Nemorubicin
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MedKoo CAT#: 201824

CAS#: 108852-90-0 (free base)

Description: Nemorubicin, also known as PNU152243A, is a doxorubicin derivative that differs significantly from its parent drug in terms of spectrum of antitumor activity, metabolism and toxicity profile. The drug is active on tumors resistant to alkylating agents, topoisomerase II inhibitors and platinum derivatives. It works primarily through topoisomerase I inhibition. Of note, Nemorubicin is active in cells with upregulation of the nucleotide excision repair (NER) pathway, where current therapies fail. Nemorubicin is biotransformed in the liver into cytotoxic metabolites that may further contribute to render this drug highly active against primary liver tumors or liver metastases.


Chemical Structure

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Nemorubicin
CAS# 108852-90-0 (free base)

Theoretical Analysis

MedKoo Cat#: 201824
Name: Nemorubicin
CAS#: 108852-90-0 (free base)
Chemical Formula: C32H37NO13
Exact Mass: 643.22649
Molecular Weight: 643.63
Elemental Analysis: C, 59.71; H, 5.79; N, 2.18; O, 32.32

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2.0g USD 6950.0 2 Weeks
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Related CAS #: 108943-08-4 (HCl)   108852-90-0 (free base)  

Synonym: PNU152243A; PNU-152243A; PNU 152243A; Nemorubicin, methoxymorpholinyl-doxorubicin

IUPAC/Chemical Name: (8S,10S)-6,8,11-trihydroxy-10-(((2R,4S,5S,6S)-5-hydroxy-4-((S)-2-methoxymorpholino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

InChi Key: CTMCWCONSULRHO-UHQPFXKFSA-N

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

SMILES Code: O=C1C2=C(O)C(C[C@](C(CO)=O)(O)C[C@@H]3O[C@H]4C[C@H](N5C[C@@H](OC)OCC5)[C@H](O)[C@H](C)O4)=C3C(O)=C2C(C6=C1C=CC=C6OC)=O

Appearance: Red to pink solid powder

Purity: >95% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Nemorubicin (Methoxymorpholinyl doxorubicin) is a Doxorubicin derivative with potent antitumor activity and IC70s of 578 nM, 468 nM, 193 nM, 191 nM, 68 nM.
In vitro activity: The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. The cytotoxicity and antitumor activity of PNU-159682 was examined using a panel of in vitrocultured human tumor cell lines and tumor-bearing mice, respectively. HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3Amediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNAexpressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro. Clin Cancer Res. 2005 Feb 15;11(4):1608-17. https://pubmed.ncbi.nlm.nih.gov/15746066/
In vivo activity: This study investigated methoxymorpholinyl-doxorubicin (MMDX), a novel CYP3A-activated anticancer prodrug. 9L and 9L/3A4 tumors were implanted s.c. and grown in male scid mice. Tumor vol (A) and body weight (B) were measured twice a week. In the absence of drug treatment, 9L/3A4 tumors grew somewhat slower than 9L tumors (doubling time of 5.8 d vs. 4.6 d; Table 2). Arrows indicate days on which each of three weekly doses of MMDX (60 µg/kg) was administered, either by i.v. or i.t. injection, as indicated, beginning when the tumors reached 300–400 mm3 in size. MMDX was highly toxic by the i.v. administration route, with 4 out of 4 i.v. injected 9L tumor-bearing mice dying by day 21 (i.e., 7 d after completing the cycle of three weekly MMDX injections), and 3 out of 4 i.v. MMDX-injected 9L/3A4 tumor-bearing mice dying by day 24. Drug toxicity was not observed for the i.t. MMDX 9L/3A4 tumor group until after completion of a second cycle of three weekly MMDX injections, with 1 mouse dying on day 52 and a second mouse on day 56. Notably, intratumoral expression of CYP3A4 increased MMDX antitumor activity dramatically, even though MMDX itself has substantial intrinsic anticancer activity, and despite the fact that MMDX-activating CYP3A enzymes are already expressed endogenously at a high level in mouse liver , as they are in human liver . The strong chemosensitization of 9L/3A4 tumors to MMDX reported here further suggests that MMDX may be particularly active against tumors that express CYP3A4 endogenously, i.e., without the introduction of a gene therapy vector. Cancer Gene Ther. 2009 May; 16(5): 393–404. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669851/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 60.0 101.0

Preparing Stock Solutions

The following data is based on the product molecular weight 643.63 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Quintieri L, Geroni C, Fantin M, Battaglia R, Rosato A, Speed W, Zanovello P, Floreani M. 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. doi: 10.1158/1078-0432.CCR-04-1845. PMID: 15746066. 2. Quintieri L, Fantin M, Palatini P, De Martin S, Rosato A, Caruso M, Geroni C, Floreani M. 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. doi: 10.1016/j.bcp.2008.07.003. Epub 2008 Jul 11. PMID: 18671948. 3. Broggini M. Nemorubicin. Top Curr Chem. 2008;283:191-206. doi: 10.1007/128_2007_6. PMID: 23605633. 4. Lu H, Chen CS, Waxman DJ. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404. doi: 10.1038/cgt.2008.93. Epub 2008 Nov 14. PMID: 19011599; PMCID: PMC2669851
In vitro protocol: 1. Quintieri L, Geroni C, Fantin M, Battaglia R, Rosato A, Speed W, Zanovello P, Floreani M. 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. doi: 10.1158/1078-0432.CCR-04-1845. PMID: 15746066. 2. Quintieri L, Fantin M, Palatini P, De Martin S, Rosato A, Caruso M, Geroni C, Floreani M. 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. doi: 10.1016/j.bcp.2008.07.003. Epub 2008 Jul 11. PMID: 18671948.
In vivo protocol: 1. Broggini M. Nemorubicin. Top Curr Chem. 2008;283:191-206. doi: 10.1007/128_2007_6. PMID: 23605633. 2. Lu H, Chen CS, Waxman DJ. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404. doi: 10.1038/cgt.2008.93. Epub 2008 Nov 14. PMID: 19011599; PMCID: PMC2669851.

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1: Mazzini S, Scaglioni L, Mondelli R, Caruso M, Sirtori FR. 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. Bioorg Med Chem. 2012 Dec 15;20(24):6979-88. doi: 10.1016/j.bmc.2012.10.033. Epub 2012 Nov 3. PubMed PMID: 23154079.

2: Sabatino MA, Marabese M, Ganzinelli M, Caiola E, Geroni C, Broggini M. 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. doi: 10.1186/1476-4598-9-259. PubMed PMID: 20868484; PubMed Central PMCID: PMC2955619.

3: Lu H, Chen CS, Waxman DJ. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404. doi: 10.1038/cgt.2008.93. Epub 2008 Nov 14. PubMed PMID: 19011599; PubMed Central PMCID: PMC2669851.

4: Quintieri L, Fantin M, Palatini P, De Martin S, Rosato A, Caruso M, Geroni C, Floreani M. 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. doi: 10.1016/j.bcp.2008.07.003. Epub 2008 Jul 11. PubMed PMID: 18671948.

5: Broggini M. Nemorubicin. Top Curr Chem. 2008;283:191-206. doi: 10.1007/128_2007_6. PubMed PMID: 23605633.

6: Sessa C, Valota O, Geroni C. Ongoing phase I and II studies of novel anthracyclines. Cardiovasc Toxicol. 2007;7(2):75-9. Review. PubMed PMID: 17652808.

7: Quintieri L, Geroni C, Fantin M, Battaglia R, Rosato A, Speed W, Zanovello P, Floreani M. 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. PubMed PMID: 15746066.

8: Fraier D, Frigerio E, Brianceschi G, James CA. LC-MS-MS determination of nemorubicin (methoxymorpholinyldoxorubicin, PNU-152243A) and its 13-OH metabolite (PNU-155051A) in human plasma. J Pharm Biomed Anal. 2002 Oct 15;30(3):377-89. PubMed PMID: 12367663.



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