Amonafide

DNA intercalator,Topo II inhibitor CAS# 69408-81-7

Amonafide

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Chemical structure

Amonafide

3D structure

Chemical Properties of Amonafide

Cas No. 69408-81-7 SDF Download SDF
PubChem ID 50515 Appearance Powder
Formula C16H17N3O2 M.Wt 283.33
Type of Compound N/A Storage Desiccate at -20°C
Synonyms AS1413
Solubility DMSO : 75 mg/mL (264.71 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione
SMILES CN(C)CCN1C(=O)C2=CC=CC3=CC(=CC(=C32)C1=O)N
Standard InChIKey UPALIKSFLSVKIS-UHFFFAOYSA-N
Standard InChI InChI=1S/C16H17N3O2/c1-18(2)6-7-19-15(20)12-5-3-4-10-8-11(17)9-13(14(10)12)16(19)21/h3-5,8-9H,6-7,17H2,1-2H3
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 Amonafide

DescriptionAmonafide is a topoisomerase II inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA.In Vitro:Amonafide is a topoisomerase II inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA[1]. Amonafide produces protein-associated DNA cleavage, single-strand breaks (SSB) and DPC and DNA double-strand cleavage. Amonafide (Nafidimide, 400 nM-2.4 μM) reduces the colony-forming ability of the leukemic cell lines in a dose-dependent manner[2]. Amonafide (0.05-0.4 μg/mL) reduces several tumor growth. However, Amonafide is active against only 12% of tumors compared with standard agents (5-fluorouracil, mitomycin C, cisplatin, and etoposide), which are active against more than 40% of tumors in the human bone marrow inhibitory range[3]. Amonafide inhibits the growth of HT-29, HeLa, and PC-3 cell lines, with IC50s of 4.67, 2.73, and 6.38 μM[4].

References:
[1]. Allen SL, et al. Amonafide: a potential role in treating acute myeloid leukemia. Expert Opin Investig Drugs. 2011 Jul;20(7):995-1003. [2]. Andersson BS, et al. In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia. Cancer Res. 1987 Feb 15;47(4):1040-4. [3]. Ajani JA, et al. In vitro activity of amonafide against primary human tumors compared with the activity of standard agents. Invest New Drugs. 1988 Jun;6(2):79-85.

Protocol

Cell Assay [2]
In experiments measuring survival following 1 h drug treatments, 2 × 106cells are resuspended in 2 mL warm (37°C) HBSS with 5% PCS; the appropriate drug (Amonafide) level is attained with the addition of less than 50 μL. Cells are incubated for 60 min at 37°C after which 10 mL ice cold PBS is added. The cells are then centrifuged at 200 × g for 10 min at 4°C. The wash is repeated once and the cells are resuspended in HBSS with 5% PCS and added to the agar-medium mixture for assessment of surviving clonogenic cells[2].

References:
[1]. Allen SL, et al. Amonafide: a potential role in treating acute myeloid leukemia. Expert Opin Investig Drugs. 2011 Jul;20(7):995-1003. [2]. Andersson BS, et al. In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia. Cancer Res. 1987 Feb 15;47(4):1040-4. [3]. Ajani JA, et al. In vitro activity of amonafide against primary human tumors compared with the activity of standard agents. Invest New Drugs. 1988 Jun;6(2):79-85.

Amonafide Dilution Calculator

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Amonafide Molarity Calculator

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Preparing Stock Solutions of Amonafide

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.5295 mL 17.6473 mL 35.2945 mL 70.5891 mL 88.2363 mL
5 mM 0.7059 mL 3.5295 mL 7.0589 mL 14.1178 mL 17.6473 mL
10 mM 0.3529 mL 1.7647 mL 3.5295 mL 7.0589 mL 8.8236 mL
50 mM 0.0706 mL 0.3529 mL 0.7059 mL 1.4118 mL 1.7647 mL
100 mM 0.0353 mL 0.1765 mL 0.3529 mL 0.7059 mL 0.8824 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 Amonafide

IC50: 4.67, 2.73, and 6.38 for HT-29, HeLa, and PC3 cells, respectively

Amonafide is a novel topoisomerase II inhibitor. Topoisomerase II plays critical roles including DNA transcription, replication and chromosome segregation. Though the biological functions of topoisomerase II are important for insuring genomic integrity, the ability to interfere with topoisomerase II and generate enzyme mediated DNA damage is an effective strategy for cancer chemotherapy.

In vitro: Amonafide intercalated with DNA and disrupted the loading of topoisomerases. In contrast to the classic agents, amonafide was found to induce higher molecular weight fragmentation, resulting in the apoptosis without DNA cleavage. Amonafide was found to act in an ATP-independent manner and seemed unlikely to induce the chromosome translocations associated with treatmentinduced leukemia [1].

In vivo: Amonafide was found to be able to inhibit IP L1210 leukemia, with optimal increased life spans (ILS) of 61% to 106% following single 16 mg/kg dosing on days 1 to 9. Similar efficacy was noted against IP P388 murine leukemia and the SC implanted L1210 leukemia. Additionally, amonafide demonstrated activity against two nonleukemic IP implanted murine tumors, the M5076 sarcoma and the B16 melanoma [2].

Clinical trial: A multicenter, open-label, combination Phase II study was conducted for patients with sAML, evaluating the efficacy of cytarabine and amonafide administered as a continuous iv. Infusion of cytarabine on days 1-7 combined with 600 mg/m2/day for days 1-5[1].

References:
[1] Freeman CL,Swords R,Giles FJ.  Amonafide: a future in treatment of resistant and secondary acute myeloid leukemia Expert Rev Hematol.2012 Feb;5(1):17-26.
[2] Saez R,Craig JB,Kuhn JG,Weiss GR,Koeller J,Phillips J,Havlin K,Harman G,Hardy J,Melink TJ, et al.  Phase I clinical investigation of amonafide. J Clin Oncol.1989 Sep;7(9):1351-8.

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References on Amonafide

Induction of apoptosis and suppression of ERCC1 expression by the potent amonafide analogue 8-c in human colorectal carcinoma cells.[Pubmed:23426174]

Anticancer Drugs. 2013 Apr;24(4):355-65.

Previous studies have reported that 8-c [6-(2-(2-(dimethylamino)ethylamino)ethylamino)-2-octyl-1H-benzo[de]isoquinoline-1 ,3(2H)-dione], a novel Amonafide analogue, was generated as a new anticancer candidate. However, little is known about its activity in chemoresistant cells. In this study, the antitumor effects of 8-c on the multi-drug-resistant human colorectal carcinoma cancer cell lines HCT-116/L-OHP and HCT-8/VCR have been investigated for the first time. 8-c showed similar concentration-dependent inhibitory activities against multi-drug-resistant cells and corresponding parental cell lines by the MTT assay after 48 h of treatment. 8-c treatment resulted in the induction of apoptosis, as evidenced by fluorescent staining analysis, comet assay data, and the increase in the number of apoptotic cells as detected by flow cytometry. Western blot, qPCR, and siRNA techniques were used to elucidate the molecular mechanism. Our study suggested that the apoptotic effect of 8-c can be attributed to the upregulation of p53, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) and the downregulation of Bcl-2. Furthermore, ERCC1 is essential for nucleotide excision repair. ERCC1 expression was correlated with sensitivity to chemotherapy in various colon cancer cell lines. It is intriguing that decreases in ERCC1 protein and mRNA levels were also observed in the HCT-116/L-OHP and HCT-8/VCR cells after exposure to 8-c. Further transient transfection of multi-drug-resistant cells with ERCC1 siRNA enhanced 8-c-induced cytotoxicity. In contrast, epidermal growth factor-induced increase in ERCC1 protein levels was shown to rescue cell viability upon 8-c treatment. These findings suggest that 8-c has a strong potential to be developed as a new antitumor agent for the treatment of multi-drug-resistant colon cancer cells, and is worthy of further studies.

Phase III open-label randomized study of cytarabine in combination with amonafide L-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia.[Pubmed:25732165]

J Clin Oncol. 2015 Apr 10;33(11):1252-7.

PURPOSE: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and Amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. PATIENTS AND METHODS: Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m(2) continuous intravenous (IV) infusion once per day on days 1 to 7 plus either Amonafide 600 mg/m(2) IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m(2) IV over 30 minutes once per day on days 1 to 3 (D + C arm). RESULTS: The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively. CONCLUSION: Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.

Synthesis and evaluation of novel amonafide-polyamine conjugates as anticancer agents.[Pubmed:27762101]

Chem Biol Drug Des. 2017 May;89(5):670-680.

With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of Amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing, and the protein expression of cyclic D1 and MMP9. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side-effects compared to that of Amonafide.

Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues.[Pubmed:26001344]

Bioorg Med Chem. 2015 Jul 1;23(13):3135-46.

A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9muM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58muM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73muM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19muM range.

Description

Amonafide is a topoisomerase II inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA.

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