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| ln Vitro |
In vitro, perilocymarin (IC50 values: 0.02-0.29 µM) inhibits the proliferation of PC3, U937, HCT-8, Bel-7402, BGC823, A549, and A2780 cell lines.
Periplocymarin (100 μM and 200 μM) showed high apparent permeability (Papp) across MDCK-II-WT and MDCK-II-MDR1 cell monolayers. In MDCK-II-WT cells, the Papp from apical to basolateral (AP→BL) was 15.70×10⁻⁶ cm/s at 100 μM and 31.5×10⁻⁶ cm/s at 200 μM. The net efflux ratio (NER) was 0.80 at 100 μM and 1.51 at 200 μM, indicating that Periplocymarin is not a P-gp substrate. Co-incubation with cyclosporine A (10 μM) did not change the NER (0.82). Periplocymarin did not competitively inhibit P-gp in the Rhodamine 123 (R123) accumulation assay: at 100 μM and 200 μM, it did not significantly increase R123 accumulation in MDCK-II-MDR1 cells compared to controls. Periplocymarin at 5 μM and 50 μM did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in a recombinant human CYP450 inhibition assay. [1] The cytotoxicity of Periplocymarin on MDCK-II-WT cells was evaluated using an XTT assay after 4 h exposure. At concentrations ranging from 0.025 mM to 0.5 mM, Periplocymarin showed no significant cytotoxic effects compared to control (0.1% DMSO) (p > 0.05, n=3). [1] |
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| Enzyme Assay |
The inhibitory potential of Periplocymarin (5 and 50 μM) on recombinant human CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was assessed using a luminogenic P450-Glo™ Screening System. The assay mixture (based on 1 M potassium phosphate buffer) was pre-incubated with the test compound or control inhibitor for 10 min at 37°C. Enzyme reactions were initiated by adding an NADPH regenerating system (12.5 μl) and incubated for 20 min (CYP1A2 and CYP2C19) or 30 min (CYP2C9, CYP2D6, CYP3A4) at 37°C. The reaction was stopped by adding 50 μl of luciferin detection reagent and incubating for 20 min at room temperature. Relative luminescence units (RLU) were read with a luminometer. Positive control inhibitors were: 1 μM α-naphthoflavone for CYP1A2, 10 μM sulfaphenazole for CYP2C9, 10 μM troglitazone for CYP2C19, 1 μM quinidine for CYP2D6, and 5 μM ketoconazole for CYP3A4. Periplocymarin at both concentrations did not significantly decrease the relative activity of any of these CYP450 isoforms. [1]
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| Cell Assay |
Periplocymarin cytotoxicity was evaluated on MDCK-II-WT cells using an XTT-based colorimetric assay. Cells were seeded in 96-well plates at 1×10⁴ cells/well and incubated for 48 h. Periplocymarin was dissolved in DMSO to a 0.5 M stock and diluted to working concentrations between 0.5 mM and 0.02 mM using RP1640 with 5% FBS. Control samples included cells in 0.1% DMSO and culture medium without cells. The experiment started by replacing the culture medium with 100 μl of sample solution and incubating for 4 h. Then 50 μl of XTT (1 mg/ml) labeling reagent was added to each well, followed by another 4 h incubation at 37°C. Absorbance was read at 490 nm. No significant cytotoxicity was observed at 0.025–0.5 mM. [1]
The R123 accumulation assay was performed to evaluate whether Periplocymarin inhibits P-gp. MDCK-II-MDR1 cells were seeded in 24-well plates and cultured for 48 h. Cells were pre-incubated with HBSS for 20 min, then incubated with 0.5 ml of 5 μM R123 with or without Periplocymarin (100 or 200 μM), verapamil (100 μM), or cyclosporine A (100 μM) for 60 min at 37°C. Cells were washed with ice-cold HBSS, lysed by ultrasonication, and centrifuged at 14,000 rpm for 10 min at 4°C. Supernatant fluorescence was measured (excitation 480 nm, emission 535 nm). Periplocymarin did not significantly increase R123 accumulation compared to verapamil or cyclosporine A. [1] Bi-directional transport assays were performed using MDCK-II-WT and MDCK-II-MDR1 cell monolayers cultured on Millicell inserts for 5 days. Monolayer integrity was checked by TEER (≥80 Ω·cm² for WT, ≥90 Ω·cm² for MDR1). Transport buffer containing Periplocymarin (100 or 200 μM) with or without 10 μM CsA was added to apical (0.4 ml) or basolateral (0.6 ml) side. Incubation at 37°C with shaking at 90 rpm for 180 min. Samples (100 μl) were withdrawn from receiver chamber at 30, 60, 90, 120, 150, 180 min and replenished with pre-warmed buffer. Periplocymarin concentration was analyzed by HPLC. [1] |
| Animal Protocol |
In situ single-pass intestinal perfusion was performed in male Wistar rats (8-10 weeks, 200-250 g) to determine the effective permeability (Peff(rat)) of Periplocymarin. Rats were fasted overnight with free access to water. Anesthesia was induced by intraperitoneal injection of urethane (140 mg/kg). Body temperature was maintained at 37°C. A midline abdominal incision (3-4 cm) was made, and a proximal jejunal segment (approximately 10 cm length) was cannulated with polyvinyl chloride tubing. The segment was rinsed with normal saline at 37°C. Periplocymarin solution in Kreb's-Ringer buffer (pH 6.8) with or without 10 μM cyclosporine A was perfused at 1 ml/min for 10 min to fill the segment, then the perfusion rate was set to 0.2 ml/min. After a 30 min incubation period, outlet samples were collected at 10 min intervals for up to 90 min. The perfused intestinal segment was cut, and its width and length were measured. Periplocymarin concentrations were analyzed by HPLC. The Peff(rat) values were calculated using the equation: Peff(rat) = [-Qin ln(Ccor/Cin)] / (2πrl). [1]
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| ADME/Pharmacokinetics |
Periplocymarin is highly permeable. In MDCK-II-WT cells, Papp (AP→BL) > 10×10⁻⁶ cm/s (15.70×10⁻⁶ cm/s at 100 μM; 31.5×10⁻⁶ cm/s at 200 μM). In the rat single-pass intestinal perfusion model, Peff(rat) of Periplocymarin at 5 μg/ml was 5.49×10⁻⁵ cm/s; at 12.5 μg/ml was 5.25×10⁻⁵ cm/s; at 0.5-2.0 μg/ml ranged from 4.2×10⁻⁵ to 5.09×10⁻⁵ cm/s. The presence of cyclosporine A (10 μM) did not change Peff(rat) (5.394×10⁻⁵ cm/s vs 5.490×10⁻⁵ cm/s). Using prediction equations from rat to human, Periplocymarin (5 μg/ml) is predicted to have human permeability of 2.80×10⁻⁴ cm/s and fraction absorbed (Fa) of 87.88%. [1]
Periplocymarin is independent of P-gp influence; it does not competitively inhibit P-gp. It does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at 5 and 50 μM. [1] |
| Toxicity/Toxicokinetics |
No significant cytotoxic effects of Periplocymarin were observed on MDCK-II-WT cells at concentrations from 0.025 mM to 0.5 mM after 4 h exposure (p > 0.05, n=3). Periplocymarin is unlikely to pose drug-drug interaction risks with P-gp and the tested CYP450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). [1]
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| References |
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| Additional Infomation |
Periplocymarin is a cardiac glycoside. 4-[(3S,5S,10R,13R,14S,17S)-5,14-dihydroxy-3-[(2S,5R)-5-hydroxy-4-methoxy-6-methyl-oxacyclohexane-2-yl]oxy-10,13-dimethyl-2,3,4,6,7,8,9,11,12,15,16,17-dodecylhydro-1H-cyclopenta[A]phenanthrene-17-yl]-5H-furan-2-one has been reported in Strophanthus hispidus, Periploca sepium, and other organisms with available data.
Periplocymarin is a cardiac glycoside and a potential anticancer compound isolated from Periploca sepium and Periploca graeca. P. sepium and P. graeca are widely used to treat cardiac palpitations and rheumatoid arthritis. The class of cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. One obstacle for their clinical use in antitumor treatment is their narrow therapeutic safety range. Periplocymarin has shown anticancer activity by inhibiting cell growth in PC3 prostate cancer cells (via caspase-dependent apoptosis) and inducing cell cycle impairment in U937 leukemia cells. At cytostatic doses, it sensitizes U937 cells to TRAIL more quickly than ouabain. This study confirms that Periplocymarin has high permeability, is not a P-gp substrate, and does not inhibit major CYP450s, suggesting it may be a new chemical entity for drug development unlikely to pose significant P-gp and CYP450 DDI risks. Future studies should explore interactions with MRP2, BCRP, and non-CYP450 enzymes. [1] |
| Molecular Formula |
C30H46O8
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|---|---|
| Molecular Weight |
534.68144
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| Exact Mass |
534.319
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| CAS # |
32476-67-8
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| PubChem CID |
12305974
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| Appearance |
White to off-white solid
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| Density |
1.27±0.1 g/cm3 (20 ºC 760 Torr)
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| Boiling Point |
690.9±55.0℃ at 760 mmHg
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| Melting Point |
209-211 ºC
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| LogP |
3.254
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
38
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| Complexity |
983
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| Defined Atom Stereocenter Count |
12
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| SMILES |
O1[C@H](C[C@H](OC)[C@H](O)[C@H]1C)O[C@H]1CC[C@]2(C)[C@@]3([H])CC[C@]4(C)[C@@H](C5=CC(=O)OC5)CC[C@]4(O)[C@]3([H])CC[C@]2(O)C1
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| InChi Key |
XRWQBDJPMXRDOQ-YUUDFPFBSA-N
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| InChi Code |
InChI=1S/C30H46O8/c1-17-26(32)23(35-4)14-25(37-17)38-19-5-9-27(2)21-6-10-28(3)20(18-13-24(31)36-16-18)8-12-30(28,34)22(21)7-11-29(27,33)15-19/h13,17,19-23,25-26,32-34H,5-12,14-16H2,1-4H3/t17-,19+,20-,21+,22-,23+,25+,26-,27-,28-,29+,30+/m1/s1
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| Chemical Name |
3-[(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-3-[(2R,4S,5R,6R)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-10,13-dimethyl-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~187.03 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.68 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.68 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8703 mL | 9.3514 mL | 18.7028 mL | |
| 5 mM | 0.3741 mL | 1.8703 mL | 3.7406 mL | |
| 10 mM | 0.1870 mL | 0.9351 mL | 1.8703 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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