147-94-4 Usage
Uses
1. Used in Anticancer Applications:
Cytarabine is used as an antineoplastic and antiviral agent for the treatment of acute granulocytic leukemia (adults), acute lymphocytic leukemia (children), and Hodgkin's disease. It is a selective inhibitor of DNA synthesis and does not inhibit RNA synthesis. The drug is active following intracellular activation to the nucleotide metabolite ara-CTP, which is incorporated into DNA, resulting in chain termination and inhibition of DNA synthesis and function. Resistance can occur due to decreased activation or transport and increased catabolic breakdown.
2. Used in Antiviral Applications:
Cytarabine is used as an antiviral agent for the treatment of herpes zoster (shingles), herpetic keratitis, and viral infections that resist idoxuridine. It is usually administered topically.
3. Used in Pharmaceutical Industry:
Cytarabine is used as an antimetabolite in the development of various pharmaceutical products, particularly for the treatment of leukemia and other cancer-related conditions.
4. Used in Research and Development:
Cytarabine is used as a nucleoside analog that interferes with DNA synthesis and transcription, particularly in tumor cells. Cellular enzymes convert it to its nucleotide form, Ara-CTP, which disrupts DNA and RNA synthesis when polymerases attempt to incorporate it. This property makes it valuable in research and development for understanding the mechanisms of cancer cell proliferation and the development of new therapeutic strategies.
Toxic Substances:
Cytarabine is classified as a toxic substance. Its toxicity occurs on bone marrow, the gastrointestinal (GI) tract, and the kidneys. Toxicities include myelosuppression, leukopenia and thrombocytopenia, nausea and vomiting, anorexia, diarrhea, and mucositis. Neurotoxicity is usually expressed as ataxia, lethargy, and confusion. An allergic reaction often described in pediatric patients includes fever, myalgia, malaise, bone pain, skin rash, conjunctivitis, and chest pain.
Brand Names:
Cytarabine is available under the brand names Cytosar-U (Sicor) and Depocyt (Skyepharma).
Antiviral drugs
Cytarabine is a kind of purine nucleoside-class antiviral chemical synthesis that initially extracted from the medium of streptomyces, and then produced from chemical synthesis. It is a white crystalline powder and is very slightly soluble in water. Its monophosphate ester is easily soluble in water. It has inhibitory effect on various kinds of DNA virus such as Herpes simplex virus HSV1 and HSV2, hepatitis B virus, varicella-zoster virus and cytomegalovirus however has no effect on the smallpox virus, adenovirus, and other kinds of DNA or RNA viruses, bacteria and fungi. The exact mechanism of the antiviral effect of cytarabine is currently not fully understood. The mechanism is primarily related to inhibition of viral replication. The drugs and their metabolites can inhibit the viral DNA synthesis through inhibiting viral DNA polymerase while only a very small amount of the drug itself is incorporated into the viral DNA molecule. In the human body, the antiviral effect of the drugs only partially depends on the host immune function with drugs having no immunosuppression effect. Upon intravenous administration in vivo, 75% to 87% of the drug quickly deaminized into arabinose hypoxanthine through the action of deadenylated deoxygenase, Arabinose hypoxanthine has a significant lower antiviral activity than the prototype, and is rapidly distributed in some parts of the tissues; administer 10 mg of drugs per kg of body weight; the peak value of the plasma concentration of arabinose hypoxanthine is 3~6μ/ml while the peak value of plasma concentration of vidarabine is 0.2~0.4μg/ml. Arabinose hypoxanthine can penetrate through the blood-brain barrier with the cerebrospinal fluid drug concentrations being approximately 1/3 of plasma drug concentration. 41% to 53% of the daily dosage is excreted through urinary in the form of arabinose hypoxanthine. 1% to 3% is excreted out in the form of prototype. Cytarabine is clinically mainly used for the treatment of herpes simplex virus encephalitis as well as being used for treating the herpes zoster and chicken pox of immunosuppressed patients but is invalid in treating cytomegalovirus. It also has certain pharmacological activity of inhibition of hepatitis B virus replication. Topical medication is applied to the treatment of herpes simplex virus keratitis and occasionally used for treating vaccinia virus keratitis.
The above information is edited by the lookchem of Dai Xiongfeng.
Anti-tumor drug
Cytarabine is currently one of the most effective drugs in clinical treatment of acute non-lymphatic myeloid leukaemia. It was first successfully synthesized in 1959 f, and is also presented in the sponge. In 1961, it was found that it has inhibitor effect on in mice S180 sarcoma and leukemia L1210. Cross resistance phenomenon was not observed in animal experiments for cytarabine being used in combination with conventional antineoplastic agents such as 6-thioguanine, methotrexate, prednisone, vincristine, mechlorethamine, cyclophosphamide, daunorubicin, methyl cellosolve acetate gag, fluorouracil and mercaptopurine. This drug belongs to pyrimidine-type anti-metabolite class of anti-tumor agents and having cell cycle specificity with s-phase cells being most sensitive to it. It interferes with the cell proliferation through inhibiting the intracellular DNA synthesis. After entering into the human body, cytarabine is converted into cytarabine triphosphate and cytarabine diphosphate through the phosphorylation reaction catalyzed by kinase. The former one can strongly inhibits the synthesis of DNA polymerase while the later one is capable of inhibiting the conversion between cytidine diphosphate to deoxycytidine diphosphate and thereby inhibiting the synthesis and polymerization of cellular DNA. However, its Inhibitory effect on RNA and protein synthesis is very slight.
It is clinically mainly applied to the treatment of the induction stage and maintenance and consolidation phase of acute lymphoblastic leukemia and non-lymphocytic leukemia, the acute transformation phase of chronic myeloid leukemia and malignant lymphoma. In ophthalmology, it is for the treatment of viral conjunctivitis and epidemic keratitis. It also has certain efficacy in the treatment of head and neck cancer, gastrointestinal cancer and lung cancer; In addition, the drug also has inhibitory effect on the proliferation of herpes simplex virus, smallpox virus, and vaccinia virus as well as the immune response of the body.
Pharmacokinetics
The oral administration of drugs yield a low absorption amount, and is also extremely easy to get deaminated and lose function in the action of the cytosine deaminase in the gastrointestinal tract and liver. Therefore, it is not recommended to subject to oral administration. It can be absorbed through intravenous, subcutaneous, intramuscular or intrathecal injection. After intravenous injection, it can be widely distributed in the body fluids, tissues and cells. After intravenous infusion of the drug, there is a moderate amount of drugs which can penetrate through the blood-brain barrier with the cerebrospinal fluid drug concentration being about 40% of the plasma concentration. The drug is mainly metabolized in tissues such as liver and kidney. It is quickly deaminated by the cytosine deaminase to form the inactive uracil arabinoside. In the cerebrospinal fluid, due to relative low content of the deaminase, the domination reaction is very slow. For intravenous administration, the half-life of α-phase is 10 to 15 minutes, with beta phase being 2 to 2.5 hours; for intrathecal administration, the half-life can be extended to 11 hours. Within 24 hours, among the given drug, about 10% of drug is excreted through the kidney while the rest 90% is excreted in the form of uracil cytarabine.
Dosing instructions
1. Upon administration of cytarabine, we should appropriately increase the fluid intake of the patient, so that the urine can be maintained basic. If necessary, the patient can also administer allopurinol in combination in order to prevent the increase of bleeding uric acid and uric acid nephropathy.
2. Though it can cause severe adverse reactions such as nauseas and vomiting upon rapid intravenous injection, the drug has relative slight effect on bone marrow suppression which can be generally tolerated by the patients.
3. The intravenous infusion solution should be diluted to 0.5mg/ml.
4. The prepared injection solution can be stored on the at 4 ℃ (refrigerator) for about seven days. However, at room temperature, it can only be stored for 24 hours.
5. For intrathecal injection of drug, the diluted solution should be free of preservatives.
6. Upon adopting moderate dose or high-dose cytarabine for therapy, some patients may get severe adverse reaction in gastrointestinal and nervous system such as gastrointestinal ulcers, gastrointestinal cystic gas, necrotizing enterocolitis, peripheral neuropathy, brain or cerebellar dysfunction such as personality changes, hypotonia, epilepsy, lethargy, stupor, disorientation, nystagmus, dysarthria, and ataxia; Moreover, hemorrhagic conjunctivitis, skin rashes, hair loss, peeling, severe myocardial disease can also occur.
7. Upon the emergence of various kinds of serious adverse reactions, the drug administration should be discontinued immediately with taking effective measures immediately for treatment. Some patients can be given adrenocorticotropic hormone which may alleviate the adverse reactions caused by moderate-dose or high-dose cytarabine.
Dosage
Adult Usage:
1, the induction therapy of acute leukemia: often applied in combination with other chemotherapy drugs, 1~3mg/kg each time, intravenous infusion, q: 12h, continuously administer for 5 to 7 days. Repeat at a interval of 1 to 2 weeks.
2, Moderate, large reduction therapy: this is commonly used in the intensive treatment of refractory or relapsed acute leukemia or acute leukemia after remission. For moderate dose: administer 500~1000mg/m2 per time, intravenous infusion of 1 to 3 hours, q12h, 2~6 day as a course. Large doses means 1000~3000mg /m2 per time with similar usage as for moderate dosage. Owing to that the adverse reaction is enhanced with increased dose cytarabine, large doses mainly in turn negatively affect its efficacy, thereby it is now more in favor of moderate dosage protocol.
3, subcutaneous injection: 10mg/m2 per time, q12h, 14~21 as a course of treatment. If the symptom is not alleviated and the patient's condition allows, the treatment can be repeated for another course after 2 to 3 weeks. This protocol can be used for the treatment of myelodysplastic syndrome with increased amount of original cells, low proliferative leukemia, and acute non-lymphocytic leukemia of elderly patients.
4, intrathecal injection: for treating meningeal leukemia, administer 25~75 mg per time; together with 5 mg of dexamethasone; subject to intrathecal injection after using NS for dissolving; administer 1 or 2 times per week until the cerebrospinal fluid (CSF) examination becomes normal. For preventive medicine purpose, administer 1 time in every 4 to 8 weeks.
For children usage: acute leukemia induction therapy, 100mg/(m2 ? d), continuously administer for 5 to 7 days.
Side effects
Digestive System: common adverse reactions include loss of appetite, nausea, vomiting, diarrhea, gastritis, stomatitis and gastrointestinal ulcers. Some patients get abnormal liver function, elevated level of bilirubin and aminotransferase. Large-dose treatment can cause significant liver dysfunction and jaundice; it can cause the occlusion of central vein of liver and vein of liver lobule, resulting in jaundice, hepatomegaly, ascites and hepatic encephalopathy.
Blood system: bone marrow suppression increases with increased dose; exhibit as the decrease of leukopenia and thrombocytopenia.
Local reactions: pain at the infusion site and thrombophlebitis mostly disappear after stopping; there are still occasionally reactions such as itching and rashes; treatment of topical ophthalmic drugs can often cause temporary burning, itching and other mild irritation and can also cause tears, foreign body sensation, conjunctival hyperemia, superficial punctate keratitis, pain, photophobia and other reactions.
Central nervous system: occasional discomfort, fatigue, tremors, dizziness, hallucinations, psychotic symptoms and fuzzy sense. These adverse reactions are dose-related and usually disappear after stopping drug. Cases of headache and encephalopathy have also been reported with the later often being difficult for distinguish from protopathy disease can often occurs in the patients with liver and kidney dysfunction.
Overdose performance: when the daily administered cytarabine dose is higher than 20mg/kg, bone marrow suppression can occur; once overdose occur, the patients need to subject to close monitor of the blood system and changes in liver and kidney function .
Other adverse reactions: transient increase in alanine aminotransferase is often observed. Increase of serum total bilirubin also occurs occasionally. Dizziness, fever, hair loss, rash, etc., can also occur. Moreover, it can result in male reproductive dysfunction. Patients of allergy, pregnant women and lactating women should be disabled. Patients with decreased white blood cell count and decreased platelet counts decreased significantly, biliary tract disease, history of gout or urate kidney stones, and who have recently received cytotoxic drugs or radiation therapy, as well as with liver and kidney dysfunction should take with caution.
Function
Ara-C inserts into DNA, and forms complex with topoisomerase I (topoisomerase I) to inhibit DNA replication, causing DNA cleavage. It can’t inhibit RNA synthesis. It can be used as anti-leukemia substance for being used in various types of acute leukemia.
Toxicity grading
Poisoning
Acute toxicity
Oral-rat: LD50> 5000 mg/kg; Oral-Mouse LD50: 3150 mg/kg
Stimulus data
Skin-people 45 mg/3 weeks, moderate, three weeks; eyes-people 105 mg/7 days
Skin allergy agent
Flammability hazard characteristics
Combustible; combustion produces toxic fumes of nitrogen oxides
Storage Characteristics
Treasury: ventilation, low-temperature and drying; store it separately from food raw materials
Extinguishing agent
Dry powder, foam, sand, carbon dioxide, water spray
Originator
Cytosar,Upjohn,US,1969
Indications
Cytarabine (cytosine arabinoside, ara-C, Cytosar-U) is
an analogue of the pyrimidine nucleosides cytidine and
deoxycytidine. It is one of the most active agents available
for the treatment of acute myelogenous leukemia.
Cytarabine kills cells in the S-phase of the cycle by competitively
inhibiting DNA polymerase. The drug must
first be activated by pyrimidine nucleoside kinases to
the triphosphate nucleotide ara-cytosine triphosphate
(ara-CTP). The susceptibility of tumor cells to cytarabine
is thought to be a reflection of their ability to activate
the drug more rapidly (by kinases) than to inactivate
it (by deaminases).
Manufacturing Process
(A) Preparation of 1- (2,3,5-Tri-O-Acetyl-β-D-Arabinofuranosyl)-4-Thiouracil: A
mixture of 1.85 g (5.0 mmol) of 1-(2,3,5-tri-O-acetyl-β-arabinofuranosyl)
uracil, 1.23 g (5.55 mmol) of phosphorus pentasulfide, and 30 ml of pyridine
was heated under gentle reflux for 2.5 hours with exclusion of moisture. The
reaction mixture was cooled, and the supernatant solution was transferred by
means of a pipette into a mixture of crushed ice and water. The reaction flask
was washed twice with pyridine, and these washings were added to the icewater mixture. This mixture was kept at about 25°C until the ice had melted,
and was then stored at 0°C for one hour. A pale yellow precipitate that formed
was collected on a filter, washed with ice-water, and dried in air.This material was triturated with chloroform, and the chloroform mixture was
filtered. A small amount of undissolved material collected on the filter and it was washed with chloroform. The chloroform solution (filtrate plus washings)
was washed three times with ice-water, twice with ice-cold 3 N sulfuric acid,
twice with ice-cold saturated aqueous sodium bicarbonate solution, twice with
ice-water, and then dried over anhydrous sodium sulfate. The chloroform was
removed under reduced pressure at a bath temperature of about 40°C,
leaving a yellow, somewhat gummy residue. This yellow residue was dissolved
in absolute methanol which was then evaporated at reduced pressure at about
40°C, and the residue was then held for 2 hours at 0.5 to 2.0 mm pressure
and a bath temperature of about 50°C. There was thus obtained 1.69 g of 1-
(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-4-thiouracil.(B) Preparation of 1-β-D-Arabinofuranosylcytosine: In a glass liner, a mixture
of 1.16 g (3.0 mmol) of 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-4-
thiouracil prepared in (A) and about 60 ml of absolute methanol which had
been saturated with anhydrous ammonia at 0°C was heated in a steel bomb
at 98° to 105°C for 35 hours. After cooling to about 25°C and venting the
bomb, the dark solution was filtered into a round-bottom flask. The methanol
and excess ammonia were then removed under reduced pressure at about
25°C. The residual syrup was dissolved in absolute methanol, and the
methanol was removed under reduced pressure at a bath temperature of
about 40°C. This procedure of dissolving in absolute methanol and removing
the solvent was repeated, and the residue was held under reduced pressure at
a bath temperature of 45°C for 12 hours.The resulting semisolid was triturated thoroughly with absolute methanol, and
the resulting suspension was chilled at 0°C. A pale tan solid that separated
was collected on a filter and washed repeatedly with methanol. After washing
with anhydrous ether, there was obtained 430 mg of 1-β-Darabinofuranosylcytosine.(C) Preparation of 1-β-D-Arabinofuranosylcytosine Hydrochloride: The absolute
methanolic filtrate obtained after triturating and filtering the 1-β-Darabinofuranosylcytosine in (B) above was warmed and stirred with
decolorizing charcoal. The mixture was filtered through a bed of filter aid, and
the filter bed was washed repeatedly with absolute methanol. The combined
filtrate and washings were pale yellow. The solution was diluted to faint
cloudiness with anhydrous ether, and an excess of anhydrous hydrogen
chloride was introduced. Crystallization began at about 25°C and further
crystallization was induced by chilling at 0°C for 14 hours. The crystalline
product was collected on a filter, washed with anhydrous ether, and dried in
air. There was thus obtained 180 mg of pale yellow 1-β-Darabinofuranosylcytosine hydrochloride melting at 186° to 189°C.The pale yellow product was dissolved in warm, absolute methanol, and the
solution after mixing with decolorizing charcoal was filtered through a bed of
filter aid. The filter bed was washed with warm absolute methanol, and the
combined methanolic filtrate and washings were warmed and diluted with
anhydrous ether to incipient crystallization. The methanol-ether mixture was
kept at about 25°C for about 1 hour and then chilled, first at 0°C, and then at
-20°C. The resulting colorless needles were collected on a filter, washed with
anhydrous ether, and dried at 85°C, yielding 100 mg of 1-β-Darabinofuranosylcytosine hydrochloride having a melting point of 186° to
188°C.
Therapeutic Function
Cancer chemotherapy
Air & Water Reactions
Water soluble.
Health Hazard
ACUTE/CHRONIC HAZARDS: Very toxic. Hazardous decomposition products. May cause irritation on contact. Teratogen. Mutagen. Central nervous system effects.
Biochem/physiol Actions
Ara-C incorporates into DNA and inhibits DNA replication by forming cleavage complexes with topoisomerase I resulting in DNA fragmentation; does not inhibit RNA synthesis. Anti-leukemia agent.
Mechanism of action
Cytarabine is rapidly metabolized in the liver, kidney,
intestinal mucosa, and red blood cells and has a
half-life in plasma of only 10 minutes after intravenous
bolus injection. The major metabolite, uracil arabinoside
(ara-U), can be detected in the blood shortly after
cytarabine administration. About 80% of a given
dose is excreted in the urine within 24 hours, with less
than 10% appearing as cytarabine; the remainder is
ara-U.When the drug is given by continuous infusion,
cytarabine levels in CSF approach 40% of those in
plasma.
Clinical Use
Cytarabine is used in the chemotherapy of acute
myelogenous leukemia, usually in combination with an
anthracycline agent, thioguanine, or both. It is less useful
in acute lymphoblastic leukemia and the lymphomas
and has no known activity against other tumors. It has
been used intrathecally in the treatment of meningeal
leukemias and lymphomas as an alternative to methotrexate.
Safety Profile
Moderate to low toxicity byingestion. Human systemic effects: allergic dermatitis,ataxia, blood changes, central nervous system effectsconjunctive irritation, degenerative brain changes, hearingacuity change, lachrymation, peripheral nervefasciculati
Synthesis
Cytarabine, 4-amino-1-β-arabinofuranosyl-2(1H)pyrimidone (30.1.3.8), is
made from 1-β-D-arabinofuranosyluracil by preliminary acylation of the hydroxyl group,
forming a triacetyl derivative (30.1.3.6), and subsequent replacement of the carbonyl group at
position 4 of the pyrimidine ring with a thiocarbonyl group using phosphorous pentachloride,
and finally replacing the mercapto group of 30.1.3.7 with an amino group using ammonia and
simultaneous hydrolysis of the acetyl-substituted groups, giving cytarabine (30.1.3.8).
Veterinary Drugs and Treatments
In veterinary medicine, cytarabine is used primarily in small animals
as an antineoplastic
agent for lymphoreticular neoplasms,
myeloproliferative disease (leukemias), and CNS lymphoma. Refer
to the Dosages below or the Protocols (in the appendix), for more
information.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Metabolism
Cytarabine is converted by phosphorylation to an active
form, which is rapidly deaminated, mainly in the liver and
the kidneys, by cytidine deaminase to inactive 1-β-darabinofuranosyluracil (uracil arabinoside, ara-U).
Approximately 80% of an intravenous dose is excreted
in the urine within 24 hours, mostly as the inactive
metabolite with about 10% as unchanged cytarabine. A
small amount is excreted in the bile.
Purification Methods
Purify cytarabin by recrystallisation from aqueous EtOH or a large volume of H2O (it solubility at ~20o is 5%). It has max 212 and 279nm at pH 2 and 272nm at pH 12. It is an acute leukaemic agent. [Walwick et al. Proc Chem Soc (London) 84 1959, Beilstein 25 III/IV 3669.]
References
Derissen and Beijnen (2020), Intracellular Pharmacokinetics of Pyrimidine Analogues used in Oncology and the Correlation with Drug Action; Clin. Pharmacokinet., 59 1521
Z Li et al. (2017), Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells; Molecules, 22 E499
Zhang & Kiechle (2004), Cytosine Arabinoside Substitution Decreases Transcription Factor-DNA Binding Element Complex Formation; Arch. Pathol. Lab. Med., 128 1364
Renis (1973), Antiviral Activity of Cytarabine in Herpesvirus–Infected Rats; Antimicrob. Agents Chemother., 4 439
Qin et al. (2007), Effect of Cytarabine and Decitabine in Combination in Human Leukemic Cell Lines; Clin. Cancer Res., 13 4225
Walter et al. (2020), Optimal Dosing of Cytarabine in Induction and Post-Remission Therapy of Acute Myeloid Leukemia; Leukemia, 35 295
Check Digit Verification of cas no
The CAS Registry Mumber 147-94-4 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,4 and 7 respectively; the second part has 2 digits, 9 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 147-94:
(5*1)+(4*4)+(3*7)+(2*9)+(1*4)=64
64 % 10 = 4
So 147-94-4 is a valid CAS Registry Number.
InChI:InChI=1/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6+,7?,8-/m1/s1
147-94-4Relevant articles and documents
Radiolytic activation of a cytarabine prodrug possessing a 2-oxoalkyl group: One-electron reduction and cytotoxicity characteristics
Hirata, Nao,Fujisawa, Yusuke,Tanabe, Kazuhito,Harada, Hiroshi,Hiraoka, Masahiro,Nishimoto, Sei-Ichi
, p. 651 - 654 (2009)
An anti-tumour agent of cytarabine (ara-C) was conjugated with a 2-oxopropyl group at the N(4) position to obtain a radiation-activated prodrug (oxo-ara-C) that targeted hypoxic tumour tissues with selective cytotoxicity. The parent anti-tumour agent, ara
Enzymatic acylation and alkoxycarbonylation of α-, xylo-, anhydro-, and arabino-nucleosides
Moris,Gotor
, p. 10089 - 10098 (1993)
5'-O-acyl and 5'-O-alkoxycarbonyl derivatives of α-, anhydro-, xylo- and arabinonucleosides could be obtained through a lipase-mediated reaction with SP 435 lipase (from Candida antarctica) by using acetoxime butyrate or butyric anhydride, together with benzyloxycarbonyl-O-acetoxine as acylating agents. Alkoxycarbonylation gave poorer yields than acylation and other lipases tested gave non-selective reaction or not reaction at all.
AN ENZYMIC SYNTHESIS OF PURINE D-ARABINONUCLEOSIDES
Krenitski, Thomas A.,Koszalka, George, W.,Tuttle, Joel V.,Rideout, Janet L.,Elion, Gertrude B.
, p. 139 - 146 (1981)
A method is described for the synthesis of purine D-arabinonucleosides that uses purine bases and 2,2'-anhydro-(1-β-D-arabinofuranosylcytosine), AraC-an, as the starting materials.AraC-an was chosen as the precursor to the D-arabinosyl donor, because it is more readily available than any of the products that may be sequentially derived from it, namely, 1-β-D-arabinofuranosylcytosine ( AraC ), 1-β-D-arabinofuranosyluracil ( AraU ), and α-D-arabinofuranosyl-1-phosphate ( Araf 1-P ), a D-arabinofuranosyl donor.Four reactions were involved in the ovarall procass; ( a ) AraC-an was nonenzymically hydrolyzed at alkaline pH to AraC which was then ( b ) deaminated by deaminase to AraU, a nucleoside, ( c ) phosphorylyzed by uridine phosphorylase to Araf 1-P, and ( d ) this ester caused to react with a purine base to afford a purine D-arabinonucleoside, the reaction being catalyzed by purine nucleoside phosphorylase.All four rections occured in situ, the first and second being performed sequentially, whereas the third and fourth were combined in a single step.The three enzyme catalysts were purified from Escherichia coli.The efficiency of the method is exemplified by the synthesis of the D-arabinonucleosides of 2,6-diaminopurine and adenine; the overall yields, based on AraC-an, were 60 and 80 percent respectively.
BIOCATALYTIC PRODUCTION OF NUCLEOSIDE ANALOGUES AS ACTIVE PHARMACEUTICAL INGREDIENTS
-
Paragraph 0238, (2016/04/09)
A biocatalytic process for producing active pharmaceutical ingredients (APIs) or intermediates thereof, wherein those APIs or their intermediates are nucleoside analogues (NAs) of formula I and wherein said NAs are active as pharmaceutically relevant antivirals and anticancer medicaments, intermediates or prodrugs thereof.
Synthesis and cytotoxic activity of novel 5-substituted-1-(β-L- arabinofuranosyl) pyrimidine nucleosides
Sendula, Robert,Orban, Erika,Hudecz, Ferenc,Sagi, Gyula,Jablonkai, Istvan
experimental part, p. 482 - 500 (2012/07/28)
A series of new 5-halogeno-1-(β-L-arabinofuranosyl)uracils and their cytosine analogues were synthesized by halogenation of ara-L-uridine and ara-L-cytidine, respectively. The 5-(2-thienyl) and 5-halogenothienyl derivatives of both series were also prepared in excellent yields by Stille coupling followed by halogenation. All of these syntheses were based on benzoyl-protected derivatives. In vitro cytotoxicity experiments carried out using L1210 mouse leukemia cells showed that 5-(2-thienyl)- ara-L-uridine was the most potent compound of the new compounds; the majority of the analogues were not effective up to 200 μM concentrations. Copyright Taylor and Francis Group, LLC.
THERAPEUTIC FOR HEPATIC CANCER
-
, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
Unprecedented gas-phase chiroselective logic gates
Botta, Bruno,Fraschetti, Caterina,D'Acquarica, Ilaria,Sacco, Fabiola,Mattay, Jochen,Letzel, Matthias C.,Speranza, Maurizio
supporting information; experimental part, p. 1717 - 1719 (2011/05/03)
The gas-phase encounters between 2-aminobutane and proton-bound chiral resorcin[4]arene/nucleoside complexes behave in the gas phase as supramolecular "chiroselective logic gates" by releasing the nucleoside depending on the resorcin[4]arene and the 2-aminobutane configurations.
Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
-
, (2010/05/13)
Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
Bisphosphonate derivatives of nucleoside antimetabolites: Hydrolytic stability and hydroxyapatite adsorption of 5′-β,γ-methylene and 5′-β,γ-(1-hydroxyethylidene) triphosphates of 5-fluorouridine and ara-cytidine
Ora, Mikko,Loennberg, Tuomas,Florea-Wang, Diana,Zinnen, Shawn,Karpeisky, Alexander,Loennberg, Harri
, p. 4123 - 4130 (2008/09/21)
(Chemical Equation Presented) Kinetics of the hydrolytic reactions of four bisphosphonate derivatives of nucleoside antimetabolites, viz., 5-fluorouridine 5′-β,γ-(1-hydroxyethylidene) triphosphate (4), 5-fluorouridine 5′-β,γ-methylene triphosphate (5), ara-cytidine 5′-β,γ-(1-hydroxyethylidene) triphosphate (6), and ara-cytidine 5′-β,γ-methylene triphosphate (7), have been studied over a wide pH range (pH 1.0-8.5) at 90°C. With each compound, the disappearance of the starting material was accompanied by formation of the corresponding nucleoside 5′-monophosphate, the reaction being up to 2 orders of magnitude faster with the β,γ-(1-hydroxyethylidene) derivatives (4, 6) than with their β,γ-methylene counterparts (5, 7). With compound 7, deamination of the cytosine base competed with the phosphate hydrolysis at pH 3-6. The measurements at 37°C (pH 7.4) in the absence and presence of divalent alkaline earth metal ions (Mg2+ and Ca2+) showed no sign of metal ion catalysis. Under these conditions, the initial product, nucleoside 5′-monophosphate, underwent rapid dephosphorylation to the corresponding nucleoside. Hydrolysis of the β,γ-methylene derivatives (5, 7) to the corresponding nucleoside 5′-monophosphates was markedly faster in mouse serum than in aqueous buffer (pH 7.4), the rate-acceleration being 5600- and 3150-fold with 5 and 7, respectively. In human serum, the accelerations were 800- and 450-fold compared to buffer. In striking contrast, the β,γ-(1-hydroxyethylidene) derivatives did not experience a similar decrease in hydrolytic stability. The stability in human serum was comparable to that in aqueous buffer (τ1/2 = 17 and 33 h with 4 and 6, respectively), and on going to mouse serum, a 2- to 4-fold acceleration was observed. To elucidate the mineral-binding properties of 4-7, their retention on a hydroxyapatite column was studied and compared to that of zoledronate (1a) and nucleoside mono-, di-, and triphosphates.
BIOREDUCTIVELY-ACTIVATED PRODRUGS
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Page/Page column 25, (2010/10/20)
The present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, Formula: (1); wherein: R1 is a substituted aryl or heteroaryl group bearing at least one nitro or azido group or is an optionally substituted benzoquinone, optionally substituted naphthoquinone or optionally substituted fused heterocycloquinone; R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl or heteroaryl; and R3 is selected such that R3NH2 represents a cytotoxic nucleoside analogue or an ester or phosphate ester prodrug of a cytotoxic nucleoside analogue, with the proviso that if R1 is an aryl group then R2 is not H.
