25316-40-9

Basic information

• Product Name: Doxorubicin hydrochloride
• Synonyms: ADRIACIN;ADRIBLASTINA;ADRIBLASTINA HYDROCHLORIDE;ADRIAMYCIN HCL;ADRIAMYCIN HYDROCHLORIDE;(8s-cis)-10-[(3-amino-2,3,6-trideoxy-alpha-l-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxynaphthacene-5,12-dione hydrochloride;14-HYDROXYDAUNOMYCIN HCL;14-HYDROXYDAUNOMYCIN HYDROCHLORIDE
• CAS NO: 25316-40-9
• Molecular Formula: C₂₇H₃₀NO₁₁*Cl
• Molecular Weight: 579.98
• EINECS: 246-818-3
• Product Categories: APIs;Active Pharmaceutical Ingredients;API;Intermediates & Fine Chemicals;Pharmaceuticals;Antitumour;Adriamycin;inhibitor;Anti-cancer&immunity;Inhibitors
• Mol File: 25316-40-9.mol
• Article Data: 13

Chemical Properties

• Melting Point: 216 °C (dec.)(lit.)
• Boiling Point: 810.3 °C at 760 mmHg
• Flash Point: 443.8 °C
• Appearance: orange to dark red/
• Vapor Pressure: 9.64E-28mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: H2O: 10 mg/mL, clear, red-orange
• PKA: pKa 8.25±0.60 (Uncertain);8.43±0.70 (Uncertain);11.9±0.4 (Uncertain);12.95±0.1 (Uncertain);13.8±0.70 (Uncertain)
• Water Solubility: Soluble in water.
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20° for up to 3 months.
• Merck: 14,3439
• BRN: 4229251
• CAS DataBase Reference: Doxorubicin hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Doxorubicin hydrochloride(25316-40-9)
• EPA Substance Registry System: Doxorubicin hydrochloride(25316-40-9)

Safety Data

• Hazard Codes: T,T+,Xi
• Statements: 45-22-40-26/27/28-36/38
• Safety Statements: 53-45-36/37/39-22-7/9
• WGK Germany: 3
• RTECS: QI9295900
• F: 10-21
• Hazardous Substances Data: 25316-40-9(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
Doxorubicin hydrochloride is used as an antitumor agent for its broad spectrum of activity against various cancers, including leukemias, soft and bone tissue sarcomas, Wilms tumor, neuroblastoma, small cell lung cancer, and ovarian and testicular cancer. It inhibits DNA topoisomerase II by inducing double-stranded DNA breaks and acts as a substrate for MDR1, making it a potent chemotherapeutic agent.
Used in Pharmaceutical Industry:
Doxorubicin hydrochloride is used as a strong fluorescent dye intercalating into DNA for its applications in research and development of new drugs and therapies. Its physicochemical properties and chromatographic behavior are important considerations in the formulation and development of pharmaceutical products.
Used in Research Applications:
Doxorubicin hydrochloride is used as an inhibitor of reverse transcriptase and RNA polymerase, making it a valuable tool in molecular biology research. Its effects on heart mitochondrial DNA also provide insights into the mechanisms of action and potential side effects of this drug.
Used in Drug Delivery Systems:
Doxorubicin hydrochloride is used in the development of novel drug delivery systems, such as liposomal preparations, to improve its delivery, bioavailability, and therapeutic outcomes. These systems aim to enhance the efficacy of doxorubicin hydrochloride while minimizing its toxic effects.
Used in Antibacterial Applications:
Doxorubicin hydrochloride is used as an antibacterial agent, demonstrating its broad-spectrum activity against various bacterial strains. Its DNA intercalating properties contribute to its effectiveness in this application.

Indications

Doxorubicin is a potent antitumour agent active against a wide spectrum of malignancies, including leukaemias, sarcomas, breast cancer, small cell lung cancer and ovarian cancer. Doxorubicin is used to produce regression in disseminated neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer. Doxorubicin does not playa crucial role in the treatment of tumours that can be cured with chemotherapy, such as testicular carcinoma, nephroblastoma, Burkitt's tumour and choriocarcinoma[3]. Like most other cytostatic agents, doxorubicin is not effective in the most frequently occurring malignancies such as colorectal cancer and non-small cell lung cancer.

Mechanism of action

Doxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action, however, remaining not fully understood: Data pointing to the role of free radicals, and to damage of mitochondria and membranes, have modified the original hypothesis that DNA-intercalation was the sole cytotoxic mechanism. Meanwhile, the focus on plasma pharmacokinetics has been shifted towards pharmacodynamic studies, with emphasis on cellular doxorubicin concentrations in haematopoietic tissues[4], in solid tumours[5], and in cell constituents. Doxorubicin forms complexes with DNA by intercalation between base pairs. In addition, doxorubicin-iron complexes bind tightly to DNA[6]. However, contrary to intercalated doxorubicin, the doxorubicin-iron complex preserves its ability to catalyze the formation of oxygen free radicals in the presence of double-stranded DNA[6]. Thus, the doxorubicin-iron complex-driven hydroxyl radical formation can proceed in close proximity to DNA and has therefore the potential to damage DNA efficiently, especially since DNA seems to catalyze hydroxyl radical formation by this complex[7]. Hydroxyl radicals are probably involved in damaging of DNA since the generation of hydroxyl radicals by the Dox-iron complex correlates with its ability to cleave DNA[7] and also since catalase, iron chelates and hydroxyl radical scavengers are protective in this system[6]. Relatively high concentrations of hydroxyl radical scavengers were required for protection, indicating that these radicals were indeed generated in a site-specific way. Moreover, it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Topoisomerase II causes transient double-strand breaks during the twisting of 2 double-stranded DNA helices. Singleand double-stranded DNA breaks have been documented after in vivo and in vitro treatment with doxorubicin of P388 leukaemia cells in mice[8]. Special reference must be made to observations that interference with the cell membrane alone may lead to cell death [9]. Doxorubicin binding to membranes, and particularly its covalent binding to cardiolipin, a phospholipid with 2 negatively charged phosphate head groups, has received much attention[10]. Cardiolipin is found in the inner leaflet of the mitochondrial membrane and is closely associated with electron transport mechanisms. Goormaghtigh et al. (1983) [10] have shown that doxorubicin bound to cardiolipin undergoes redox cycling, producing covalent binding of doxorubicin to cardiolipin in mitochondrial membranes. The hydrophobic nature of the chromophore of anthracyclines allows partitioning into the lipid phase, resulting in changed fluidity of the membrane. Diminished membrane fluidity is related to doxorubicin resistance. A detailed study of the mechanisms involved in doxorubicin-induced changes in membrane structure and function has not been undertaken. However, doxorubicin binds to the epidermal growth factor receptor at clinically relevant drug concentrations, and alters its function.

Mechanism of action

Liposomes are taken up selectively into tumor cells, presumably because of their persistence in the bloodstream and enhanced permeability of tumor vascular membranes. In liposomal form, the drug is protected against enzymes that generate cardiotoxic free radicals, although this form of the drug can still induce potentially fatal congestive heart failure. Clinical experience with the liposomal formulation is limited, and few studies comparing the long-term toxicity with that of conventional doxorubicin therapy have been conducted. Therefore, all precautions outlined for the use of doxorubin also are employed when the liposomal formulation is used.

Administration and formulation

Doxorubicin is available as a dry powder; reconstituted in water, it is most stable at a mildly acidic pH of 4, and unstable at a very acidic or basic pH[11]. When diluted in 0.9% sodium chloride or dextrose 5%, less than 5% decomposition occurred over 7 to 30 days[12]. It is stable in light at room temperature for at least 24 hours [12], although stability may be shorter in plasma and culture media[11]. Doxorubicin has been administered intravenously, intra-arterially, intraperitoneally, intrapleurally and intravesically. A bioavailability of 5% prohibits oral administration[13]. Subcutaneous, intramuscular and intrathecal application cannot be used, as severe tissue necrosis results, as in extravasation.

Pharmacokinetics

Absorption An intravenous bolus injection of doxorubicin produces high plasma concentrations, which fall quickly due to rapid and extensive distribution into tissues. 50 to 85% of plasma doxorubicin is bound to protein[13], independent of the absolute drug concentration in plasma, leaving 15 to 50% of the total doxorubicin and doxorubicinol as free drug. After repeated injections no accumulation in plasma occurs. Apparent volumes of distribution are in the range of 20 to 30 L/kg (1400 to 3000L)[14]. Doxorubicin does not cross the blood-brain barrier and is therefore inactive against tumours in the central nervous system[15]. Some transplacental passage has been observed, although healthy children have been born after pregnancies during which doxorubicin was administered from the first to the third trimester[16]. Negligible doxorubicin concentrations have been found in breast milk. Salivary doxorubicin concentrations are 6 to 26% of plasma concentrations during the first 75 minutes after administration[17]. Metabolism Doxorubicin is rapidly metabolized into the hydrophilic 13-hydoxy1 metabolite, doxorubicinol, and the poorly water-soluble aglycones, doxorubicinone and 7-deoxydoxorubicinone. Like doxorubicin, doxorubicinol is cytotoxic, but doxorubicinone is not[18]. Metabolism to doxorubicino1 occurs by cytoplasmatic NADPH-dependent aldoketoreductases, present in all cells, but particularly in red cells, and liver and kidney cells[18]. The non-cytotoxic aglycones are formed by an NADPH-dependent, cytochrome reductase-mediated cleavage of the amino sugar moiety in microsomes. This enzymatic reduction of doxorubicin is of paramount importance, as it finally produces the OH?-radicals, which cause extensive cell damage and cell death[19]. Elimination Doxorubicin and its catabolites are primarily excreted in the bile[20]. Over 50% is eliminated during the first transit through the liver. Cumulative faecal excretion over 7 days has been estimated at 25 to 45%[21]; no evidence for enterohepatic recirculation has been observed. Although patients often notice a reddish coloration of the urine during the first hours to days after doxorubicin administration, only 0.7 to 23% (on average, approximately 5%) of a dose has been recovered in the urine[20, 21], of which approximately two-thirds is unaltered drug. Nevertheless, doxorubicin-induced nephrotoxicity has been noted only in mice, rats, rabbits and dogs, and not in humans. The reason for this interspecies difference has not been explained, although stimulated lipid peroxidation may play a role[22]. The doxorubicin plasma concentration-time curve can be best described by a biexponentia1 model, which is characterized by a distribution half-life of less than 5 to 10 minutes, and a terminal phase elimination half-life of 30 ± 8 hours[14]. A triphasic curve with half-lives of 12 ± 8 minutes, 3.3 ± 2.2 hours and 30 ± 14 hours has also been proposed[23].

Side effects

Doxorubicin is a carcinogenic and mutagenic substance. Phlebitis is frequently observed after long-term intravenous infusion[24]. Paravasal leakage causes severe necrosis of skin and adjacent tissues, the extent of which depends on the degree of extravasation[25]. An appropriate antidote is not available. A number of agents injected locally may even worsen the necrosis; however, ice packs and 48 hours' rest may be beneficial[25]. Acute doxorubicin toxicity consists of gastrointestinal complaints and cardiac arrhythmias. Nausea and vomiting occur within 4 to 8 hours of doxorubicin administration and can only be partially controlled by antiemetic drugs. Arrhythmias and electrocardiographic changes are transient. Anaphylactoid and hypersensitivity reactions ('flare') may occur during injection, thus mimicking extravasation, but discontinuation of therapy is not necessary[26]. In long term, infusion the occurrence of acute side effects is almost completely abolished. Repeated administrations of doxorubicin bolus injections, and the resultant high doxorubicin plasma concentrations, have been associated with an increased risk of acute and late-onset cardiotoxicity. Delayed toxicity consists mainly of myelosuppression, alopecia and cardiomyopathy. At approximately 16 days after a single dose of doxorubicin the white blood cell and platelet counts reach their lowest point. Myelosuppression and alopecia are dose related, but independent of the mode of administration (i.e. peak plasma concentration). The onset of myelosuppression occurs after 7 to 10 days, and recovery at 19 to 24 days after doxorubicin administration. This side effect, although reversible, is dose limiting. Hair loss starts approximately 3 weeks after the first administration of doxorubicin; however, hair growth resumes a few weeks after the last therapy[26]. Local application of ice-packs to prevent hair loss have been of limited value. Mucositis and/or diarrhoea are noticed especially during long-term infusion regimens[24].

Overdosage

Acute overdosage with doxorubicin enhances the toxic effect of mucositis, leukopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antimicrobials, platelet transfusions, and symptomatic treatment of mucositis. Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered. The 150 mg doxorubicin hydrochloride for injection and the 75 mL and 100 mL (2 mg/mL) doxorubicin hydrochloride injection vials are packaged as multiple dose vials and caution should be exercised to prevent inadvertent overdosage. Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and resultant congestive heart failure (see WARNINGS). Treatment consists of vigorous management of congestive heart failure with digitalis preparations, diuretics, and after-load reducers such as ACE inhibitors.

References

Arcamone F, et al 1998. Pharmacol Ther 76: 117–124. Grein A. 1987. Adv Appl Microbiol 32: 203–214 Zubrod CG. Historic milestones in curative chemotherapy. Seminars in Oncology 6: 490-505, 1979 Speth PAJ, et al Clinical Pharmacology and Therapeutics 41: 661-665, 1987 Cummings J, et al Cancer Chemotherapy and Pharmacology 17: 80-84, 1986 ELIOT, H., et al (1984) Biochemistry 23: 928-936. MUINDI, J. R. F., et al FEBS Lett. 172: 226-230. Russo P, et al Anticancer Research 6: 1297-1304, 1986 Tritton TR, et al Science 217: 248-250, 1982 Goormaghtigh E, et al Biochemical Pharmacology 32: 889-893, 1983 Bouma J, et al Pharmaceutisch Weekblad, Scientific Edition 8: 109-133, 1986 Benvenuto JA, et al Cancer chemotherapy by infusion, pp. 100-113, Precept Press, Chicago, 1987 Harris PA, et al Cancer Chemotherapy Reports 59: 819-825, 1975 Greene RF, et al Cancer Research 43: 3417-3421, 1983 Mooney C, et al European Journal of Cancer and Oinical Oncology 19: 1037-1038, 1983 Fassas A, et al Nouvelle Revue Fran~ise Hematologique 26: 19-24, 1984 Celio LA, et al European Journal of Clinical Pharmacology 24: 261-266, 1983 Bachur NR, et al Journal of Medicinal Chemistry 19: 651-654, 1976 Myers CE, et al In Lawn (Ed.) Anthracyclines in press, 1988 Takanashi S, et al Drug Metabolism and Disposition 4: 79-87, 1976 DiFronzo G, et al Biomedicine 19: 169-171, 1973 Mimnaugh EG, et al Biochemical Pharmacology 35: 4327-4335, 1986 Benjamin RS, et al Cancer Research 37: 1416-1420, 1977 Legha SS, Hortobagyi GN, benjamin RS. Anthracyclines. In Lokich JJ (Ed) Cancer chemotherapy by infusion, pp. 100-113, Precept Press, Chicago, 1987 Rudolph R, Journal of Clinical Oncology 5: 1116-1126, 1987 Maral RJ, et al Cancer Treatment Reports 65 (Suppl. 4): 9-18, 1981

References

1) Zeman et al. (1998), Characterization of covalent adriamycin-DNA adducts; Proc. Natl. Acad. Sci., 95 11561 2) Katoh et al. (1998), Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor; Cancer Res., 58 5565 3) Perez et al. (2011), Anti-MDR-1 siRNA restores chemosensitivity in chemoresistant breast carcinoma and osteosarcoma cell lines; Anticancer Res., 31 2813

Therapeutic Function

Cancer chemotherapy

Biological Functions

The C13 substituent of doxorubicin is hydroxymethyl, which retards the action of cytosolic aldoketoreductase and slows the conversion to the equally active, but chronically cardiotoxic, doxorubicinol.

Air & Water Reactions

Water soluble.

Reactivity Profile

Amines, like Doxorubicin hydrochloride, are weak chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

Fire Hazard

Doxorubicin hydrochloride is probably combustible.

Biological Activity

Antitumor antibiotic agent that inhibits DNA topoisomerase II. DNA intercalator that inhibits nucleic acid synthesis and induces apoptosis.

Biochem/physiol Actions

Naturally fluorescent anthracycline antibiotic, anticancer drug. Doxorubicin is a substrate of MRP1 which was first cloned from a DOX-resistant lung cancer cell line. Fluorescent property has been exploited for the measurement of drug efflux pump activities as well as resolving the important question of intracellular localization of various multidrug resistance proteins and the role of subcellular organelles (Golgi and lysosome) in the sequestration of drugs and its implication in drug resistant phenotypes.

Clinical Use

Doxorubicin is utilized either alone or in combination therapy to treat a wide range of neoplastic disorders, including hematologic cancers and solid tumors in breast, ovary, stomach, bladder, and thyroid gland. A liposomal formulation of doxorubicin is used in the treatment of AIDS-related Kaposi's sarcoma and organoplatinum-resistant ovarian cancer.

Veterinary Drugs and Treatments

Doxorubicin is perhaps the most widely used antineoplastic agent at present in small animal medicine. It may be useful in the treatment of a variety of lymphomas, carcinomas, leukemias, and sarcomas in both the dog and cat, either alone or in combination protocols. Refer to the Dosage references or the Protocols found in the appendix for more information.

Drug interactions

Potentially hazardous interactions with other drugsAntipsychotics: avoid with clozapine, increased risk of agranulocytosis.Ciclosporin: increased risk of neurotoxicityCytotoxics: possible increased risk of cardiotoxicity with trastuzumab - avoid for 28 weeks after stopping trastuzumab.Avoid with live vaccines.

Metabolism

This contributes to the longer duration of action compared to analogues that have CH3 at this position (e.g., daunorubicin). Doxorubicin is highly lipophilic and concentrates in the liver, lymph nodes, muscle, bone marrow, fat, and skin. Elimination is triphasic, and the drug has a terminal half-life of 30 to 40 hours. The majority of an administered dose is excreted in the feces.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

InChI:InChI=1/C27H29NO11.ClH/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34;/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3;1H/t10-,13-,15-,17-,22+,27-;/m0./s1

Synthetic route

14-bromodaunorubicin hydrochloride (29742-67-4) → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
In water; dimethyl sulfoxide at 80℃; for 2h;	64%

C61H69N7O18*5.7HCl → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With human protease plasmin In various solvent(s) at 37℃; pH=7.3; Product distribution; Enzymatic reaction;

C63H70N8O18*7.5HCl → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With human protease plasmin In various solvent(s) at 37℃; pH=7.3; Product distribution; Enzymatic reaction;

C69H76N8O20*6.5HCl → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With human protease plasmin In various solvent(s) at 37℃; pH=7.3; Product distribution; Enzymatic reaction;

daunomycin hydrochloride (23541-50-6) → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 54 percent / bromine / methanol; dioxane; CHCl3 / 144 h / 0 - 5 °C 2: 64 percent / dimethylsulfoxide; H2O / 2 h / 80 °C View Scheme

doxorubicin hydrochloride → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
Purification / work up;

doxorubicin → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With 3,6-dimethyl-1,2,4,5-tetrazine In acetonitrile Reagent/catalyst;
With 3,6-dimethyl-1,2,4,5-tetrazine In acetonitrile Reagent/catalyst;

N-((R)-1-((R)-2-(((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide → N-(pyridin-4-carbonyl)-D-Ala-L-Proline + doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With fibroblast activating protein In water Kinetics; Reagent/catalyst; Enzymatic reaction;

C44H42F2N4O14 → C17H15F2N3O4 + doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With fibroblast activating protein In water Enzymatic reaction;

C47H55N5O20S2 → C21H30N4O10S3 + doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
Stage #1: C47H55N5O20S2 With triethyl ammonium acetate; triethylamine In aq. buffer at 20℃; for 2h; pH=9.5 - 9.9; Darkness; Stage #2: With acetic acid In aq. buffer pH=8.2; Darkness; Stage #3: In aq. buffer pH=6-7; Darkness;

C63H88BNO17S2 → doxorubicin hydrochloride (25316-40-9)

Conditions	Yield
With dihydrogen peroxide for 48h;

doxorubicin hydrochloride (25316-40-9) → doxorubicin (23214-92-8)

Conditions	Yield
With triethylamine In chloroform at 25℃; for 24h; Darkness;	100%
With 4 Å molecular sieves Aqueous carbonate buffer;	73%
With triethylamine In dimethyl sulfoxide for 1h;

naphthalene-2-sulfonate (120-18-3) + doxorubicin hydrochloride (25316-40-9) → doxorubicin naphthalene-2-sulfonate (1246449-86-4)

Conditions	Yield
Stage #1: doxorubicin hydrochloride With potassium tert-butylate In tetrahydrofuran at 20.2 - 21.4℃; for 1.41667h; Inert atmosphere; Stage #2: naphthalene-2-sulfonate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	100%

Fmoc-Phe-Lys(MMT)-PABC-PNP + doxorubicin hydrochloride (25316-40-9) → Fmoc-Phe-Lys(MMT)-PABC-Dox (847871-55-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃;	99.6%

N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide (82911-69-1) + doxorubicin hydrochloride (25316-40-9) → N-Fmoc doxorubicin

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; Darkness;	99%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	80%
With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h;	80%

carbonic acid 4-(2,5-dioxo-3,4-bis-phenylsulfanyl-2,5-dihydro-pyrrol-1-yl)-benzyl ester 4-nitro-phenyl ester (1451073-54-3) + doxorubicin hydrochloride (25316-40-9) → {3-hydroxy-2-methyl-6-[3,5,12-trihydroxy-3-(2-hydroxy-acetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacen-1-yloxy]-tetrahydro-pyran-4-yl}-carbamic acid 4-(2,5-dioxo-3,4-bis-phenylsulfanyl-2,5-dihydro-pyrrol-1-yl)-benzyl ester (1451073-56-5)

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 72h;	99%
With triethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 72h; Darkness;	99%

doxorubicin hydrochloride (25316-40-9) + biotinamidocaproate N-hydroxysuccinimide ester (89889-52-1) → C43H54N4O14S (1401539-59-0)

Conditions	Yield
With pyridine; dmap at 20℃; for 16h;	98%

doxorubicin hydrochloride (25316-40-9) + trifluoroacetic acid (76-05-1) + adipic acid dihydrazide (1071-93-8) → C33H41N5O12*2C2HF3O2

Conditions	Yield
In methanol at 20℃; for 5h;	97%

doxorubicin hydrochloride (25316-40-9) + toluene-4-sulfonic acid (104-15-4) → doxorubicin tosylate

Conditions	Yield
Stage #1: doxorubicin hydrochloride With potassium tert-butylate In tetrahydrofuran at 19 - 22.4℃; for 1.91667h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 0.5h;	97%

C47H51N7O11S2 + doxorubicin hydrochloride (25316-40-9) → C68H75N7O19S2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; under 760.051 Torr; for 16h; Inert atmosphere;	97%

4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid N-succinimidyl ester (64987-85-5) + doxorubicin hydrochloride (25316-40-9) → doxorubicin-succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (400647-59-8)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	96%
With triethylamine In N,N-dimethyl-formamide at 20℃;
With triethylamine In N,N-dimethyl-formamide
With triethylamine In N,N-dimethyl-formamide at 20℃; pH=Ca. 8; Darkness;

doxorubicin hydrochloride (25316-40-9) + benzenesufonyl hydrazide (80-17-1) → 13-benzenesulfonylhydrazone-doxorubicin hydrochloride

Conditions	Yield
In methanol at 0 - 45℃; for 16 - 240h;	96%

poly(17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ester of 6-(2-methacryloylamino)hexanoic acid-co-N1-(6-hydrazino-6-oxohexyl)-2-methylacrylamide-co-N-(2-hydroxypropyl)methacrylamide) + doxorubicin hydrochloride (25316-40-9) → PHPMA-AH-NH-N=DOX-co-MA-AH-chol

Conditions	Yield
acetic acid In methanol at 25℃; for 22h;	96%

C21H20N2O6 + doxorubicin hydrochloride (25316-40-9) → C42H44N2O14

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h;	96%

C19H14Cl2N2O6 + doxorubicin hydrochloride (25316-40-9) → C40H38Cl2N2O14

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h;	95%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h;	95%

(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl) 4-nitrophenyl carbonate (1350891-95-0) + doxorubicin hydrochloride (25316-40-9) → N-(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyloxycarbonyl)doxorubicin (1350892-00-0)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide	94%

C59H106N2O30 + doxorubicin hydrochloride (25316-40-9) → C82H130N2O38

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 14h; Inert atmosphere; Darkness;	94%

doxorubicin hydrochloride (25316-40-9) + trifluoroacetic anhydride (407-25-0) → N-Trifluoroacetyladriamycin (26295-56-7)

Conditions	Yield
With pyridine In diethyl ether at -30 - 0℃; for 3h; Schlenk technique;	94%
With pyridine In diethyl ether at -20℃; for 0.5h;	91%

(9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-(((S)-4-amino- 1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1,4-dioxobutan-2-yl)amino)- 1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate + doxorubicin hydrochloride (25316-40-9) → Nα-Fmoc-Ala-Ala-Asn-PABC-doxorubicin

Conditions	Yield
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Darkness;	94%

(E)-2,5-dioxopyrrolidin-1-yl 1-(cyclooct-4-en-1-yloxy)-1-oxo-5,8,11,14-tetraoxa-2-azaheptadecan-17-oate + doxorubicin hydrochloride (25316-40-9) → C47H62N2O18

Conditions	Yield
With triethylamine In dimethyl sulfoxide at 20℃; for 24h; Darkness;	94%

6-azidohexanoic hydrazide (1039044-92-2) + doxorubicin hydrochloride (25316-40-9) → C33H40N6O11*ClH

Conditions	Yield
With acetic acid; sodium sulfate In methanol at 20℃; for 12h; Darkness;	93%
With acetic acid; sodium sulfate In methanol at 65℃; for 24h; Darkness;	62.4%
With acetic acid; sodium sulfate In methanol at 65℃; for 24h;	62.4%
With acetic acid In methanol

C27H25N3O14S2 + doxorubicin hydrochloride (25316-40-9) → C48H49N3O22S2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;	93%

linolenyl hydrazide (1169394-01-7) + doxorubicin hydrochloride (25316-40-9) → C45H59N3O11*ClH

Conditions	Yield
With trifluoroacetic acid In methanol at 20℃;	92%

C17H15N5O8 (1596412-91-7) + doxorubicin hydrochloride (25316-40-9) → C38H39N5O16 (1596412-92-8)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	92%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;

3,4-dithiophenoylmaleimide-N-hexanoic acid + doxorubicin hydrochloride (25316-40-9) → N-(hexanamide-N-doxorubicin)-3,4-dithiophenoylmaleimide

Conditions	Yield
Stage #1: 3,4-dithiophenoylmaleimide-N-hexanoic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; under 760.051 Torr; for 0.05h; Inert atmosphere; Stage #2: doxorubicin hydrochloride In N,N-dimethyl-formamide at 20℃; under 760.051 Torr; for 6h; Inert atmosphere;	92%

doxorubicin hydrochloride (25316-40-9) + diprop-2-enyl N-<(4-<<4-nitrophenoxycarbonyloxy>methyl>phenyl)carbamoyl>-L-glutamate (180839-15-0) → N-<4-(dipropen-2-yl-L-glutamylcarbonylamino)benzyloxycarbonyl>doxorubicin

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 3.5h; Ambient temperature;	91.1%

doxorubicin hydrochloride (25316-40-9) + N-(9-fluorenylmethoxycarbonyl)-β-alanyl-L-leucyl-L-alanyl-L-leucine → N-[N-(9-fluorenylmethoxycarbonyl)-β-alanyl-L-leucyl-L-alanyl-L-leucyl]doxorubicin (274913-06-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h;	90%

doxorubicin hydrochloride (25316-40-9) + trifluoroacetic acid (76-05-1) + 4-(4-(N-maleimido)phenyl)butyric acid hydrazide hydrochloride → C41H42N4O13*C2HF3O2

Conditions	Yield
In methanol at 20℃; for 5h;	90%

cis-aconitic anhydride (6318-55-4) + doxorubicin hydrochloride (25316-40-9) → cis-aconitic anhydride doxorubicin (1425615-40-2)

Conditions	Yield
Stage #1: doxorubicin hydrochloride With sodium hydrogencarbonate In water at 0℃; Stage #2: cis-aconitic anhydride In 1,4-dioxane; water at 0 - 20℃; for 0.666667h; pH=8.5; Stage #3: With hydrogenchloride In 1,4-dioxane; water	90%
With triethylamine In N,N-dimethyl-formamide at 25℃; for 24h;
With triethylamine In N,N-dimethyl-formamide

4-nitrophenyl 2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (874302-76-8) + doxorubicin hydrochloride (25316-40-9) → doxorubicin 2-(pyridy-2-yldithio)ethylcarbamate (1058725-05-5)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	90%
With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 12h; Darkness;	87%
With triethylamine In dichloromethane; N,N-dimethyl-d6-formamide at 20℃; for 12h; Darkness;	87%

N-(p-benzoic acid)-3,4-dithiophenoylmaleimide + doxorubicin hydrochloride (25316-40-9) → N-( p-benzamide-N-doxorubicin)-3,4-dithiophenoylmaleimide

Conditions	Yield
Stage #1: N-(p-benzoic acid)-3,4-dithiophenoylmaleimide With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; under 760.051 Torr; for 0.05h; Inert atmosphere; Stage #2: doxorubicin hydrochloride In N,N-dimethyl-formamide at 20℃; under 760.051 Torr; for 6h; Inert atmosphere;	90%

Upstream product

• 23541-50-6 daunomycin hydrochloride 
• 29742-67-4 14-bromodaunorubicin hydrochloride 

Downstream Products

• 89164-77-2 3'-deamino-3'-(3-cyano-4-morpholinyl)-13-dihydrodoxorubicin 
• 80875-73-6 3'-deamino-3'-(4-morpholinyl)-13-dihydrodoxorubicin 
• 80790-68-7 3'-deamino-3'-(4-morpholinyl)doxorubicin 
• 88254-07-3 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin 
• 188530-64-5 Doxo-MBS 
• 636595-43-2 N-(5-{4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]but-2-ynyloxymethyl}-2-hydroxybenzamidomethyl)doxorubicin 
• 400647-59-8 doxorubicin-succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate 
• 925893-58-9 AEC-D-Ala-Phe-Lys(Aloc)-PABC-PABC-Dox 
• 1136860-49-5 EMC-Glu-Phe-Lys(Mtt)-PABC-doxorubicin 

Relevant articles and documents

Reversing the undesirable pH-profile of doxorubicin: Via activation of a di-substituted maleamic acid prodrug at tumor acidity

The acid-labile behavior of di-substituted maleamic acid (DMA) and its equilibrium with di-substituted maleimide (DMI) are exploited to build an ultra acid-sensitive, small molecule prodrug that can be activated by tumor extracellular pH (pHe) in the range of 6.5-6.9. Such a DMA prodrug reversed the unfavorable pH-profile of doxorubicin (Dox), which may improve its therapeutic window.

ADIPOCYTE MEDIATED DELIVERY OF ANTICANCER THERAPEUTICS

Disclosed are compositions and methods related to the use of adipocytes for sustained release of anti-cancer therapeutics and treatment of cancer.

FAP-ACTIVATED THERAPEUTIC AGENTS, AND USES RELATED THERETO

Disclosed are prodrugs of cytotoxic anthracyclines (such as doxorubicin) and other therapeutic agents that are selectively cleaved and activated by fibroblast activating protein (FAP). The prodrugs are useful for targeted delivery of cytotoxic and other agents to FAP- expressing tissues, including cancer (e.g., solid tumors). Also provided are pharmaceutical compounds comprising the prodrugs, as well as methods of using the prodrugs to treat a disorder characterized by FAP upregulation, e.g., cancer, fibrosis, and inflammation.

CHANNEL PROTEIN ACTIVATABLE LIPOSOMES

Disclosed is a liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a channel protein releasably linked to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are used in a kit comprising the liposome, the liposomal membrane of which comprises a channel protein linked to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises the eight- membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.

ACTIVATABLE LIPOSOMES

Disclosed are reactive liposome, comprising a lipid bilayer enclosing a cavity, wherein the bilayer comprises a linkage to an eight-membered non-aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The liposomes are use in a kit comprising the liposome linked, directly or indirectly, to a Trigger, and an Activator for the Trigger, wherein the Trigger comprises an eight-membered non-aromatic cyclic alkenylene group, and the Activator comprises a diene.

Method for identifying an enzyme to design anti-cancer compounds

The present invention relates to a method for identification of enzymes that are preferentially expressed in certain tumor tissue as compared with rapidly growing normal cells or tissue, use of said enzymes for the compound design to generate an active anti-cancer substance selectively in tumor tissue, compounds designed based on said enzymes, their pharmaceutically acceptable salts as well as pharmaceutical composition thereof.

Crystallization of doxorubicin hydrochloride

Disclosed are a crystallizing method of doxorubicin hydrochloride from a doxorubicin hydrochloride-containing solution, particularly a method for carrying out the crystallization under a condition of 40° C. or higher, and a doxorubicin hydrochloride crystalline aggregate having particularly an excellent solubility in water.

NOVEL PROTEIN AND DNA THEREOF

Because the protein of the present invention has in its amino acid sequence a homology with, for example, ribonucleotide reductase, the protein of the present invention, its DNA, antibodies to these and the like are useful in the prevention, treatment and diagnosis, etc. of cancer.

Prodrugs activated by targeted catalytic proteins

Prodrugs that are activated by and conjugated to a catalytic antibody conjugated to a moiety that binds to a tumor cell population are provided.

Elongated multiple electronic cascade and cyclization spacer systems in activatible anticancer prodrugs for enhanced drug release

The design and synthesis of several novel elongated self-elimination spacer systems for application in prodrugs is described. These elongated spacer systems can be incorporated between a cleavable specifier and the parent drug. Naphthalene- and biphenyl-containing spacers were synthesized but did not eliminate. Prodrugs of the anticancer agents doxorubicin and paclitaxel are reported that contain two or three electronic cascade spacers. A novel catalytic application of HOBt was found for the synthesis of N-aryl carbamates through reacting a 4-nitrophenyl carbonate with an aniline derivative, to connect the 1,6-elimination spacers via a carbamate linkage. In addition, a double spacer-containing paclitaxel prodrug was synthesized, comprising a 1,6-elimination spacer and a bis-amine linker connected to paclitaxel via a 2′-carbamate linkage. Prodrugs in which the novel spacer systems were incorporated between a specific tripeptide specifier and the parent drug doxorubicin or paclitaxel proved to be significantly faster activated by plasmin in comparison with prodrugs containing conventional spacer systems. It is expected that the generally applicable novel spacer systems reported herein will contribute to future development of improved enzymatically activated prodrugs.