Amsacrin

AMSA · CI-880 · m-AMSA · C01553 · Amekrin · Amsidyl · Amsakrin · AMSIDINE

Identifikatoren & physikalische Daten

CAS No.	51264-14-3
Summenformel	C21H19N3O3S
Durchschnittliche Molmasse	393,5 g/mol
Monoisotopische Masse	393,11471247 g/mol
SMILES	COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
InChIKey	XCPGHVQEEXUHNC-UHFFFAOYSA-N
PubChem CID	2179
ChEMBL	CHEMBL43
ChEBI	CHEBI:2687
EC No.	257-094-3
DTXSID	DTXSID4022604
Lokaler Name	Amsacrin

Chemische & physikalische Eigenschaften

XLogP	4
Polarare Oberfläche (TPSA)	88,7
H-Brücken-Donoren	2
H-Brücken-Akzeptoren	6
Frei drehbare Bindungen	5
Schwere Atome	28
Formalladung	0
Komplexität	601
Arzneimittel	Pharmaceuticals -> Listed in ZINC15
LogP (Verteilungskoeffizient)	log Kow = 2.85 @ pH 7.43.8
Color/Form	Yellow crystalline powder
Löslichkeit	<1 mg/mLSlightly soluble in chloroform, ethanol, and methanol.Insoluble in water (less than 1.0 mg/ml)3.17e-03 g/LWater < 1.0 (mg/mL)pH 4 buffer < 1.0 (mg/mL)Soluble in DMSO
Decomposition	When heated to decomposition it emits very toxic fumes of /nitric oxides & sulfur oxides/
Schmelzpunkt	230-240 °C234 - 236 °C
Physical Description	Solid
Stability/Shelf Life	Three yr at ambient temp not exceeding 25 °C, protected from light.Amsacrine is relatively stable in an aq vehicle, provided reconstitution takes place in the presence of lactate ions, and pH remains acidic. It is stable for 48 hr after dilution in 5% glucose. ... Saline must be avoided as a diluent.Physical stability is not significantly affected by normal temp ranges. The drug is light-sensitive. After dilution in 5% glucose at a final concn of 150 ug/ml, amsacrine is stable during exposure to diffuse daylight or fluorescent light over a 48 hr period.Bulk: A sample stored at 60 °C for 30 days showed no decomposition (IR, TLC or UV). Solution: A sample was dissolved in methanol and diluted with water (1:33). No decomposition was detected by UV after standing 4 days at room temperature and exposed to light.
Collision Cross Section	193.1 Å² [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]191.71 Å² [M+H]+ [CCS Type: TW
Other Experimental Properties	Mol wt 429.93. Crystals, mp 197-199 °C /Hydrochloride/Mol wt 489.57. Crystals, mp 292-293 °C /Methanesulfonate/
Siedepunkt	563.0±60.0 °C(Predicted)
Dichte	1.2205 (rough estimate)
Brechungsindex	1.6740 (estimate)
Lagerbedingungen	2-8°C(protect from light)
Aggregatzustand	Powder
pKa (Säurekonstante)	8.55±0.10(Predicted)
Farbe	Orange to red
CAS Datenbank	51264-14-3

Sicherheit & Vorschriften

GHS-Einstufung	DangerH301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P261, P264, P270, P272, P280, P301+P316, P302+P352, P318, P321, P330, P333+P317, P362+P364, P405, and P501 (click each P-code to see the statement)The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.
Regulatorische Informationen	Hazard Traits - Carcinogenicity
Weitere Sicherheitsinformationen	IMAP assessments - Methanesulfonamide, N-(4-(9-acridinylamino)-3-methoxyphenyl)-: Human health tier I assessment
Hazard Classes and Categories	Acute Tox. 3 (100%)
Shipment Methods and Regulations	PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/
Hazardous Reactivities and Incompatibilities	/Amsacrine/... is incompatible with chloride or sulphate ions ... .
Lagerbedingungen	PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/
Reinigungsverfahren	PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/
Entsorgungsverfahren	PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/
Preventive Measures	PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/For more Preventive Measures (Complete) data for AMSACRINE (9 total), please visit the HSDB record page.
Personal Protective Equipment (PPE)	PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/
Wechselwirkungen	Leukopenic and/or thrombocytopenic effects of amsacrine may be increased with concurrent or recent therapy if these medications /blood dyscrasia-causing medications/ cause the same effectsdosage adjustment of amsacrine, if necessary, should be based on blood counts.Additive bone marrow depression, including severe dermatitis and/or mucositis, may occurdosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.
Expositionspfade	Poorly absorbed.
Toxizitätsübersicht	Amsacrine binds to DNA through intercalation and external binding. It has a base specificity for A-T pairs. Rapidly dividing cells are two to four times more sensitive to amsacrine than are resting cells. Amsacrine appears to cleave DNA by inducing double stranded breaks. Amsacrine also targets and inhibits topoisomerase II. Cytotoxicity is greatest during the S phase of the cell cycle when topoisomerase levels are at a maximum.
Signs and Symptoms	Symptoms of overdose include nausea and vomiting, diarrhea, some cardiotoxicity (rarely).
Ongoing Test Status	The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=51264-14-3]
Medical Surveillance	PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/
Human Toxicity Excerpts	/SPECIAL STUDIES/ It caused DNA double-strand breaks and DNA-protein cross-links ... in human cell lines at a concentration of about 1 umol/l. Amsacrine caused DNA breaks preferentially ... at a very specific site within the AML1 locus in several human cell lines./SPECIAL STUDIES/ Amsacrine caused chromosomal aberrations in ... HeLa cells and in cultured human peripheral blood lymphocytes. It also induced micronuclei in neonatal human lymphocytes. Fluorescence in-situ hybridization techniques revealed a high freqency of dicentrics and stable translocations in amsacrine-treated human peripheral blood lymphocytes. ... In one study, amsacrine caused chromosomal aberrations, but no sister chromatid exchange in blood lymphocytes of patients treated with this drug by intravenous infusion.
Carcinogen Classification	AmsacrineGroup 2B: Possibly carcinogenic to humansVolume 76: (2000) Some Antiviral and Antineoplastic Drugs, and Other Pharmaceutical Agents19992B, possibly carcinogenic to humans. (L135)
Drug Induced Liver Injury	Drug-Induced Liver Injury Severity and Toxicity (DILIst)amsacrineDILI PositiveIntravenousDOI:10.1016/j.drudis.2019.09.022
Non-Human Toxicity Excerpts	/LABORATORY ANIMALS: Acute Exposure/ Poison by ingestion, intravenous, subcutaneous, and intraperitoneal routes./LABORATORY ANIMALS: Acute Exposure/ Amsacrine, a DNA intercalator and topoisomerase II inhibitor, is efficacious as an antileukemogenic agent. This study was conducted to assess the subchronic toxicity of amsacrine in rats following a cyclic clinical dosing regimen and as a range-finding experiment for a subsequent carcinogenicity bioassay. Groups of 30 male Wistar rats were administered drug intravenously at doses of 0, 0.25, 1.0, and 3.0 mg/kg daily for 5 days followed by 23 days without treatment. This cycle of dosing and recovery was repeated six times to simulate human clinical usage of the drug. Assessments of hematology, clinical chemistry, and gross and microscopic pathology were conducted 3 and 21 days following completion of dosing in the first, third, and sixth cycles. There were no deaths during the study. Hair loss, diarrhea, tail injuries, chromodacryorrhea, and rhinorrhea were observed primarily in animals administered 3 mg/kg. Hair loss and diarrhea occurred during periods of dosing and generally resolved during the recovery phase of each cycle. Both of these signs became progressively more severe during the latter half of the study. Body weight loss and reduced food consumption also occurred in the 3 mg/kg group during each week of dosing. At study termination, mean body weight and food consumption of the 3 mg/kg group were significantly less than those of controls by approximately 20 and 50%, respectively. Marked, reversible leukopenia associated with reductions in both neutrophil and lymphocyte counts occurred in cycles one and three in animals administered 1 and 3 mg/kg, respectively. Reversible neutropenia was also observed in the 3 mg/kg group in cycle 6. Similar effects on platelet counts were seen in the 3 mg/kg group in all three cycles analyzed. Absolute and relative testes weights of the 3 mg/kg group were significantly less than the vehicle controls at all time points in the third and sixth cycles. Relative testes weights were also decreased in the 1 mg/kg group in cycle 6. Reversible decreases in absolute relative spleen weights occurred in all drug-treated groups in cycle 1 and for the 3 mg/kg group in cycle 3. Lymphoid depletion (spleen, thymus, lymph node), marked hypocellularity of bone marrow, segmental degeneration of seminiferous tubules, and intestinal epithelial cell degeneration were observed at 3 mg/kg. With the exception of testicular changes which remained evident at the end of cycle 6, pathologic lesions were reversible during the 23-day recovery period of each cycle. The results show that the subchronic toxicity of amsacrine is consistent with a cytotoxic mechanism and that target organs are generally tissues with the highest rates of cell turnover. The doses administered in this study induced a range of effects which were minimal at 0.25 mg/kg and dose-limiting at 3 mg/kg and therefore were considered appropriate for use in the subsequent carcinogenicity bioassay./LABORATORY ANIMALS: Acute Exposure/ In dogs given single doses, the toxic effects at the highest non-lethal dose (3.1 mg/kg body weight) were leukopenia, anemia and increased serum activity of liver enzymes. Controls receiving 100 mg/ml N,N-dimethylacetamide and 2.8 mg/ml L-lactic acid (pH 3.2) also showed signs of liver toxicity. Similar toxic effects were seen at the highest non-lethal regimes of five daily doses of 0.39 mg/kg body weight in dogs and five daily doses of 5.2 mg/kg body weight in rhesus monkeys./LABORATORY ANIMALS: Acute Exposure/ Toxic effects on the gastrointestinal and central nervous system were observed at lethal doses in dogs (6.25 mg/kg body weight as a single dose, 0.78 mg/kg with five daily doses), but no cardiac toxic effects were reported in any species. In subsequent studies, evidence of cardiotoxicity was not seen in rats, but cardiac rhythm abnormalities and ectopic pulses were seen in rabbits at doses of 2.5-7.5 mg/kg body weight and in an isolated rabbit heart preparation, in which dose-related negative ionotropic effects were seen at therapeutically relevant concentrations.For more Non-Human Toxicity Excerpts (Complete) data for AMSACRINE (22 total), please visit the HSDB record page.
Evidence for Carcinogenicity	Evaluation: There is inadequate evidence in humans for the carcinogenicity of amsacrine. There is sufficient evidence in experimental animals for the carcinogenicity of amsacrine. Overall evaluation: Amsacrine is possibly carcinogenic to humans (Group 2B).
Antidote and Emergency Treatment	Contact with skin: wash with soap and water./SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B//SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/
UN-Transportnummer	3249
Toxizität	LD50 in male, female CDF1 mice: 810 mg/m2729 mg/m2 orally (Pavkov)
Gefahrenklasse	6.1(b)
Verpackungsgruppe	III
Gefahrstoffdaten	51264-14-3(Hazardous Substances Data)

Anwendungen & Verwendung

Beschreibung

Amsacrine is a cytostatic reported to be active against adult lymphoblastic leukemia which has failed primary treatment or become resistant. Its clinical use, however, is associated with significant neuro-, gastro- and hepatotoxicity.

Verwenden

Amsacrine (Amsidyl) is used as an Investigational drug.