HaCaT cells undergo necroptosis when exposed to Lily of the Valley toxin [4].

In two mouse models of psoriasis, the toxin from lily of the valley exhibits antipsoriatic action [4].

Absorption, Distribution and Excretion
The intestinal absorption of 15 cardenolides was examined after the (3)H-labeled substances were injected intraluminally into ligated duodenal loops of cats. Concentrations of (3)H were followed in the portal circulation and in the bile.
Isolated, everted rat jejunal preparations absorbed convallatoxin by an active transport mechanism. No relation was observed between the amount of cardiotonic glycoside actively transported and the oxygen consumption of the tissue.
Digitalis-like compounds (DLCs), such as digoxin and digitoxin that are derived from digitalis species, are currently used to treat heart failure and atrial fibrillation, but have a narrow therapeutic index. Drug-drug interactions at the transporter level are frequent causes of DLCs toxicity. P-glycoprotein (P-gp, ABCB1) is the primary transporter of digoxin and its inhibitors influence pharmacokinetics and disposition of digoxin in the human body; however, the involvement of P-gp in the disposition of other DLCs is currently unknown. In present study, the transport of fourteen DLCs by human P-gp was studied using membrane vesicles originating from human embryonic kidney (HEK293) cells overexpressing P-gp. DLCs were quantified by liquid chromatography-mass spectrometry (LC-MS). The Lily of the Valley toxin, convallatoxin, was identified as a P-gp substrate (Km: 1.1+/-0.2 mM) in the vesicular assay. Transport of convallatoxin by P-gp was confirmed in rat in vivo, in which co-administration with the P-gp inhibitor elacridar, resulted in increased concentrations in brain and kidney cortex. To address the interaction of convallatoxin with P-gp on a molecular level, the effect of nine alanine mutations was compared with the substrate N-methyl quinidine (NMQ). Phe343 appeared to be more important for transport of NMQ than convallatoxin, while Val982 was particularly relevant for convallatoxin transport. We identified convallatoxin as a new P-gp substrate and recognized Val982 as an important amino acid involved in its transport. ...

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Metabolism / Metabolites
Helveticoside and convallatoxin were converted hydrolytically into strophanthidine during perfusion through an isolated rat small intestine segment. Also, the C10-aldehyde group of these compounds was reduced enzymatically to helveticosol, convallatoxol, and strophanthidol. This reduction of strophanthidine cardenolides, beside the hydrolysis reaction, appeared to be the most important biotransformation reaction in the rat small intestine.

Toxicity Summary
IDENTIFICATION AND USE: Convallotoxin is a cardiac glycoside. A phytotoxin from the flowers of Adonis vernalis, Convallaria majalis (Lily of the Valley), Ornthogalum umbellatum and Antiaris toxicaria. The aglycone is convallatoxigenin and the sugar is a rhamnose. Convallatoxin is used in acute and chronic congestive heart-failure and paroxysmal tachycardia. HUMAN STUDIES: Convallotoxin induced cytostatic and cytotoxic effects in human lung A549 cells. Convallotoxin inhibited the Na,K-ATPase in A549 cells at nM concentrations. ANIMAL STUDIES: When administered in a single iv injection at minute to lethal doses to rats or cats, convallatoxin caused vascular disorders in the heart, liver, and kidneys. When injected daily at doses corresponding to 0.2 to 0.4 LD100 for 15 days, it caused dystrophic changes and increased the infiltration and proliferation processes. When injected iv into mice, the LD50 value of convallatoxin was 6.3 mg/kg. The glycoside caused tremor, convulsions, and paralysis of the limbs and affected respiration. The preparation caused disorders in the cardiac activity and a transient coronary insufficiency. The effects of a single or repeated ip injections of convallatoxin on the histology of the heart, liver, kidney, spleen, and lungs was studied in mice, rats, and cats. A single injection dilated blood vessels in the heart, liver, and kidneys, caused hemorrhage in the liver, and caused an infiltrative-proliferative effect in the heart and liver. After chronic injections, the infiltrative-proliferative effect was more pronounced than after the acute administration, and dystrophic changes were observed in the liver. ECOTOXICITY STUDIES: Convallatoxin (20 uM) could significantly prolong the lifespan of wild-type Caenorhabditis elegans up to 16.3% through daf-16, but not sir-2.1 signalling and increased thermotolerance and resistance to paraquat-induced oxidative stress. Convallatoxin also improved pharyngeal pumping, locomotion, reduced lipofuscin accumulation and reactive oxygen species levels in C. elegans, which were attributed to hormesis, free radical-scavenging effects in vivo, and up-regulation of stress resistance-related proteins, such as SOD-3 and HSP-16.1. Furthermore, aging-associated genes daf-16, sod-3, and ctl-2 also appeared to contribute to the stress-resistance effect of convallatoxin.
Convallatoxin (CNT) is classified as a cardiac glycoside. Cardiac glycosides are well known Na+/K+-ATPase inhibitors, and some of them are used to treat congestive heart failure and atrial arrhythmias. Recent studies have reported that cardiac glycosides have potential as anticancer agents. CNT exerts cytotoxic effects on a number of cancer and normal cell lines and induces apoptosis by increasing caspase-3 and poly ADP ribose polymerase (PARP) cleavage. Moreover, dose- and time-dependent autophagic activity was detected in CNT-treated cells, and mammalian target of rapamycin (mTOR)/p70S6K signal pathway inhibition was observed. Notably, CNT inhibits human umbilical vein endothelial cell (HUVEC) growth and exerts anti-angiogenic activity in vitro and in vivo. (A15340)

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Non-Human Toxicity Values
LD50 Mice ip 10 mg/kg
LD50 Rat iv 15 mg/kg
LD50 Mice sc 15 mg/kg
LD50 Mice iv 1 mg/kg
For more Non-Human Toxicity Values (Complete) data for Convallatoxin (6 total), please visit the HSDB record page.

[1]. Convallatoxin protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB signaling through activation of PPARγ. Pharmacol Res. 2019 Sep;147:104355.

[2]. Convallatoxin: a new P-glycoprotein substrate. Eur J Pharmacol. 2014 Dec 5;744:18-27.

[3]. Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Sci Rep. 2019 Feb 20;9(1):2405.

[4]. Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models. Biomed Pharmacother. 2020 Jan;121:109615.

Convallatoxin is a cardenolide glycoside that consists of strophanthidin having a 6-deoxy-alpha-L-mannopyranosyl (L-rhamnosyl) group attached at position 3. It has a role as a vasodilator agent and a metabolite. It is an alpha-L-rhamnoside, a 19-oxo steroid, a 14beta-hydroxy steroid, a 5beta-hydroxy steroid, a steroid lactone and a steroid aldehyde. It is functionally related to a strophanthidin.
Convallatoxin has been reported in Convallaria majalis, Saussurea stella, and other organisms with data available.
Convallatoxin is a glycoside extracted from Convallaria majalis. Convallatoxin is also isolated from the trunk bark of Antiaris toxicaria (A15340).

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Mechanism of Action
The inhibitory activity of glycosides and related compounds toward Na+-K+-ATPase was determined and related to their cardiotonic activity in cats. It appeared that the active site of Na+-K+-ATPase consists of 2 sections; 1 section binds the cardiosteroids to the receptor and orients the molecules relative to the 2nd or catalytic section. The relation of these results to the cardiotonic activity of strophanthidol analogs is discussed.

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Therapeutic Uses
Vasodilator Agents
/EXPL THER/ Convallatoxin improved myocardial relaxation and elevated the rate and force of systolic heart contraction in dogs in the initial stages of cor pulmonale (in chronic pneumonia). The positive inotropic effect in experimental cor pulmonale with high pulmonary blood pressures was accompanied by increased overload on the right ventricle and further elevation of pulmonary blood pressures.
/EXPL THER/ Convallotoxin had no effect on left ventricular hemodynamics in intact dogs, but decreased right intraventricular pressure and increased dp/dt max and dp/dt minimum. In animals with surgical stenosis of the pulmonary trunk, an increase in pressure and dp/dt max of the right ventricle, a decrease in left ventricular end-diastolic pressure, and an increase in left dp/dt max were observed. Administration of convallotoxin to dogs 1 month following stenosis did not improve cardiohemodynamics.
/EXPL THER/ Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases the morbidity and mortality of immunocompromised individuals. The current FDA-approved treatments for CMV infection are intended to be virus specific, yet they have significant adverse side effects, including nephrotoxicity and hematological toxicity. Thus, there is a medical need for safer and more effective CMV therapeutics. Using a high-content screen, we identified the cardiac glycoside convallatoxin as an effective compound that inhibits CMV infection. Using a panel of cardiac glycoside variants, we assessed the structural elements critical for anti-CMV activity by both experimental and in silico methods. Analysis of the antiviral effects, toxicities, and pharmacodynamics of different variants of cardiac glycosides identified the mechanism of inhibition as reduction of methionine import, leading to decreased immediate-early gene translation without significant toxicity. Also, convallatoxin was found to dramatically reduce the proliferation of clinical CMV strains, implying that its mechanism of action is an effective strategy to block CMV dissemination. Our study has uncovered the mechanism and structural elements of convallatoxin, which are important for effectively inhibiting CMV infection by targeting the expression of immediate-early genes. IMPORTANCE: Cytomegalovirus is a highly prevalent virus capable of causing severe disease in certain populations. The current FDA-approved therapeutics all target the same stage of the viral life cycle and induce toxicity and viral resistance. We identified convallatoxin, a novel cell-targeting antiviral that inhibits CMV infection by decreasing the synthesis of viral proteins. At doses low enough for cells to tolerate, convallatoxin was able to inhibit primary isolates of CMV, including those resistant to the anti-CMV drug ganciclovir. In addition to identifying convallatoxin as a novel antiviral, limiting mRNA translation has a dramatic impact on CMV infection and proliferation.

C29H42O10

550.64

550.278

508-75-8

441852

White to off-white solid powder

1.41 g/cm3

757.3ºC at 760 mmHg

235-242ºC

247.1ºC

1.622

0.75

5

10

4

39

1050

13

C[C@H]1[C@@H]([C@H]([C@H]([C@@H](O1)O[C@H]2CC[C@@]3([C@H]4CC[C@@]5([C@H](CC[C@@]5([C@@H]4CC[C@@]3(C2)O)O)C6=CC(=O)OC6)C)C=O)O)O)O

HULMNSIAKWANQO-JQKSAQOKSA-N

InChI=1S/C29H42O10/c1-15-22(32)23(33)24(34)25(38-15)39-17-3-8-27(14-30)19-4-7-26(2)18(16-11-21(31)37-13-16)6-10-29(26,36)20(19)5-9-28(27,35)12-17/h11,14-15,17-20,22-25,32-36H,3-10,12-13H2,1-2H3/t15-,17-,18+,19-,20+,22-,23+,24+,25-,26+,27-,28-,29-/m0/s1

(3S,5S,8R,9S,10S,13R,14S,17R)-5,14-dihydroxy-13-methyl-17-(5-oxo-2H-furan-3-yl)-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde

Korglykon Corglykon Convallatoxin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~90.80 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)