DNA intercalator

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].

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].

Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3'',4'-anhydro-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. 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 . Experimental design: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. Results: 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 PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated 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 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. Conclusions: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.[1]

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Correlation Studies. [1] Nemorubicin /MMDX (20 μmol/L) was incubated with microsomal fractions from 10 individual human livers; the incubation protocol was the same as that described above. The rates of PNU-159682 formation obtained in these experiments were correlated with several known CYP form-selective catalytic activities evaluated in the same microsomal samples (data provided by BD Gentest except those for nifedipine oxidation and erythromycin N-demethylation). Coefficients of determination (r2) and P values were determined by linear regression analysis.

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Chemical and Immunochemical Inhibition Studies. [1] Formation of PNU-159682 from 20 μmol/L Nemorubicin /MMDX by pooled HLMs was evaluated in the absence (i.e., control) and presence of known CYP form-selective chemical inhibitors. The following inhibitors were examined at concentrations previously identified as being appropriate to cause CYP form-selective inhibition in HLMs: 7,8-benzoflavone (1 μmol/L, CYP1A2-selective), sulfaphenazole (20 μmol/L, CYP2C9-selective), quinidine (5 μmol/L, CYP2D6-selective), diethyldithiocarbamate (25 μmol/L; CYP2A6/E1-selective), troleandomycin (100 μmol/L, CYP3A-selective) and ketoconazole (1 μmol/L, CYP3A-selective). In experiments with reversible inhibitors, i.e., 7,8-benzoflavone, quinidine, sulfaphenazole, and ketoconazole, the inhibitor was coincubated with the substrate; the incubation protocol was the same as described above. In experiments with mechanism-based inhibitors, i.e., diethyldithiocarbamate and troleandomycin, the inhibitor was preincubated with liver microsomes and NADPH (0.5 mmol) at 37°C for 15 minutes before adding the substrate and additional 0.5 mmol NADPH. The reactions were then conducted as described above.
Immunochemical inhibition studies were carried out using mouse ascites fluids containing inhibitory MAbs which have been shown to be specific for different human CYP enzymes. Pooled HLMs (0.25 mg microsomal protein/mL; 20 pmol of total CYP) were preincubated with the designated amount of mouse ascites containing anti-CYP MAb (20-140 μg) at 37°C for 5 minutes in 0.3 mol/L Tris (pH 7.4); the reaction was then initiated by the addition of MMDX (final concentration, 20 μmol/L) and NADPH (final concentration, 0.5 mmol/L) in a total volume of 0.2 mL, and conducted as described above. The highest concentration of each MAb used in these trials (i.e., 7 μg ascites protein/pmol of total CYP) was previously shown to be saturating for an appropriate CYP form-specific reaction in HLMs. Control incubations were carried out in the absence of MAb.

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Incubation of Nemorubicin /MMDX with cDNA-expressed Human Cytochrome P450 Enzymes [1] Incubations of MMDX with microsomes containing cDNA-expressed CYP enzymes were done as described for HLMs, except that the amount of enzyme used was 50 pmol/mL and incubations were terminated after 60 minutes; substrate concentration was 20 μmol/L. All incubations were done in duplicate. Aliquots of the supernatants from each sample were analyzed for PNU-159682 content by HPLC with fluorescence detection.

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Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3'',4'-anhydro-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. 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.
Experimental design: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively.
Results: HLMs converted Nemorubicin /MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated 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 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts.
Conclusions: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.[1]

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Researchers 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.[2]

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].

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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Disseminated L1210 Leukemia. [1]
Eight-week-old inbred female CD2F1 (BALB/c × DBA/2) were used for evaluation of the therapeutic efficacy of PNU-159682 , in comparison with that of Nemorubicin /MMDX. Disseminated neoplasia was induced by i.v. injection of 105 L1210 cells; 1 day later, the animals were randomly assigned to an experimental group (n = 10) and received a single i.v. injection of MMDX, PNU-159682 , or saline (control group). Treatment efficacy was evaluated by comparing the median survival time in the treated and control groups, and expressed as increase in life span as follows: % increase in life span = (100 × median survival time of drug treated mice / median survival time of control mice) − 100. Statistical comparison between the groups was made using the nonparametric Mann-Whitney test.

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Subcutaneous MX-1 Human Mammary Adenocarcinoma Xenografts. [1]
Four- to six-week-old female CD-1 athymic nude mice were used for evaluation of the activity of PNU-159682 against MX-1 human mammary carcinoma xenografts. On day 0, animals (n = 14) were grafted s.c. with MX-1 tumor fragments in the right flank. Eight days later, they were randomly assigned to the drug treatment group or control group (n = 7 mice per group), and treatment was started. PNU-159682 was given i.v. (4 μg/kg) according to a q7dx3 (every 7 days for three doses) schedule; control animals received saline injections. Tumor volume was estimated from measurements done with a caliper using the formula: tumor volume (mm3) = D × d2 / 2; where D and d are the longest and the shortest diameters, respectively. For ethical reasons, control animals were sacrificed on day 21 when the mean tumor volume in the group was ∼2,500 mm3; animals receiving drug treatment were monitored up to day 50, at which point they were sacrificed.

Objective: Nemorubicin (3'-deamino-3'-[2''(S)-methoxy-4''-morpholinyl]doxacin; MMDX) is an investigational drug currently undergoing phase II/III clinical trials for hepatocellular carcinoma. A bioactive derivative of MMDX, 3'-deamino-3'',4'-dehydrat-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxacin (PNU-159682), was recently discovered in the incubation medium of MMDX with NADPH-supplemented rat liver microsomes. This study aimed to obtain information on the biotransformation of MMDX into PNU-159682 in humans and to investigate the antitumor activity of PNU-159682. Experimental Design: This study used human liver microsomes (HLM) and genetically engineered cell lines expressing specific human cytochrome P450 (CYP) to investigate the biotransformation of MMDX. Furthermore, we investigated the cytotoxicity and antitumor activity of PNU-159682 using in vitro cultured human tumor cell lines and tumor-bearing mice, respectively. Results: HLM converted MMDX into a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of the synthesized PNU-159682. In HLM libraries from 10 donors, the rate of PNU-159682 production was significantly correlated with the activities mediated by three different CYP3A groups. CYP3A inhibitors traclomycin and ketoconazole significantly reduced PNU-159682 production in HLM; CYP3A4/5 monoclonal antibodies inhibited this reaction in a concentration-dependent manner. Of the 10 cDNA-expressed CYP enzymes tested, only CYP3A4 could generate PNU-159682. Furthermore, PNU-159682 exhibited stronger cytotoxicity than MMDX and doxorubicin in vitro and was effective in both of the in vivo tumor models tested (i.e., disseminated mouse L1210 leukemia and MX-1 human breast cancer xenograft). Conclusion: CYP3A4 is the major CYP enzyme in the human liver, which can convert MMDX into the more cytotoxic metabolite PNU-159682, which retains its antitumor activity in vivo. [5]

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We recently demonstrated that the investigational antitumor drug Nemorubicin (MMDX) can be converted into the active metabolite PNU-159682 by human hepatic cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate the metabolism of MMDX in the liver microsomes of experimental animals (male and female mice, rats, and dogs) to determine whether PNU-159682 was also produced in these species and to identify the CYP enzyme responsible for its production; (2) to compare the metabolism of MMDX in animal and human liver microsomes (HLM) to determine which animal species is most similar to humans; and (3) to investigate whether the differences in PNU-159682 production are the cause of previously reported species and sex differences in MMDX host toxicity. The metabolism of MMDX in animals is similar in nature to that in human liver microsomes (HLM) because, in all the species tested, MMDX is primarily converted to PNU-159682 by a single CYP3A enzyme. However, significant quantitative differences in kinetic parameters were observed between different species and within the same species. The V(max) and intrinsic metabolic clearance (CL(int)) values of mice and male rats were closest to those of humans, indicating that these species are the most suitable animal models for studying MMDX biotransformation. The CL(int) of MMDX was significantly negatively correlated with the previously reported LD(50) values of MMDX in the same species, sex, and strain, suggesting that the differences in MMDX toxicity in vivo are likely due to sex and species differences in the degree of PNU-159682 production. [6]

[1]. 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]. 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]. 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]. Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404.

[5]. 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.

[6]. 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.

[7]. 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.

[8]. 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 belongs to the morpholine class of compounds and is an anthracycline antibiotic. It is also a primary and tertiary α-hydroxy ketone. Functionally, it is related to doxorubicin. Nemorubicin is a morpholine analog of the anthracycline antibiotic doxorubicin and possesses antitumor activity. Nemorubicin is metabolized by the P450 CYP3A enzyme to a highly cytotoxic derivative. Unlike most anthracycline antibiotics, Nemorubicin is a topoisomerase I inhibitor, and its mechanism of action appears to be mediated through the nucleotide excision repair (NER) system. Furthermore, this drug does not exhibit cross-resistance with other anthracyclines. We recently demonstrated that the investigational antitumor drug nemorubicin (MMDX) can be converted into the active metabolite PNU-159682 via human hepatic cytochrome P450 (CYP) 3A4. This study aimed to: (1) investigate the metabolism of MMDX in liver microsomes of experimental animals (male and female mice, rats, and dogs) to determine whether PNU-159682 is also present in these species and to identify the CYP enzyme responsible for its generation; (2) compare the metabolism of MMDX in animal and human liver microsomes (HLM) to determine which animal species is most closely related to humans; and (3) explore whether the differences in PNU-159682 generation are the cause of previously reported species and sex differences in MMDX host toxicity. Animal metabolism of MMDX is similar in nature to that in human liver microsomes (HLM) because, in all tested species, MMDX is primarily converted to PNU-159682 by a single CYP3A enzyme. However, significant quantitative differences in kinetic parameters were observed between and within species. The V(max) and intrinsic metabolic clearance (CL(int)) values of mice and male rats were closest to those of humans, indicating that these species are the most suitable animal models for studying MMDX biotransformation. A strong negative correlation exists between the CL(int) of MMDX and the previously reported LD(50) values of MMDX in animals of the same species, sex, and strain, suggesting that the differences in in vivo toxicity of MMDX are likely due to sex and species differences in the degree of PNU-159682 production. Source: Biochem Pharmacol. 2008 Sep 15; 76(6):784-95.

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Antibody-drug conjugates (ADCs) are typically composed of humanized antibodies and small molecule drugs linked by chemical linkers. After decades of preclinical and clinical research, a range of ADCs have been widely used in the clinical treatment of specific types of tumors, such as brentuximab (Adcetris®) for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma, gemtuzumab (Mylotarg®) for the treatment of acute myeloid leukemia, ado-trastuzumab (Kadcyla®) and inotuzumab ozogamicin (Besponsa®) for the treatment of HER2-positive metastatic breast cancer, and recently polatuzumab vedotin-piiq (Polivy®) for the treatment of B-cell malignancies. To date, more than 80 antibody-drug conjugates (ADCs) are in different stages of clinical trials in approximately 600 clinical trials. This review summarizes the key elements of ADCs, highlighting the latest advances in ADCs, important lessons learned from clinical data, and future directions. [3]

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Background: EDV nanocells loaded with doxorubicin and microRNA16a showed good safety in a phase I clinical trial of relapsed glioma and mesothelioma. This study plans to conduct a safety analysis of an ongoing first-in-human, open-label phase I/IIa clinical trial in patients with refractory metastatic pancreatic cancer to evaluate the safety, biological, and clinical activity of EGFR-targeting EDV nanocells carrying the cytotoxic drug PNU-159682 (designed to overcome resistance) in combination with EDV nanocells carrying the immunomodulatory adjuvant α-galactosylceramide (designed to stimulate antitumor immune responses). Methods: Nine patients with advanced pancreatic cancer were enrolled in a dose-escalation phase to assess the safety of the EDV combination regimen. The dose was gradually escalated from 2 × 10⁹ EDV/dose to a maximum dose of 7 × 10⁹ EDV/dose at week 7, followed by administration at the maximum dose achieved in cycle 1. Tumor response was assessed using iRECIST criteria after each cycle, and blood samples were collected for cytokine and peripheral blood mononuclear cell (PBMC) analysis. Results: The EDV combination regimen was well tolerated, with no dose-limiting toxicities (DLTs) or drug-related serious adverse events (SAEs). A small number of patients experienced Grade 1 infusion responses, which resolved rapidly with supportive care. Of the 9 patients, 8 achieved partial remission (PR) or stable disease (SD) at 8 weeks (89% clinical benefit rate), and 4 of the 5 evaluable patients achieved confirmed remission at 4 months (80%), with 2 patients experiencing remission for more than 6 months. Exploratory analysis showed elevated IFN-α and IFN-γ levels in almost all evaluable patients (6/8). Furthermore, we observed elevated levels of CD8+ T cells (2/8), iNKT cells, dendritic cells, and NK cells (3/8), and decreased levels of exhausted CD8+ T cells (3/8), suggesting activation of both innate and adaptive immune responses. Conclusion: EDV, carrying cytotoxic drugs and immune adjuvants, is safe and well-tolerated. Early signals indicate durable efficacy, which may be related to the generation of innate and adaptive immune responses and cytotoxic effects on drug-resistant tumor cells. A Phase IIa study plans to recruit an additional 35 patients to further evaluate its safety and antitumor efficacy. Clinical trial information: ACTRN12619000385145. [4]

C32H37NO13

643.63508

643.226

C, 59.71; H, 5.79; N, 2.18; O, 32.32

108852-90-0

Nemorubicin;108852-90-0; 108943-08-4 (HCl)

65907

Red to pink solid powder

1.6±0.1 g/cm3

852.2±65.0 °C at 760 mmHg

469.2±34.3 °C

0.0±0.3 mmHg at 25°C

1.681

4.7

5

14

7

46

1160

7

COC1=C2C(C(C3=C(O)C(C[C@](C(CO)=O)(O)C[C@]4([H])O[C@H]5C[C@H](N6CCO[C@H](OC)C6)[C@H](O)[C@H](C)O5)=C4C(O)=C3C2=O)=O)=CC=C1

CTMCWCONSULRHO-UHQPFXKFSA-N

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

(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

Methoxymorpholinyldoxorubicin; PNU 152243; PNU-152243A; PNU152243A; PNU-152243A; PNU 152243A; Nemorubicin; Nemorubicin; 108852-90-0; Nemorubicin [INN]; Methoxymorpholino-doxorubicin; Methoxymorpholinyl doxorubicin; FCE-23762; Nemorubicin (GMP); 3'-DESAMINO-3'-(2-METHOXY-4-MORPHOLINYL)-DOXORUBICIN; methoxymorpholinyl-doxorubicin; 3′-deamino-3′-[2″(S)-methoxy-4″-morpholinyl]doxorubicin; MMDX

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~65 mg/mL (~101 mM)

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.

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