Nemorubicin

Doxorubicin analog,anticancer drug CAS# 108852-90-0

Nemorubicin

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Chemical structure

Nemorubicin

3D structure

Chemical Properties of Nemorubicin

Cas No. 108852-90-0 SDF Download SDF
PubChem ID 65907 Appearance Powder
Formula C32H37NO13 M.Wt 643.64
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Methoxymorpholinyldoxorubicin; PNU 152243; PNU-152243A
Solubility DMSO : ≥ 47 mg/mL (73.02 mM)
*"≥" means soluble, but saturation unknown.
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
SMILES CC1C(C(CC(O1)OC2CC(CC3=C(C4=C(C(=C23)O)C(=O)C5=C(C4=O)C=CC=C5OC)O)(C(=O)CO)O)N6CCOC(C6)OC)O
Standard InChIKey CTMCWCONSULRHO-UHQPFXKFSA-N
Standard InChI 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
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 Nemorubicin

DescriptionNemorubicin is an anticancer drug with IC50 value of 0.08 μM.
Targetscancer    
IC500.08 μM     

Protocol

Cell Assay [4]
9L and CHO cells are plated in triplicate wells of a 96-well plate at 3000 cells per well 24 hr prior to drug treatment. Cells are treated with various concentrations of Nemorubicin or IFA for 4d. Cells are then stained with crystal violet (A595) and relative cell survival is calculated. IC50 values are determined from a semi-logarithmic graph of the data points using Prism 4[4].

Animal Administration [4]
9L and 9L/3A4 cells are grown as solid tumors in male ICR/Fox Chase SCID mice. Cells cultured in DMEM medium to 75% confluence are trypsinized and washed in PBS and then adjusted to 2 × 107 cells/mL of FBS-free DMEM. Four-week-old SCID mice (18-20 g) are implanted with either 9L or 9L/3A4 tumor cells by injection of 4 × 106 cells/0.2 mL of cell suspension, s.c. on each hind flank. Tumor sizes (length and width) are measured twice a week using Vernier calipers beginning 7d after tumor implantation. When the average tumor size reach 300 to 400 mm3, Nemorubicin dissolved in PBS is administered by tail vein injection (i.v.) or by direct intratumoral (i.t.) injection (three injections spaced 7 d apart, each at 60 µg Nemorubicin per kg body weight). Intratumoral injections are performed using a syringe pump set a 1 µL/s with a 30-gauge needle. Each i.t. treatment dose is divided into three injections per tumor, with the injected volume set at 50 µL per tumor per 25 g mouse. Thus, for a 30 g mouse, a total of 120 µL of 15 µg/mL of Nemorubicin solution is administered: 20 µL per site × 3 sites per tumor × 2 tumors/mouse. Drug-free controls are injected i.t. with the same vol of PBS. In some experiments, Nemorubicin is administered by i.p. injection at 40 or 60 µg/kg body weight. Tumor sizes and body weights are measured twice/wk for the duration of the study. Tumor volumes are calculated using the formula: V = π/6 (L × W)3/2. Percent tumor regression is calculated as 100 × (V1-V2)/V1, where V1 is the tumor vol on the day of drug treatment and V2 is the vol on the day when the largest the decrease in tumor size is seen following drug treatment. Tumor doubling time is calculated as the time required for tumors to double in vol after drug treatment[4].

References:
[1]. Quintieri L, et al. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005 Feb 15;11(4):1608-17. [2]. Quintieri L, et al. In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes. Biochem Pharmacol. 2008 Sep 15;76(6):784-95. [3]. Sabatino MA, et al. Down-regulation of the nucleotide excision repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells. Mol Cancer. 2010 Sep 24;9:259. [4]. Lu H, et al. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404.

Nemorubicin Dilution Calculator

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Nemorubicin Molarity Calculator

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Preparing Stock Solutions of Nemorubicin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.5537 mL 7.7683 mL 15.5366 mL 31.0733 mL 38.8416 mL
5 mM 0.3107 mL 1.5537 mL 3.1073 mL 6.2147 mL 7.7683 mL
10 mM 0.1554 mL 0.7768 mL 1.5537 mL 3.1073 mL 3.8842 mL
50 mM 0.0311 mL 0.1554 mL 0.3107 mL 0.6215 mL 0.7768 mL
100 mM 0.0155 mL 0.0777 mL 0.1554 mL 0.3107 mL 0.3884 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 Nemorubicin

Nemorubicin is an anticancer drug with IC50 value of 0.08μM [1].

Nemorubicin is a morpholinyl analog of doxorubicin and is developed to be an anticancer drug. It is less cardiotoxic and more cytotoxic against multidrug-resistant tumor cells. The SRB in vitro assay shows nemorubicin can inhibit the proliferation of HCC cell lines with average IC50 value of 0.08μM. It is much more potent(from 10 to 380 times) than other anticancer drugs. The treatments of nemorubicin at doses of both 25μg/kg and 50μg/kg cause growth inhibition of human HCC xenografts BEL-7402 and Zip-177 in nude mice. When the dose is up to 100μg/kg, the high toxicity causes the death of mice. In phase I study, nemorubicin shows a terminal half-life in eight patients of 11.1±10.8 h. And the hematotoxicity tests show a <70% colony growth inhibition without correlation between the growth inhibition effect and the degree of myelotoxicity in the same patient. Besides that, nausea and vomiting is a limit of the application of nemorubicin [1, 2].

References:
[1] Shengtao Yuan, Xiongwen Zhang, Lijuan Lu, Chenghui Xu, Weiyi Yang and Jian Ding. Anticancer activity of methoxymorpholinyl doxorubicin (PNU 152243) on human hepatocellular carcinoma. Anti-Cancer Drugs. 2004, 15(6): 641-646.
[2] Cristiana Sessa, Massimo Zucchetti Michele Ghielmini, Jean Bauer, Maurizio D'Incalci Jolanda de Jong, Huguette Naegele, Simona Rossi Maria Adele Pacciarini, Letizia Domenigoni Franco Cavalli. Cancer Chemother Pharmacol. 1999, 44:403-410.

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References on Nemorubicin

The interaction of nemorubicin metabolite PNU-159682 with DNA fragments d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) shows a strong but reversible binding to G:C base pairs.[Pubmed:23154079]

Bioorg Med Chem. 2012 Dec 15;20(24):6979-88.

The antitumor anthracycline Nemorubicin is converted by human liver microsomes to a major metabolite, PNU-159682 (PNU), which was found to be much more potent than its parent drug toward cultured tumor cells and in vivo tumor models. The mechanism of action of Nemorubicin appears different from other anthracyclines and until now is the object of studies. In fact PNU is deemed to play a dominant, but still unclear, role in the in vivo antitumor activity of Nemorubicin. The interaction of PNU with the oligonucleotides d(CGTACG)(2), d(CGATCG)(2) and d(CGCGCG)(2) was studied with a combined use of (1)H and (31)P NMR spectroscopy and by ESI-mass experiments. The NMR studies allowed to establish that the intercalation between the base pairs of the duplex leads to very stable complexes and at the same time to exclude the formation of covalent bonds. Melting experiments monitored by NMR, allowed to observe with high accuracy the behaviour of the imine protons with temperature, and the results showed that the re-annealing occurs after melting. The formation of reversible complexes was confirmed by HPLC-tandem mass spectra, also combined with endonuclease P1digestion. The MS/MS spectra showed the loss of neutral PNU before breaking the double helix, a behaviour typical of intercalators. After digestion with the enzyme, the spectra did not show any compound with PNU bound to the bases. The evidence of a reversible process appears from both proton and phosphorus NOESY spectra of PNU bound to d(CGTACG)(2) and to d(CGATCG)(2). The dissociation rate constants (k(off)) of the slow step of the intercalation process, measured by (31)P NMR NOE-exchange experiments, showed that the kinetics of the process is slower for PNU than for doxorubicin and Nemorubicin, leading to a 10- to 20-fold increase of the residence time of PNU into the intercalation sites, with respect to doxorubicin. A relevant number of NOE interactions allowed to derive a model of the complexes in solution from restrained MD calculations. The conformation of PNU bound to the oligonucleotides was also derived from the coupling constant values.

Virtual Cross-Linking of the Active Nemorubicin Metabolite PNU-159682 to Double-Stranded DNA.[Pubmed:28068470]

Chem Res Toxicol. 2017 Feb 20;30(2):614-624.

The DNA alkylating mechanism of PNU-159682 (PNU), a highly potent metabolite of the anthracycline Nemorubicin, was investigated by gel-electrophoretic, HPLC-UV, and micro-HPLC/mass spectrometry (MS) measurements. PNU quickly reacted with double-stranded oligonucleotides, but not with single-stranded sequences, to form covalent adducts which were detectable by denaturing polyacrylamide gel electrophoresis (DPAGE). Ion-pair reverse-phase HPLC-UV analysis on CG rich duplex sequences having a 5'-CCCGGG-3' central core showed the formation of two types of adducts with PNU, which were stable and could be characterized by micro-HPLC/MS. The first type contained one alkylated species (and possibly one reversibly bound species), and the second contained two alkylated species per duplex DNA. The covalent adducts were found to produce effective bridging of DNA complementary strands through the formation of virtual cross-links reminiscent of those produced by classical anthracyclines in the presence of formaldehyde. Furthermore, the absence of reactivity of PNU with CG-rich sequence containing a TA core (CGTACG), and the minor reactivity between PNU and CGC sequences (TACGCG.CGCGTA) pointed out the importance of guanine sequence context in modulating DNA alkylation.

Nemorubicin and doxorubicin bind the G-quadruplex sequences of the human telomeres and of the c-MYC promoter element Pu22.[Pubmed:26922833]

Biochim Biophys Acta. 2016 Jun;1860(6):1129-38.

BACKGROUND: Intra-molecular G-quadruplex structures are present in the guanine rich regions of human telomeres and were found to be prevalent in gene promoters. More recently, the targeting of c-MYC transcriptional control has been suggested, because the over expression of the c-MYC oncogene is one of the most common aberration found in a wide range of human tumors. METHODS: The interaction of Nemorubicin and doxorubicin with DNA G-quadruplex structures has been studied by NMR, ESI-MS and molecular modelling, in order to obtain further information about the complex and the multiple mechanisms of action of these drugs. RESULTS AND CONCLUSIONS: Nemorubicin intercalates between A3 and G4 of d(TTAGGGT)4 and form cap-complex at the G6pT7 site. The presence of the adenine in this sequence is important for the stabilization of the complex, as was shown by the interaction with d(TTGGGTT)4 and d(TTTGGGT)4, which form only a 1:1 complex. The interaction of doxorubicin with d(TTAGGGT)4 is similar, but the complex appears less stable. Nemorubicin also binds with high efficiency the c-MYC G-quadruplex sequence Pu22, to form a very well defined complex. Two Nemorubicin molecules bind to the 3'-end and to the 5'-end, forming an additional plane of stacking over each external G-tetrad. The wild type c-MYCPu22 sequence forms with Nemorubicin the same complex. GENERAL SIGNIFICANCE: Nemorubicin and doxorubicin, not only intercalate into the duplex DNA, but also result in significant ligands for G-quadruplex DNA segments, stabilizing their structure; this may in part explain the multiple mechanisms of action of their antitumor activity.

In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes.[Pubmed:18671948]

Biochem Pharmacol. 2008 Sep 15;76(6):784-95.

We recently demonstrated that Nemorubicin (MMDX), an investigational antitumor drug, is converted to an active metabolite, PNU-159682, by human liver cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate MMDX metabolism by liver microsomes from laboratory animals (mice, rats, and dogs of both sexes) to ascertain whether PNU-159682 is also produced in these species, and to identify the CYP form(s) responsible for its formation; (2) to compare the animal metabolism of MMDX with that by human liver microsomes (HLMs), in order to determine which animal species is closest to human beings; (3) to explore whether differences in PNU-159682 formation are responsible for previously reported species- and sex-related differences in MMDX host toxicity. The animal metabolism of MMDX proved to be qualitatively similar to that observed with HLMs since, in all tested species, MMDX was mainly converted to PNU-159682 by a single CYP3A form. However, there were marked quantitative inter- and intra-species differences in kinetic parameters. The mouse and the male rat exhibited V(max) and intrinsic metabolic clearance (CL(int)) values closest to those of human beings, suggesting that these species are the most suitable animal models to investigate MMDX biotransformation. A close inverse correlation was found between MMDX CL(int) and previously reported values of MMDX LD(50) for animals of the species, sex and strain tested here, indicating that differences in the in vivo toxicity of MMDX are most probably due to sex- and species-related differences in the extent of PNU-159682 formation.

Description

Nemorubicin is a derivative of doxorubicin, and has antitumor activity.

Keywords:

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