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Purity: ≥98%
Nemorubicin (also known as PNU152243A; Methoxymorpholinyldoxorubicin; PNU 152243; PNU-152243A), an analog of doxorubicin, is a DNA-intercalator, topoisomerase and RNA synthesis inhibitor that was undergoing development for cancer treatment. It was being studied in Phase II clinical trials to treat primary hepatocellular carcinoma. Preclinical evidence demonstrated that nemorubicin has a unique mode of action, overcomes anthracycline resistance, is non-cardiotoxic, and shares structural similarities with doxorubicin. Nemorubicin primarily causes DNA strand breaks via topoisomerase-I cleavage, as we have shown previously. Nemorubicin is ineffective against cells resistant to camptotecins, but it acts as expected against cells resistant to topoisomerase II inhibitors. Furthermore, we discovered that human hepatocytes or microsomes grown in vitro produce a nemorubicin metabolite (PNU-159682) that binds covalently to DNA and is 100 times more cytotoxic than the original compound. In order to gain additional insight into the mechanism of action of nemorubicin, we created an L1210 cell line that is resistant to the drug. We hypothesized that the nucleotide excision repair (NER) system might be involved in mediating the cytotoxic activity of nemorubicin since resistant L1210 cells were more sensitive than the parental cell line to UV irradiation, platinum derivatives, and alkylating agents. We used CHO cell lines that were either proficient or deficient in the excision repair cross-complementing (ERCC) genes, specifically ERCC1 and ERCC6, to test this hypothesis. The NER system may be involved in the induction of nemorubicin cytotoxicity, as evidenced by our finding that nemorubicin is more cytotoxic in NER proficient cells than in deficient ones. Testing PNU-159682 on NER proficient or deficient cells produced comparable results. In conclusion, nemorubicin has a unique mechanism of action that involves the NER system, despite having structural similarities to doxorubicin. This provides justification for clinical combination studies of nemorubicin with alkylating agents or platinum derivatives.
| ln Vitro |
Nemorubicin exhibits antitumor activity against the HT-29, A2780, DU145, EM-2, Jurkat, and CEM cell lines, with IC70s of 578 nM, 468 nM, 193 nM, 191 nM, 68 nM, and 131 ± 9 nM, respectively[1].
Nemorubicin, an anticancer prodrug activated by CYP3A, has the ability to generate PNU-159682, a more potent metabolite[1][2]. Nemorubicin exerts its effects by means of the nucleotide excision repair (NER) system. Compared to L1210/0 cells lacking XPG, NER-preserved L1210/DDP cells exhibit higher levels of nemorubicin (0-0.3 μM) activity. UV damage is more sensitive in cells that are resistant to nemorubicin[3]. Nemorubicin has an IC50 of 0.2 nM, which is 120 times lower than that of 9L cells lacking P450 (IC50, 23.9 nM), indicating that it is cytotoxic to 9L/3A/4 cells. Also, with an IC50 of 1.4 nM, nemoribucicin significantly suppresses Adeno-3A4-infected U251 cells. Nemorubicin is more cytotoxic when P450 reductase is overexpressed[4]. |
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| ln Vivo |
Nemorubicin is changed into PNU-159682 in rat, mouse, and dog liver microsomes by human liver cytochrome P450 (CYP) 3A4[2]. When administered intravenously (IV) or intratumorally (i.t.) to mice with 9L/3A4 tumors, nemorubicin (60 µg/kg) significantly retards the growth of the tumors, but it has no discernible effect on the tumor growth delay of 9L tumors in scid mice. In mice with 9L/3A4 tumors, nemorubicin (40 µg/kg, i.p.) shows no antitumor activity and no host toxicity[4].
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| Cell Assay |
Three thousand cells per well in triplicate wells of a 96-well plate are plated with 9L and CHO cells 24 hours before treatment with medication. For four days, different concentrations of IFA or nemorubicin are applied to the cells. After staining the cells with crystal violet (A595), the relative cell survival is computed. Prism 4 is used to calculate IC50 values from a semi-logarithmic graph of the data points[4].
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| Animal Protocol |
Male ICR/Fox Chase SCID mice are used to grow 9L and 9L/3A4 cells as solid tumors. After being cultivated in DMEM medium to 75% confluence, the cells are trypsinized, rinsed in PBS, and adjusted to 2 × 107 cells/mL of DMEM without added fetal serum. Implantation of either 9L or 9L/3A4 tumor cells is done on four-week-old SCID mice (18–20 g) by injecting 4 × 106 cells/0.2 mL of cell suspension, s.c. on each hind flank. Beginning on the seventh day following tumor implantation, tumor sizes (length and width) are measured twice a week using Vernier calipers. Nemorubicin dissolved in PBS is injected intravenously (IV) or directly intratumorally (i.t.) (three injections spaced seven days apart, each at 60 µg Nemorubicin per kg body weight) when the average tumor size reaches 300 to 400 mm3. Using a 30-gauge needle and a syringe pump set to 1 µL/s, intratumoral injections are administered. Three injections are given for each tumor in an i.t. treatment, with a 50 µL injection volume per tumor per 25 g mouse. In other words, 120 µL of 15 µg/mL of Nemorubicin solution is given to a 30 g mouse, with 20 µL given per site × 3 sites per tumor × 2 tumors/mouse. The same volume of PBS is injected intraperitoneally into drug-free controls. Nemorubicin is injected intraperitoneally (i.p.) at 40 or 60 µg/kg body weight in certain experiments. For the duration of the study, body weight and tumor sizes are measured twice a week. The formula for calculating tumor volumes is V = π/6 (L × W)3/2. The formula for calculating percent tumor regression is 100 × (V1-V2)/V1, where V1 represents the tumor volume on the day of medication treatment and V2 represents the tumor volume on the day that the greatest reduction in tumor size is observed after medication treatment. The amount of time needed for tumors to double in volume following drug treatment is known as the tumor doubling time [4].
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| References |
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| Molecular Formula |
C32H37NO13
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|---|---|
| Molecular Weight |
643.63508
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| Exact Mass |
643.23
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| Elemental Analysis |
C, 59.71; H, 5.79; N, 2.18; O, 32.32
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| CAS # |
108852-90-0
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| Related CAS # |
Nemorubicin;108852-90-0
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| Appearance |
Red to pink solid powder
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| SMILES |
C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(C(=O)CO)O)N6CCO[C@@H](C6)OC)O
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| InChi Key |
CTMCWCONSULRHO-UHQPFXKFSA-N
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| InChi Code |
InChI=1S/C32H37NO13/c1-14-27(36)17(33-7-8-44-22(12-33)43-3)9-21(45-14)46-19-11-32(41,20(35)13-34)10-16-24(19)31(40)26-25(29(16)38)28(37)15-5-4-6-18(42-2)23(15)30(26)39/h4-6,14,17,19,21-22,27,34,36,38,40-41H,7-13H2,1-3H3/t14-,17-,19-,21-,22-,27+,32-/m0/s1
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| Chemical Name |
(7S,9S)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2R,4S,5S,6S)-5-hydroxy-4-[(2S)-2-methoxymorpholin-4-yl]-6-methyloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
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| Synonyms |
Methoxymorpholinyldoxorubicin; PNU 152243; PNU-152243A; PNU152243A; PNU-152243A; PNU 152243A; Nemorubicin; methoxymorpholinyl-doxorubicin
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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 |
| 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: ~65 mg/mL (~101 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 + to the above solution and mix evenly; then add 450 μL of 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5537 mL | 7.7683 mL | 15.5366 mL | |
| 5 mM | 0.3107 mL | 1.5537 mL | 3.1073 mL | |
| 10 mM | 0.1554 mL | 0.7768 mL | 1.5537 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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