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Verrucarin A

(Synonyms: 疣孢菌素,Muconomycin A) 目录号 : GC48247

A macrocyclic trichothecene with diverse biological activities

Verrucarin A Chemical Structure

Cas No.:3148-09-2

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1 mg
¥1,627.00
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产品描述

Verrucarin A is a macrocyclic trichothecene that has been found in M. verrucaria and has diverse biological activities.1,2,3,4 It induces apoptosis and production of reactive oxygen species (ROS) in MDA-MB-231 and T47D breast cancer cells when used at concentrations ranging from 100 to 500 ng/ml.1 Verrucarin A enhances LPS-induced secretion of IL-1β and IL-18 in macrophage-differentiated peripheral blood mononuclear cells (PBMCs).2 It inhibits the growth of the multidrug-resistant P. falciparum strain K1 (EC50 = 0.9 ng/ml).3 Verrucarin A is active against M. incognita root-knot nematodes (MIC = 1.88 µg/ml).4

1.Palanivel, K., Kanimozhi, V., Kadalmani, B., et al.Verrucarin A, a protein synthesis inhibitor, induces growth inhibition and apoptosis in breast cancer cell lines MDA-MB-231 and T47DBiotechnol. Lett.35(9)1395-1403(2013) 2.Kankkunen, P., Rintahaka, J., Aalto, A., et al.Trichothecene mycotoxins activate inflammatory response in human macrophagesJ. Immunol.182(10)6418-6425(2009) 3.Isaka, M., Punya, J., Lertwerawat, Y., et al.Antimalarial activity of macrocyclic trichothecenes isolated from the fungus Myrothecium verrucariaJ. Nat. Prod.62(2)329-331(1999) 4.Nguyen, L.T.T., Jang, J.Y., Kim, T.Y., et al.Nematicidal activity of verrucarin A and roridin A isolated from Myrothecium verrucaria against Meloidogyne incognitaPestic. Biochem. Physiol.148133-143(2018)

Chemical Properties

Cas No. 3148-09-2 SDF
别名 疣孢菌素,Muconomycin A
Canonical SMILES O[C@@H]([C@H](C)CCOC1=O)C(OC[C@@]23[C@@]([C@]4(CO4)[C@]5([H])O[C@]2([H])C=C(C)CC3)(C)[C@](C5)([H])OC(/C=C/C=C/1)=O)=O
分子式 C27H34O9 分子量 502.6
溶解度 Dichloromethane: soluble,DMSO: soluble,Ethanol: soluble,Methanol: soluble 储存条件 Store at -20°C; protect from light
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1 mM 1.9897 mL 9.9483 mL 19.8965 mL
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Research Update

Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma

Biomedicines 2022 Jan 7;10(1):130.PMID:35052809DOI:10.3390/biomedicines10010130.

Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound Verrucarin A (Ver-A), delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). First, the high surface expression of epidermal growth factor receptor (EGFR) in glioblastoma patient tissue and cell lines was confirmed using immunohistochemistry staining, flow cytometry, and Western blotting. mAb-EV-Ver-A was constructed by packing Ver-A and tagging anti-EGFR mAb to EV generated from HEK293F culture. Confocal microscopy and the In Vivo Imaging System demonstrated that mAb-EV could penetrate the blood-brain barrier, target intracranial glioblastoma xenografts, and deliver drug intracellularly. The in vitro cytotoxicity study showed IC50 values of 2-12 nM of Ver-A. The hematoxylin and eosin staining of major organs in the tolerated dose study indicated minimal systemic toxicity of mAb-EV-Ver-A. Finally, the in vivo anti-tumor efficacy study in intracranial xenograft models demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth, but the combination with VEGF mAb did not improve the therapeutic efficacy. This study suggested that mAb-EV is an effective drug delivery vehicle and natural Ver-A has great potential to treat glioblastoma.

Folate-targeted Verrucarin A reduces the number of activated macrophages in a mouse model of acute peritonitis

Bioorg Med Chem Lett 2021 Jun 15;42:128091.PMID:33964441DOI:10.1016/j.bmcl.2021.128091.

Activated macrophages contribute prominently to the progression and maintenance of almost all inflammatory and autoimmune diseases. Although non-specific elimination of these phagocytes has been shown to treat animal models of inflammatory disease, the same therapies have been compromised by unacceptable toxicities, because they also kill quiescent macrophages in healthy tissues. In the studies below, we exploit upregulation of folate receptor beta (FRβ) on inflammatory (but not resting) macrophages to target a cytotoxic drug selectively to the inflammatory subset of macrophages. Because many of these activated macrophages are nondividing, we also employ Verrucarin A as the cytotoxic payload, since it kills both mitotic and nonmitotic cells by blocking protein synthesis. By inserting a redox-sensitive self-immolative linker between the folate and Verrucarin A, we further assure that release of unmodified Verrucarin A is triggered primarily after internalization by an FRβ-positive cell. The resulting folate-verrucarin A conjugate is shown to kill FR-expressing cells in vitro in a manner that can be inhibited by competition with 100-fold excess folic acid. The folate-verrucarin A conjugate is also shown to successfully treat a murine model of inflammatory peritonitis by eliminating inflammatory macrophages without killing other cells in the same peritonitis fluid. Based on this high specificity for inflammatory macrophages, we conclude that folate-verrucarin A warrants continued exploration as a potential therapy for inflammatory and autoimmune diseases in humans.

Identification of Verrucarin A as a potent and selective steroid receptor coactivator-3 small molecule inhibitor

PLoS One 2014 Apr 17;9(4):e95243.PMID:24743578DOI:10.1371/journal.pone.0095243.

Members of the steroid receptor coactivator (SRC) family are overexpressed in numerous types of cancers. In particular, steroid receptor coactivator 3 (SRC-3) has been recognized as a critical coactivator associated with tumor initiation, progression, recurrence, metastasis, and chemoresistance where it interacts with multiple nuclear receptors and other transcription factors to enhance their transcriptional activities and facilitate cross-talk between pathways that stimulate cancer progression. Because of its central role as an integrator of growth signaling pathways, development of small molecule inhibitors (SMIs) against SRCs have the potential to simultaneously disrupt multiple signal transduction networks and transcription factors involved in tumor progression. Here, high-throughput screening was performed to identify compounds able to inhibit the intrinsic transcriptional activities of the three members of the SRC family. Verrucarin A was identified as a SMI that can selectively promote the degradation of the SRC-3 protein, while affecting SRC-1 and SRC-2 to a lesser extent and having no impact on CARM-1 and p300 protein levels. Verrucarin A was cytotoxic toward multiple types of cancer cells at low nanomolar concentrations, but not toward normal liver cells. Moreover, Verrucarin A was able to inhibit expression of the SRC-3 target genes MMP2 and MMP13 and attenuated cancer cell migration. We found that Verrucarin A effectively sensitized cancer cells to treatment with other anti-cancer drugs. Binding studies revealed that Verrucarin A does not bind directly to SRC-3, suggesting that it inhibits SRC-3 through its interaction with an upstream effector. In conclusion, unlike other SRC SMIs characterized by our laboratory that directly bind to SRCs, Verrucarin A is a potent and selective SMI that blocks SRC-3 function through an indirect mechanism.

Verrucarin A and roridin E produced on spinach by Myrothecium verrucaria under different temperatures and CO2 levels

Mycotoxin Res 2017 May;33(2):139-146.PMID:28281009DOI:10.1007/s12550-017-0273-2.

The behavior of Myrothecium verrucaria, artificially inoculated on spinach, was studied under seven different temperature conditions (from 5 to 35 °C) and under eight different combinations of temperature and CO2 concentration (14-30 °C and 775-870 or 1550-1650 mg/m3). The isolate used for this study was growing well on spinach, and the mycotoxins Verrucarin A and roridin E were produced under all tested temperature and CO2 conditions. The maximum levels of Verrucarin A (18.59 ng/g) and roridin E (49.62 ng/g) were found at a temperature of 26-30 °C and a CO2 level of 1550-1650 mg/m3. Rises in temperature as well as in temperature and CO2 concentrations had a significant effect by increasing Myrothecium leaf spots on spinach. The biosynthesis of Verrucarin A was significantly increased at the highest temperature (35 °C), while roridin E was influenced by the CO2 concentration. These results show that a positive correlation between climate condition and macrocyclic trichothecene production is possible. However, because of the ability of M. verrucaria to produce mycotoxins, an increase in temperature could induce the spread of M. verrucaria in temperate regions; this pathogen may gain importance in the future.

Effect of T-2 toxin and Verrucarin A in combination on Kluyveromyces marxianus

Nat Toxins 1995;3(2):104-8.PMID:7613734DOI:10.1002/nt.2620030208.

The growth inhibitory effects of combinations of T-2 toxin and Verrucarin A on the yeast Kluyveromyces marxianus was studied. A combination index value was derived to indicate the type of interaction that existed between the binary mixture of these two toxins at various ratios and the target yeast cells. The type of interaction was dependent on the ratio of the toxins used to attain a particular level of growth inhibition. Further, the least change in the type and intensity of interaction or the maximally quiescent ratio (MQR) was found to be unique to the growth medium. In a rich medium, the MQR was 1.0 microgram/ml T-2 toxin:0.75 microgram/ml Verrucarin A, where the two toxins had a very stable synergistic interaction over a 2 or 3 log value concentration range. Decreasing the nutrients changed the MQR to 1.0 micrograms/ml T-2 toxin:0.38 microgram/ml Verrucarin A. Halving the concentration of the cells in the assay changed the MQR to 1.0 microgram/ml T-2 toxin:6.0 micrograms/ml Verrucarin A. We have previously shown that the hierarchy of trichothecene toxicity in yeast bioassay is Verrucarin A > roridin A > T-2 toxin > diacetoxyscirpenol > HT-2 toxin. The MQR of these toxins in combination with T-2 toxin follows the same order. This study shows an exception to the above order in that Verrucarin A and roridin A exchange places.