Cycleanine CAS NO.518-94-5

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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.

Chemical Properties of Cycleanine

Cas No.	518-94-5
PubChem ID	121313	Appearance	White crystalline powder
Formula	C38H42N2O6	M.Wt	622.75
Type of Compound	Alkaloids	Storage	Desiccate at -20°C
Solubility	Soluble in Chloroform,Dichloromethane,Ethyl Acetate,DMSO,Acetone,etc.
SMILES	CN1CCC2=CC(=C(C3=C2C1CC4=CC=C(C=C4)OC5=C6C(CC7=CC=C(O3)C=C7)N(CCC6=CC(=C5OC)OC)C)OC)OC
Standard InChIKey	ANOXEUSGZWSCQL-LOYHVIPDSA-N
Standard InChI	InChI=1S/C38H42N2O6/c1-39-17-15-25-21-31(41-3)35(43-5)37-33(25)29(39)19-23-7-11-28(12-8-23)46-38-34-26(22-32(42-4)36(38)44-6)16-18-40(2)30(34)20-24-9-13-27(45-37)14-10-24/h7-14,21-22,29-30H,15-20H2,1-6H3/t29-,30-/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.

Source of Cycleanine

The herbs of Chondodendron tomentosum

Biological Activity of Cycleanine

Description	The biological screening of cycleanine and the root bark alkaloidal extract revealed potent antibacterial, antifungal, antiplasmodial, and cytotoxic activities. Cycleanine, like its isomer – tetrandrine isolated from T. subcordata, could be a potential new anti-ovarian cancer agent acting through the apoptosis pathway. It also shows antiplasmodial activities against Plasmodium falciparum 3D7 with IC50 values of 0.08 µM.Cycleanine may have anti-inflammatory activity. Cycleanine markedly inhibited Na(+),K(+)-ATPase activity with an IC(50) value of 6.2 x 10(-4)M. It slightly inhibited Mg(2+)-ATPase, H(+)-ATPase, and Ca(2+)-ATPase, it might interact with the enzyme in Na.E(1)-P form and prevents the reaction step from Na.E(1)-P to E(2)-P.
Targets	ATPase | Sodium Channel | Potassium channel | Calcium Channel | NO | Antifection
In vitro	Cytotoxicity effects and apoptosis induction by cycleanine and tetrandrine.[Reference: WebLink] Planta Medica, 2016, 81(S 01):S1-S381. Ovarian cancer remains one of the main causes of death in all gynecologic malignancies [1]. Natural products continue to be important sources of clinically approved anti-cancer drugs [2, 3]. Triclisia subcordata Oliv (Menispermeaceae) is a medicinal plant traditionally used for the treatment of various diseases [4], including cancer, in West Africa. This study aims to evaluate the in vitro anti-ovarian cancer activities of the crude extracts and the isolated components in T. subcordata. METHODS AND RESULTS: The ethanol extract of T. subcordata and its fractions (crude alkaloids) were screened for in vitro anti-ovarian cancer activities on Ovcar-8, Ovcar-4, A2780, and Igrov-1 ovarian cancer cell lines using the Sulforhodamine B assay method to measure cell growth. Bioassay-guided fractionation using silica gel column chromatography and HPLC were used to isolate the bioactive compound, whose identity and structure was identified by NMR and LC-MS techniques. Caspase and PARP cleavage assays were used to detect apoptotic activities. The effect of isolated pure compounds on cell cycle and apoptosis was analyzed by flow cytometry. The crude alkaloids showed the strongest activity in cell growth assays on A2780 and Ovcar-8 cell lines (IC50 < 2.4 µg/mL). A bisbenzylisoquinoline alkaloid-Cycleanine was isolated using HPLC and identified by MS and NMR analyses. The IC50values of Cycleanine and tetrandrine ranged from 7 to 14µM on A2780, Ovcar-8, Ovcar-4 and Igrov-1 ovarian cancer cell lines. The IC50 of Cycleanine on human normal ovarian surface epithelial cells was 35 ± 1µM hinting at modest selectivity towards cancer cells. Both Cycleanine and tetrandrine caused apoptosis as shown by activation of caspases 3/7 and cleavage of poly (ADP) ribose polymerase (PARP) to form PARP-I. The percentage of Ovcar-8 cells in subG1 phase increased after exposure of Cycleanine and tetrandrine to cells for 48h compared to control. CONCLUSIONS: In conclusion, Cycleanine, like its isomer – tetrandrine isolated from T. subcordata, could be a potential new anti-ovarian cancer agent acting through the apoptosis pathway. Anti-malarial Activity of Isoquinoline Alkaloids from the Stem Bark of Actinodaphne macrophylla.[Pubmed: 26594753] Nat Prod Commun. 2015 Sep;10(9):1541-2. METHODS AND RESULTS: Seven isoquinoline alkaloids isolated from the bark of Actinodaphne macrophylla in this study demonstrated in vitro antiplasmodial activities against Plasmodium falciparum 3D7 with IC50 values of 0.08 µM, 0.05 µM, 1.18 µM, 3.11 µM, 0.65 µM, 0.26 µM, and 1.38 µM for Cycleanine, 10-demethylxylopinine, reticuline, laurotetanine, bicuculine, α-hydrastine and anolobine, respectively, which are comparable with the reference standard, chloroquine. CONCLUSIONS: 10-Demethylxylopinine was found to be the most active of these compounds. Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villos[Pubmed: 15234773 ] J Ethnopharmacol. 2004 Aug;93(2-3):331-5. Albertisia villosa (Menispermaceae) is a subtropical medicinal plant that is widely used in traditional African medicines against various diseases. METHODS AND RESULTS: Three known bisbenzylisoquinoline alkaloids; Cycleanine, cocsoline, and N-desmethylCycleanine have been identified. Cycleanine, the most abundant (85%) of all identified bisbenzylisoquinoline alkaloids, accounts for all of the activity of the crude drug. The biological screening of Cycleanine and the root bark alkaloidal extract revealed potent antibacterial, antifungal, antiplasmodial, and cytotoxic activities. CONCLUSIONS: These results may partly explain and support the use of Albertisia villosa root barks for the treatment of malaria and other infectious diseases in traditional Congolese medicine.

Protocol of Cycleanine

Kinase Assay	Inhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophages.[Pubmed: 7505581] Inhibition of Na+,K+-ATPase by the extract of Stephania cephararantha Hayata and bisbenzylisoquinoline alkaloid cycleanine, a major constituent.[Pubmed: 12907236 ] Biochemical Pharmacology, 2003, 66(3):379-385. The Stephania cephararantha HAYATA extract, and its constituent bisbenzylisoquinoline alkaloids, such as Cycleanine, cepharanthine, isotetrandrine, berbamine, homoaromoline, and cepharanoline were studied for effects on Na(+),K(+)-ATPase activity. METHODS AND RESULTS: The S. cephararantha HAYATA extract inhibited Na(+),K(+)-ATPase activity with an apparent IC(50) value of 540 microg/mL. Cycleanine markedly inhibited Na(+),K(+)-ATPase activity with an IC(50) value of 6.2 x 10(-4)M. It slightly inhibited Mg(2+)-ATPase, H(+)-ATPase, and Ca(2+)-ATPase. No effects on alkaline and acid phosphatase activities were observed. The inhibition by isotetrandrine, homoaromoline, cepharanthine, and berbamine was less marked, and cepharanoline showed no effect. Five synthetic analogues of cepharanthine slightly inhibited the activity. The mechanism of inhibition by Cycleanine on Na(+),K(+)-ATPase activity was examined in detail, and the following results were obtained in the overall reaction: (1) the mode of inhibition was noncompetitive with respect to ATP; (2) the degree of inhibition was decreased with a decrease of K(+) concentration; (3) it was not affected by Na(+) concentration; (4) the inhibition mechanism was different from that of ouabain. The activity of K(+)-dependent p-nitrophenyl phosphatase, a partial reaction of Na(+),K(+)-ATPase, did not appear to have been inhibited by Cycleanine in the reaction mixture containing 15 mM K(+) (optimum condition). However, Cycleanine increased the K(0.5) value for K(+) and reduced the K(i) values for Na(+) and ATP, in K(+)-dependent p-nitrophenyl phosphatase. CONCLUSIONS: Cycleanine might interact with the enzyme in Na.E(1)-P form and prevents the reaction step from Na.E(1)-P to E(2)-P. Biochem Pharmacol. 1993 Dec 3;46(11):1887-92. Bisbenzylisoquinoline (BBI) alkaloids are anti-inflammatory constituents of plants of the families Menispermaceae and Ranunculaceae, which have been used as folk remedies in Japan and China. METHODS AND RESULTS: Five BBI alkaloids (cepharanthine, chondocurine, Cycleanine, isotetrandrine and tetrandrine) were tested for suppressive effect on in vitro nitric oxide (NO) production by lipopolysaccharide-stimulated peritoneal macrophages, which were induced with thioglycollate or bacillus Calmette-Guerin in mice. CONCLUSIONS: All these BBI alkaloids significantly suppressed NO production at 5 micrograms/mL. Cepharanthine, isotetrandrine and Cycleanine were slightly more inhibitory than tetrandrine and chondocurine. The suppression persisted for at least 48 hr. As NO is one of the critical mediators in inflammation, these results may explain some aspects of the anti-inflammatory mechanisms of BBI compounds.
Cell Research	Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cells.[Pubmed: 29588214] Bioorg Med Chem Lett. 2018 May 15;28(9):1652-1656. Our previous studies demonstrated that Cycleanine, a macrocyclic bisbenzylisoquinoline (BBIQ) alkaloid, showed potent anti-ovarian cancer activity via apoptosis induction. METHODS AND RESULTS: Here, we synthesized two novel (aminoalkyl)Cycleanine analogues (2 and 3) through a simple and efficient two-step reaction starting from Cycleanine isolated from Triclisia subcordata Oliv. These analogues showed greater potency than the unmodified Cycleanine in three human ovarian cancer cell lines. Both 2 and 3 induced apoptosis in ovarian cancer cells by activations of caspases 3/7, cleavage of PARP, increase in subG1 cell cycle phase and in the percentage of apoptotic cells. Further confocal fluorescence microscopy analysis confirmed the cellular uptake of alkaloids in ovarian cancer cells by using the unique (alkynyl)Cycleanine (3) via click chemistry reaction. CONCLUSIONS: Our results suggest that Cycleanine could be a hit compound for the future development in attacking ovarian cancer.
Structure Identification	Phytochemistry, 1980, 19(8):1837-1840. Cycleanine from Synclisia scabrida: conformational information from the 1H NMR spectrum at 300 MHz.[Reference: WebLink] METHODS AND RESULTS: Cycleanine, a bisbenzylisoquinoline alkaloid, has been isolated from the roots of Synclisia scabrida. The 1H NMR spectrum at 300 MHz reveals that, in chloroform solution, Cycleanine has a conformation whereby ring B partly shields ring C′ and ring C is similarly influenced by ring B′.

Preparing Stock Solutions of Cycleanine

	1 mg	5 mg	10 mg	20 mg	25 mg
1 mM	1.6058 mL	8.0289 mL	16.0578 mL	32.1156 mL	40.1445 mL
5 mM	0.3212 mL	1.6058 mL	3.2116 mL	6.4231 mL	8.0289 mL
10 mM	0.1606 mL	0.8029 mL	1.6058 mL	3.2116 mL	4.0145 mL
50 mM	0.0321 mL	0.1606 mL	0.3212 mL	0.6423 mL	0.8029 mL
100 mM	0.0161 mL	0.0803 mL	0.1606 mL	0.3212 mL	0.4014 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.

References on Cycleanine

Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cells.[Pubmed:29588214]

Bioorg Med Chem Lett. 2018 May 15;28(9):1652-1656.

Our previous studies demonstrated that Cycleanine, a macrocyclic bisbenzylisoquinoline (BBIQ) alkaloid, showed potent anti-ovarian cancer activity via apoptosis induction. Here, we synthesized two novel (aminoalkyl)Cycleanine analogues (2 and 3) through a simple and efficient two-step reaction starting from Cycleanine isolated from Triclisia subcordata Oliv. These analogues showed greater potency than the unmodified Cycleanine in three human ovarian cancer cell lines. Both 2 and 3 induced apoptosis in ovarian cancer cells by activations of caspases 3/7, cleavage of PARP, increase in subG1 cell cycle phase and in the percentage of apoptotic cells. Further confocal fluorescence microscopy analysis confirmed the cellular uptake of alkaloids in ovarian cancer cells by using the unique (alkynyl)Cycleanine (3) via click chemistry reaction. Our results suggest that Cycleanine could be a hit compound for the future development in attacking ovarian cancer.

Anti-malarial Activity of Isoquinoline Alkaloids from the Stem Bark of Actinodaphne macrophylla.[Pubmed:26594753]

Nat Prod Commun. 2015 Sep;10(9):1541-2.

Seven isoquinoline alkaloids isolated from the bark of Actinodaphne macrophylla in this study demonstrated in vitro antiplasmodial activities against Plasmodium falciparum 3D7 with IC50 values of 0.08 microM, 0.05 microM, 1.18 microM, 3.11 microM, 0.65 microM, 0.26 microM, and 1.38 microM for Cycleanine, 10-demethylxylopinine, reticuline, laurotetanine, bicuculine, alpha-hydrastine and anolobine, respectively, which are comparable with the reference standard, chloroquine. 10-Demethylxylopinine was found to be the most active of these compounds.

Bioactive isoquinoline alkaloids from Cissampelos pareira.[Pubmed:29126362]

Nat Prod Res. 2017 Nov 10:1-6.

The phytochemical and biological investigation of Cissampelos pareira leads to the isolation of one new isoquinoline alkaloid (7) along with six known isoquinoline alkaloids, namely, magnoflorine (1), magnocurarine (2), cissamine (3), curine (4), hayatinine (5) and Cycleanine (6). Magnoflorine (1) and magnocurarine (2) were isolated for the first time from C. pareira. A new, rapid, simple and sensitive UPLC method was developed for simultaneous quantification of five pure compounds (1-5). Seasonal variation study revealed higher content of these compounds during the rainy season. The chloroform (CPCF) and n-butanol (CPBF) fractions showed cytotoxic efficacy against KB cells. Among pure compounds, hayatinine (5) was found to be most active against KB and A549, while, Cycleanine (6) against KB cells.

Interaction of cepharanthine with immobilized heat shock protein 90alpha (Hsp90alpha) and screening of Hsp90alpha inhibitors.[Pubmed:23219559]

Anal Biochem. 2013 Mar 1;434(1):202-6.

Heat shock protein 90alpha (Hsp90alpha) immobilized on aminopropyl silica gels was prepared via the N- or C-terminal, which was termed Hsp90alpha-NT or Hsp90alpha-CT, respectively. Binding interactions of biscoclaurine alkaloids (cepharanthine (CEP), berbamine (BBM), isotetrandrine (ITD), and Cycleanine (CCN)) with Hsp90alpha were examined using the Hsp90alpha-NT or -CT columns by frontal and zonal chromatography studies. The dissociation constants of CEP, BBM, ITD, and CCN to Hsp90alpha-NT were estimated to be 5.3, 18.6, 46.3, and 159 muM, respectively, by frontal chromatography techniques. Similar results were obtained with the Hsp90alpha-CT column. These data suggest that these biscoclaurine alkaloids interact with the middle domain of Hsp90alpha. This was confirmed by demonstrating that CEP competed with endothelial nitric oxide synthase at the middle domain of Hsp90alpha, where it was shown to have a dissociation constant of 15 nM. Furthermore, the Hsp90alpha-NT column was applied for preliminary screening of natural Hsp90alpha inhibitors by zonal chromatography studies.

Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.[Pubmed:21922239]

Parasitol Res. 2012 Apr;110(4):1381-92.

Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol-water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional (1)H and (13)C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1-2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S')-12-O-methyl(+)-curine (5); and Cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity.

Cytotoxicity Effects and Apoptosis Induction by Bisbenzylisoquinoline Alkaloids from Triclisia subcordata.[Pubmed:27270992]

Phytother Res. 2016 Sep;30(9):1533-9.

Triclisia subcordata Oliv (Menispermeaceae) is a medicinal plant traditionally used for the treatment of various diseases in West Africa. The ethanol extract of T. subcordata and its fractions were screened for in vitro anti-ovarian cancer activities using the Sulforhodamine B assay. The crude alkaloids showed the strongest activity in cell growth assays on Ovcar-8 and A2780 cell lines (IC50 < 2.4 microg/mL). A bisbenzylisoquinoline alkaloid-Cycleanine was isolated using HPLC and identified by mass spectrometry and nuclear magnetic resonance analyses. The IC50 values of Cycleanine and tetrandrine (an alkaloid previously reported from this plant) ranged from 7 to 14 muM on Ovcar-8, A2780, Ovcar-4, and Igrov-1 ovarian cancer cell lines. The IC50 of Cycleanine on human normal ovarian surface epithelial cells was 35 +/- 1 muM, hinting at modest selectivity toward cancer cells. Both Cycleanine and tetrandrine caused apoptosis as shown by activation of caspases 3/7 and cleavage of poly(ADP-ribose) polymerase to form poly(ADP-ribose) polymerase-1 by using western blot analysis. Flow cytometry analyses showed that the percentages of apoptotic cells and cells in subG1 phase increased after exposure of Cycleanine and tetrandrine to Ovcar-8 cells for 48 h compared with control. Cycleanine, like its isomer tetrandrine isolated from T. subcordata, could be a potential new anti-ovarian cancer agent acting through the apoptosis pathway. Copyright (c) 2016 John Wiley & Sons, Ltd.

Description

Cycleanine is a potent vascular selective Ca-antagonist. Cycleanine has analgesic, muscle relaxant and anti-inflammatory activities. Cycleanine has potential for anti-ovarian cancer acting through the apoptosis pathway.

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