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Concanamycin A

V-type (vacuolar) H+-ATPase inhibitor CAS# 80890-47-7

Concanamycin A

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Chemical structure

Concanamycin A

3D structure

Chemical Properties of Concanamycin A

Cas No. 80890-47-7 SDF Download SDF
PubChem ID 6438151 Appearance Powder
Formula C46H75NO14 M.Wt 866.09
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Folimycin
Solubility Methanol : 10 mg/mL (11.55 mM; Need ultrasonic and warming)
Chemical Name [(2R,3S,4R,6R)-6-[(2R,4R,5S,6R)-2-[(2S,3R,4S)-4-[(2R,3S,4E,6E,9R,10S,11S,12R,13R,14E,16Z)-11-ethyl-10,12-dihydroxy-3,17-dimethoxy-7,9,13,15-tetramethyl-18-oxo-1-oxacyclooctadeca-4,6,14,16-tetraen-2-yl]-3-hydroxypentan-2-yl]-2-hydroxy-5-methyl-6-[(E)-prop-1-enyl]oxan-4-yl]oxy-4-hydroxy-2-methyloxan-3-yl] carbamate
SMILES CCC1C(C(CC(=CC=CC(C(OC(=O)C(=CC(=CC(C1O)C)C)OC)C(C)C(C(C)C2(CC(C(C(O2)C=CC)C)OC3CC(C(C(O3)C)OC(=O)N)O)O)O)OC)C)C)O
Standard InChIKey DJZCTUVALDDONK-HQMSUKCRSA-N
Standard InChI InChI=1S/C46H75NO14/c1-13-16-34-28(7)37(58-38-22-33(48)43(31(10)57-38)60-45(47)53)23-46(54,61-34)30(9)41(51)29(8)42-35(55-11)18-15-17-24(3)19-26(5)39(49)32(14-2)40(50)27(6)20-25(4)21-36(56-12)44(52)59-42/h13,15-18,20-21,26-35,37-43,48-51,54H,14,19,22-23H2,1-12H3,(H2,47,53)/b16-13+,18-15+,24-17+,25-20+,36-21-/t26-,27-,28-,29+,30+,31-,32+,33-,34-,35+,37-,38+,39+,40-,41-,42-,43-,46-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Concanamycin A

DescriptionSpecific inhibitor of V-type (vacuolar) H+-ATPase that displays > 2000-fold selectivity over other H+-ATPases (IC50 values are 9.2, > 20000, > 20000 and > 20000 nM for yeast V-type, F-type, P-type H+-ATPases and porcine P-type Na+,K+-ATPase respectively). Blocks cell surface expression of virus envelope glycoproteins without affecting synthesis and exhibits cytotoxicity in several cell lines.

Concanamycin A Dilution Calculator

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Preparing Stock Solutions of Concanamycin A

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.1546 mL 5.7731 mL 11.5461 mL 23.0923 mL 28.8654 mL
5 mM 0.2309 mL 1.1546 mL 2.3092 mL 4.6185 mL 5.7731 mL
10 mM 0.1155 mL 0.5773 mL 1.1546 mL 2.3092 mL 2.8865 mL
50 mM 0.0231 mL 0.1155 mL 0.2309 mL 0.4618 mL 0.5773 mL
100 mM 0.0115 mL 0.0577 mL 0.1155 mL 0.2309 mL 0.2887 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Concanamycin A

Concanamycin A is a specific inhibitor of vacuolar-type ATPase (V-ATPase) with IC50 value of 10 nM [1].

Vacuolar-type ATPase (V-ATPase) is expressed by clear cells to acidify the lumen of the epididymis, which is essential for male fertility; what's more, it induced proton extrusion into the extracellular medium which contributes to maintaining the intracellular pH under an acidic microenvironment. V-ATPase has also been reported to involve in the process of acidificating microenvironment around/in solid tumors and inducing tumor invasion/multi-drug resistance in several malignant tumors. [2].

Concanamycin A (CMA) is a specific V-ATPase inhibitor and is different from the reported V-ATPase inhibitor SS33410. In oral squamous cell carcinoma (OSCC) OSCC cell lines (MISK81-5, SAS and HSC-4), low-concentration of CMA treatment induced the apoptosis of tumor cells [3]. Pretreated colorectal cancer cell lines with concanamycin A could significantly enhanced the Tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL)-induced apoptosis by blocking endosomal acidification by V-ATPase [4]. When tested with prostate cancer cell line C4-2B, inhibition of V-ATPase by concanamycin A reduced 80% invasion in vitro [5].

Concanamycin A also had been reported as a potent inhibitor of CTL cytotoxicity via perforin-mediated cytotoxic pathway [6].

References:
[1].  Huss, M., et al., Concanamycin A, the specific inhibitor of V-ATPases, binds to the V(o) subunit c. J Biol Chem, 2002. 277(43): p. 40544-8.
[2].  Muroi, M., et al., Folimycin (concanamycin A), a specific inhibitor of V-ATPase, blocks intracellular translocation of the glycoprotein of vesicular stomatitis virus before arrival to the Golgi apparatus. Cell Struct Funct, 1993. 18(3): p. 139-49.
[3].  Kiyoshima, T., et al., Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression. PLoS One, 2013. 8(11).
[4].  Horova V, et al., Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. FEBS J, 2013. 280(14).
[5].  Michel V, et al., Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. Int J Cancer. 2013.132(2).
[6].  Benkhoucha M et al., The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. J Neuroinflammation. 2013, 10.

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References on Concanamycin A

Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression.[Pubmed:24278362]

PLoS One. 2013 Nov 20;8(11):e80998.

V-ATPase is involved in the acidification of the microenvironment around/in solid tumors, such as oral squamous cell carcinoma (OSCC). V-ATPase is thought to induce tumor invasion and multi-drug resistance in several malignant tumors, and it also contributes to maintaining the intracellular pH under an acidic microenvironment by inducing proton extrusion into the extracellular medium. However, there is little information regarding the effects of V-ATPase inhibitors on OSCCs. In this study, the effects of a V-ATPase inhibitor, Concanamycin A1 (CMA), on the proliferation and apoptosis of OSCC were investigated in vitro. We used four OSCC cell lines, MISK81-5, SAS, HSC-4 and SQUU-B. Acridine orange staining revealed that the red fluorescence was reduced in all of the low concentration CMA-treated OSCC cells, indicating that the acidification of vesicular organelles in the OSCCs was prevented by the treatment with low-concentration of CMA. CMA treatment induced apoptosis in MISK81-5, SAS and HSC-4 cells, but not in SQUU-B cells. The p-p38 expression was not altered in CMA-treated SQUU-B cells, but their levels were increased in the other cells. The Bax/Bcl-2 ratio in CMA-treated SQUU-B cells was dramatically decreased in comparison with that in the other cell lines treated with CMA. However, when the SQUU-B cells were treated with CMA and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), the SQUU-B cells became more susceptible to the CMA-induced apoptosis. SAHA treatment led to a significantly decrease in the Bcl-2 expression in CMA-treated SQUU-B cells, resulting in a dramatically increased Bax/Bcl-2 ratio in comparison with that observed in the SQUU-B cells treated with CMA alone. These findings suggest that CMA could have an anti-tumor effect on OSCCs. In addition, combination of CMA with other agents, such as SAHA, could help improve the pro-apoptotic effects of CMA even in CMA-resistant OSCC cells.

Dissection of autophagy in tobacco BY-2 cells under sucrose starvation conditions using the vacuolar H(+)-ATPase inhibitor concanamycin A and the autophagy-related protein Atg8.[Pubmed:26368310]

Plant Signal Behav. 2015;10(11):e1082699.

Tobacco BY-2 cells undergo autophagy in sucrose-free culture medium, which is the process mostly responsible for intracellular protein degradation under these conditions. Autophagy was inhibited by the vacuolar H(+)-ATPase inhibitors Concanamycin A and bafilomycin A1, which caused the accumulation of autophagic bodies in the central vacuoles. Such accumulation did not occur in the presence of the autophagy inhibitor 3-methyladenine, and concanamycin in turn inhibited the accumulation of autolysosomes in the presence of the cysteine protease inhibitor E-64c. Electron microscopy revealed not only that the autophagic bodies were accumulated in the central vacuole, but also that autophagosome-like structures were more frequently observed in the cytoplasm in treatments with concanamycin, suggesting that Concanamycin Affects the morphology of autophagosomes in addition to raising the pH of the central vacuole. Using BY-2 cells that constitutively express a fusion protein of autophagosome marker protein Atg8 and green fluorescent protein (GFP), we observed the appearance of autophagosomes by fluorescence microscopy, which is a reliable morphological marker of autophagy, and the processing of the fusion protein to GFP, which is a biochemical marker of autophagy. Together, these results suggest the involvement of vacuole type H(+)-ATPase in the maturation step of autophagosomes to autolysosomes in the autophagic process of BY-2 cells. The accumulation of autophagic bodies in the central vacuole by concanamycin is a marker of the occurrence of autophagy; however, it does not necessarily mean that the central vacuole is the site of cytoplasm degradation.

Interactions between antiplasmodial 3,6-diamino-1'-dimethyl-9-anilinoacridine and hematin and concanamycin A.[Pubmed:18613537]

Southeast Asian J Trop Med Public Health. 2007 Nov;38(6):979-82.

Antiplasmodial 9-anilinoacridine derivatives exert their effects either by inhibiting DNA topoisomerase (topo) II or by interfering with heme crystallization within the parasite acidic food vacuole. Previous studies have shown that analogs of 9-anilinoacridine containing 3,6-diamino substitutions (in the acridine ring) inhibit Plasmodium falciparum DNA topo II in situ, whereas those with a 3,6-diCl substitution act by inhibiting beta-hematin formation, a property also seen with 3,6-diamino-1'-dimethyl-9-anilinoacridine (DDAA). To understand this seemingly anomalous property of DDAA, studies of its interaction with hematin and localization within the parasite food vacuole were undertaken. A weak interaction with hematin was demonstrated spectroscopically. Antagonism of DDAA inhibition of Plasmodium falciparum growth in culture by Concanamycin A, a macrolide antibiotic inhibitor of vacuolar H(+)-ATPase derived from Streptomyces sp, was equivocal.

Increased production of reactive oxygen species by the vacuolar-type (H(+))-ATPase inhibitors bafilomycin A1 and concanamycin A in RAW 264 cells.[Pubmed:23038011]

J Toxicol Sci. 2012;37(5):1045-8.

Treatment of the mouse leukemic cell line RAW 264 with bafilomycin A1 or Concanamycin A, inhibitors of vacuolar-type (H(+))-ATPases (V-ATPases), significantly increased the production of reactive oxygen species (ROS) and decreased cell viability. These effects were significantly suppressed by the presence of N-acetyl cysteine (NAC), an ROS scavenger. si-RNA mediated knockdown of the gene for the c subunit of the V0 domain of V-ATPase also resulted in an increase in ROS production and a decrease in cell viability. These results suggest that decreased cellular V-ATPase activity decreases cell viability by increasing ROS production in RAW 264 cells.

Nitric oxide production by the vacuolar-type (H+)-ATPase inhibitors bafilomycin A1 and concanamycin A and its possible role in apoptosis in RAW 264.7 cells.[Pubmed:16895977]

J Pharmacol Exp Ther. 2006 Nov;319(2):672-81.

In the mouse leukemic monocyte cell line RAW 264.7, the vacuolar-type (H(+))-ATPase (V-ATPase) inhibitors bafilomycin A1 and Concanamycin A induced nitric oxide (NO) production through the expression of inducible nitric-oxide synthase mRNA and its protein and decreased cell growth and survival as determined by 3-(4,5-dimethyl(thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Bafilomycin A1 and Concanamycin A activated nuclear factor (NF)-kappaB and activator protein-1 and decreased the level of IkappaB-alpha and increased that of phosphorylated c-Jun N-terminal kinase (JNK). NO production induced by these V-ATPase inhibitors was suppressed by the NF-kappaB inhibitor Bay 11-7082 [(E)3-[(4-methylphenyl)sulfonyl])-2-propenenitrile] and the JNK inhibitor SP600125 [anthra[1,9-cd]pyrazol-6(2H)-one] in parallel with the partial alleviation of the V-ATPase inhibitor-induced decrease in MTT response. The Na(+),K(+)-ATPase inhibitor dibucaine and the F-ATPase inhibitor oligomycin did not induce NO production at which concentrations the MTT response was decreased. The NO donor S-nitroso-N-acetyl-dl-penicillamine further lowered the V-ATPase inhibitor-induced decrease in the MTT response, and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (carboxy-PTIO) alleviated it partially. Mitochondrial depolarization, an index of apoptosis, was induced by bafilomycin A1 and Concanamycin A. On treatment with the nitric-oxide synthase inhibitor N(G)-monomethyl-l-arginine acetate, the disruption of mitochondrial membrane potential induced by bafilomycin A1 and Concanamycin A was alleviated partially in parallel with the decrease in NO production. Carboxy-PTIO also alleviated it partially. Our findings suggest that the V-ATPase inhibitors bafilomycin A1 and Concanamycin A similarly induce NO production and the newly produced NO participates partially in the V-ATPase inhibitor-induced apoptosis in RAW 264.7 cells.

Description

Concanamycin A (Antibiotic X 4357B) is a macrolide antibiotic and a specific vacuolar type H+-ATPase (V-ATPase) inhibitor.

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