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SOLENOPSIN Sale

目录号 : GC34053

Solenopsin是一种ATP-竞争型AKT抑制剂,withIC50值为10μM.

SOLENOPSIN Chemical Structure

Cas No.:137038-57-4

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产品描述

Solenopsin is an ATP-competitive AKT inhibitor with IC50 value of 10 μM .

[1]. Arbiser JL, et al. Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis. Blood. 2007 Jan 15;109(2):560-5. Epub 2006 Sep 21.

Chemical Properties

Cas No. 137038-57-4 SDF
Canonical SMILES CCCCCCCCCCC[C@@H]1CCC[C@@H](C)N1
分子式 C17H35N 分子量 253.47
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 3.9452 mL 19.7262 mL 39.4524 mL
5 mM 0.789 mL 3.9452 mL 7.8905 mL
10 mM 0.3945 mL 1.9726 mL 3.9452 mL
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Research Update

Akt Pathway Inhibitors

Curr Top Med Chem 2020;20(10):883-900.PMID:32091335DOI:10.2174/1568026620666200224101808.

Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product SOLENOPSIN has been identified as an inhibitor of Akt. A few promising SOLENOPSIN derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.

SOLENOPSIN A and analogs exhibit ceramide-like biological activity

Vasc Cell 2015 May 8;7:5.PMID:26015865DOI:10.1186/s13221-015-0030-2.

Background: (-)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that SOLENOPSIN exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. SOLENOPSIN has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis. Methods: Different analogs of SOLENOPSIN were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of SOLENOPSIN and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of SOLENOPSIN and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of SOLENOPSIN and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of SOLENOPSIN and analogs on ROS production was investigated. Results: In this paper we demonstrate that SOLENOPSIN analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether SOLENOPSIN and analogs act as ceramide analogs, we examined the effect of SOLENOPSIN and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native SOLENOPSIN, (-)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of SOLENOPSIN reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only SOLENOPSIN induces mitophagy, like ceramide. Conclusions: The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (-)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.

Akt Pathway Inhibition of the SOLENOPSIN Analog, 2-Dodecylsulfanyl-1,-4,-5,-6-tetrahydropyrimidine

Anticancer Res 2019 Oct;39(10):5329-5338.PMID:31570426DOI:10.21873/anticanres.13725.

Background/aim: The P13K/Akt signaling pathway is a growth-regulating cellular pathway that is constitutively activated in a variety of human cancers. In previous studies, we reported that a SOLENOPSIN analog, compound B (MU-06-SC-608-7), shows inhibitory effects on Akt phosphorylation at a key activation site, as well as on proliferation of tumorigenic cells at sub-micromolar concentrations. The purpose of this study was to evaluate the effect of compound B on downstream effectors of Akt kinase, phosphorylation of Akt at a second activation site, Akt kinase activity in vitro, tumorigenic cell viability and other signaling pathways. Materials and methods: Western blot analyses were performed using WBras1 epithelial and H2009 human carcinoma cells and cell viability assays were performed on H2009 cells. In vitro Akt kinase assays were performed using a commercially available kit. Results: Compound B decreased the phosphorylation of Akt at the Thr308 activation site and key downstream effectors of Akt kinase, but did not directly inhibit Akt kinase. Substantial decreases in cell viability were observed at concentrations above 5 μM. No effect was seen on ERK or JNK pathways. Conclusion: The results earmark this compound for further studies as a potential targeted cancer therapy.

SOLENOPSIN A, a venom alkaloid from the fire ant Solenopsis invicta, inhibits quorum-sensing signaling in Pseudomonas aeruginosa

J Infect Dis 2008 Oct 15;198(8):1198-201.PMID:18713055DOI:10.1086/591916.

In Pseudomonas aeruginosa, quorum-sensing (QS) signaling regulates the expression of virulence factors and thus represents an attractive new target for anti-infective therapy. In the present study, we investigated whether SOLENOPSIN A, a venom alkaloid from the fire ant, possessed agonistic or antagonistic QS signaling activity in P. aeruginosa. We evaluated the modulation of virulence factor expression and transcriptional levels of QS-regulated genes in P. aeruginosa by SOLENOPSIN A and demonstrated that SOLENOPSIN A efficiently disrupted QS signaling. Interestingly, exogenously added C(4)-homoserine lactone (HSL), but not 3-oxo-C(12)-HSL, restored P. aeruginosa QS signaling, suggesting that SOLENOPSIN A targets the C(4)-HSL-dependent rhl QS system.

SOLENOPSIN, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis

Blood 2007 Jan 15;109(2):560-5.PMID:16990598DOI:10.1182/blood-2006-06-029934.

Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Balpha (PKBalpha), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase-activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid SOLENOPSIN, and found that it is a potent angiogenesis inhibitor. We also found that SOLENOPSIN inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, SOLENOPSIN prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, SOLENOPSIN also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.