI) were decreased and HDL level was increased by all doses of Isosteviol. During IVGTT, serum glucose levels were decreased by Isosteviol and no significant differences were observed in insulin release between Isosteviol-treated and control groups. The effects of Isosteviol were attenuated by palmitate. Damage to pancreatic islet cells was partially attenuated, and expression profile of hepatic PPARα mRNA was enhanced by Isosteviol.
CONCLUSIONS:
Antihyperglycemic effects of Isosteviol could enhance utilization of glucose in the periphery and reduce β-cell damage induced by dyslipidemia. Modulating-lipidemic effects of Isosteviol might be related to the potential enhancement of liver PPARα mRNA expression.