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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Cadexomer Iodine


Image result for cadexomer iodine

Cadexomer Iodine

Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009

CAS 94820-09-4

Title: Cadexomer Iodine
Trademarks: Iodosorb (Perstorp)
Literature References: A hydrophilic modified starch polymer containing 0.9% (w/w) iodine within a helical matrix. Produced by the reaction of dextrin with epichlorohydrin coupled with ion exchange groups and iodine. Clinical use in venous ulcers: E. Skog et al., Br. J. Dermatol. 109, 77 (1983); M. C. Ormiston et al., Br. Med. J. 291, 308 (1985); L. Hillström, Acta Chir. Scand. Suppl. 544,53 (1988).
Therap-Cat: Vulnerary.
Keywords: Vulnerary.

Listed in 1984 (Perstorp, Finland). For the treatment of exudative and infectious wounds, such as venous ulcers. This product is in contact with wound exudate to form a non-adhesive protective layer and release antibacterial iodine

Image result for cadexomer iodine

Product of reaction of dextrin with epichlorohydrin coupled with ion-exchange groups and iodine

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.[1]

The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. One of the major functions of CDSCO is approval of new drugs in the country. During the month of March 2018, CDSCO has approved the following drugs classifying them as New Drug Approvals

Cadexomer Iodine Bulk & Powder 100 % w/w (contain 0.9 % w/v Iodine) or Cadexomer Iodine Ointment 500 mg (contains 0.9% w/v iodine)

For the treatment of chronic exuding wounds such as leg ulcers, pressure ulcers and diabetes ulcers infected traumatic and surgical wounds.

Cadexomer iodine is an iodophor that is produced by the reaction of dextrin with epichlorhydrin coupled with ion-exchange groups and iodine. It is a water-soluble modified starch polymer containing 0.9% iodine, calculated on a weight-weight basis, within a helical matrix.

In India, M/s Virchow Biotech Private Limited presented their proposal for grant of license to manufacture and market this product in India. The firm presented the Phase III Clinical trial report titled ‘Safety and efficacy of Dexadine (Cadexomer Iodine) in the treatment of chronic wounds’ before the CDSCO’s Subject Expert Committee on Antibiotics & Antivirals. After detailed deliberation, the committee recommended the manufacturing and marketing of the products (Cadexomer Iodine Ointment & Cadexomer Iodine Powder), as topical preparations for the treatment of chronic exuding wounds

History

Cadexomer iodine was developed in the early 1980s in Sweden by Perstorp AB, and given the name Iodosorb. The product was shown to be effective in the treatment of venous ulcers,.[2][3] More recently, it has been shown in studies in animals and humans that, unlike the iodophor povidone-iodine, Iodosorb causes an acceleration of the healing process in chronic human wounds. This is due to an increase in epidermal regeneration and epithelialization in both partial-thickness and full-thickness wounds.[4] In this way cadexomer iodine acts as a cicatrizant.

Properties

When formulated as a topical wound dressing Iodosorb adsorbs exudate and particulate matter from the surface of granulating wounds and, as the dressing becomes moist, iodine is released. The product thus has the dual effect of cleansing the wound and exerting a bactericidal action.

Uses

In addition to other manufacturers, Smith & Nephew distributes cadexomer iodine as Iodosorb and Iodoflex in many countries of the world for the treatment and healing of various types of wounds. The dosage forms are a paste dressing, an ointment and a gel, all of which contain 0.9% iodine.

PATENT

WO2001070242

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001070242

PATENT

WO 2008117300

https://patents.google.com/patent/WO2008117300A2/und

Improved Process for the Preparation Of
Cadexomer Iodine

The present invention describes an improved method for the preparation of cadexomer iodine. Cadexomer iodine is a hydrophilic modified starch polymer containing 0.9%w/w iodine within the helical matrix. It is used for its absorbent and antiseptic properties in the management of chronic wounds such as venous leg ulcers, pressure sores, etc. It is applied as a powder or as an ointment over the wound.
Background of the invention
Cadexomer iodine is an iodophor that releases iodine. It contains 0.9%w/w iodine in hydrophilic modified starch carrier. It is used for its absorbent and antiseptic properties, in the management of venous leg ulcers and pressure sores, burn wounds etc. It is applied as a powder of microbeads or ointment containing iodine 0.9%w/w. When applied to the wound it absorbs fluids, removing exudates, pus and debris. As they swell, iodine is released which kills bacteria. When the color of the gel changes it indicates that the dressing should be changed. It is structurally represented as shown figure 1 , and chemically is known as2-hydroxy methylene cross-linked (1-4) α-D-glucan wther containing iodine.

R=H, CH2COOH

Figure: ! Structural representation of cadexomer iodine

The method of preparation of cadexomer iodine and it applications in clinical use is described in the US patent 4,010,259(1977). The process basically consists of two steps. The step one involves preparation of water insoluble, gel forming, and water swell able organic hydrophilic carrier. The next stage involves complexation of iodine with the above organic polymeric carrier.
The carrier is prepared by a polymerization /cross-linking reaction of a polyhydroxylic organic substance by means of a bifunctional organic cross-linking agent of the type Y-R-Z, wherein Y and Z each represent epoxy groups or halogen atoms and R is an organic residue. In this polymerization/cross linking reaction each of the functional groups Y and Z react with a hydroxy group of the polyhydroxylic organic material to form ether bonds. The linking has to proceed to the extent that the formed polymer becomes insoluble in water, but is capable of absorbing water.
The polyhydroxylic starting material used is dextrin or carboxy methyl dextrin and the cross linking agent used for the polymerization reaction is a bifunctional glycerol derivative such as epichlorohydrin, which is capable of forming ether bridges. The reaction between polyhdyroxy starting material and cross-linking agent epichlorohydrin is carried out by emulsion/suspension of polymerization reaction. This type reaction requires specially designed reactors with efficient stirring and an agent to disperse/ stabilize the reaction mass.
The reaction conditions mentioned in the patent uses toluene/water emulsion system, and which is stabilized/dispersed using toluene solution of a mixture of mono and di-esters of ortho phosphoric acid. This process has the following disadvantages:

Disadvantages of the prior art process

1. During cross-linking, the reaction mixture gets dried-up and sticks to the reaction vessel.
2. Efficient stirring is not possible due to formation of lumps.
3. Particles size of the cross-linked carrier is not uniform.
4. Iodine incorporation to carrier is not efficient; hence large excess has to be used.

5. The color of the product obtained by this process is dark brown, whereas product is expected to be golden yellow in color.

6. Results are not reproducible and batch-to-batch variations observed.
7. The stabilizer solution referred in the patent (US 4,010,259) is a solution of a mixture of mono and di-esters of ortho phosphoric acid, which is not available commercially..

Essentially similar procedures are described in Fr, Demande 2,320,1 12 (1977),
Australian 506,419 (1980), Finn 59,014(1981 ), Dan Dk 150,781 ( 1989). However the chemical nature and details of composition of stabilizer solution are not disclosed in these patents also.
An improved method for the preparation of cadexomer iodine is now developed free of these problems and which can easily scaled up to manufacturing level.

ADVANTAGES OF PRESENT INVENTION

1. The particle size of cadexomer iodine by the present process is fine and uniform, which is highly suitable for powder and ointment formulations.
2. Iodine incorporation to the cross-linked dextrin is efficient and consistent and swelling is appropriate
3. The color of cadexomer iodine obtained is golden yellow which is consistent and as per the expected color of the product.
4. The process is simple and economical and can be carried out in regular reactor with out any extra investment on the specialized equipment
5. Present process uses the dispersing agents, which are available commercially.

The details of the invention are described in examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example 1
Commercial dextrin (5Og) is dissolved in sodium hydroxide (50ml of 3.1N) containing sodium borohydride (0.75g), to this dispersing agent; sorbitan monooleate (Span 80, 3.75g) dissolved in toluene (125ml) is added. Then of epichlorohydrin (10 g) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (600ml) is added to the reaction mixture, and then neutralized to a pH of 6.5 with hydrochloric acid (2N). The product is filtered washed with acetone (500ml). The product is again washed with water (1000ml) and finally with acetone (300ml). The wet product is treated with a solution of iodine (7.8g) in acetone (196ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (150ml) and dried at 250C for 24h in a vacuum

desiccator.

Yield: 33g
Iodine content: .0.91 % w/w
Swelling capacity: 5.0ml/g

Example 2
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g); to this dispersing agent; cetrimide (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After completion of 5h, water (150 ml) is added, and then the reaction mixture was neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product was filtered and washed with acetone (100ml). Again the product washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine ( 1 ,6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 4.2g
Iodine content: 0.91% w/w
Swelling capacity: 6.0ml/g

Example 3
Commercial dextrin (1Og) is dissolved in sodium hydroxide (10ml of 3.1N) containing sodium borohydride (0.15g), to this dispersing agent; glyceryl monostearate (0.25g) dissolved in toluene (25ml) is added. Then of epichlorohydrin (2.Og) is added and reaction mixture is heated at 700C for 5h. After the completion of 5h, water (150 ml) is added, and then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (100ml). Again the product is washed with water (200ml) and finally with acetone (60ml). The wet product (carrier) is treated with a solution of iodine (1.6g) in acetone (40 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (40ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 3.3g
Iodine content: 0.9% w/w
Swelling capacity: 6.2ml/g

Example 4

Commercial carboxymethyl dextrin (20g) was dissolved in sodium hydroxide (20ml of 3.1N) containing sodium borohydride (0.3g), to this dispersing agent; glyceryl monostearate (1.Og) dissolved in toluene (75ml) is added. Then of epichlorohydrin (6.Og) is added and reaction mixture is heated at 700C for 5h After completion of 5h, water (280 ml) is added, then the reaction mixture is neutralized to a pH of 6.5 with hydrochloric acid (2N). The separated product is filtered and washed with acetone (250ml). Again the product is washed with water (500ml) and finally with acetone (150ml). The wet product (carrier) is treated with a solution of iodine (3.Ig) in acetone (60 ml) and stirred at 250C for 20 hours, then at O0C for 2 hours. The product is filtered in a sintered funnel under nitrogen atmosphere, washed with chilled acetone (60ml) and dried at 250C for 24h in a vacuum desiccator.

Yield: 16gms
Iodine content: 0.92 % w/w.
Swelling capacity: 5.8 ml per gram.

References

  1. Jump up^ Merck Index, 14th Edition, p262 Merck & Co. Inc.
  2. Jump up^ Skog, E. et al. (1983). A randomized trial comparing cadexomer iodine and standard treatment in the out-patient management of chronic venous ulcers. British Journal of Dermatology 109, 77. PMID 6344906
  3. Jump up^ Ormiston, M.C., Seymour, M.T., Venn, G.E., Cohen, R.I. and Fox, J.A. (1985). Controlled trial of Iodosorb in chronic venous ulcers. British Medical Journal (Clinical Research Edition) 291, 308-310. PMID 3962169
  4. Jump up^ Drosou Anna, Falabella Anna, and Kirsner Robert S. (2003) Antiseptics on Wounds: An area of controversy. Wounds 159(5) 149-166. http://cme.medscape.com/viewarticle/456300_2Retrieved 02/03/2009

Tang, M.B.; Tan, E.S.
Hailey-Hailey disease: Effective treatment with topical cadexomer iodine
J Derm Treat 2011, 22(5): 304

Early diagnosis and early corticosteroid administration improves healing of peristomal pyoderma gangrenosum in inflammatory bowel disease
Dis Colon Rectum 2009, 52(2): 311

Cadexomer iodine
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
ChemSpider
  • none

//////////////Cadexomer Iodine, ind 2018, Cadex, Declat, Decrat, Dextrinomer iodine, Iodoflex, Iodosorb, NI-009,

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Clofarabine


Clofarabine.svg

ChemSpider 2D Image | Clofarabine | C10H11ClFN5O3

Clofarabine.png

Clofarabine

  • Molecular FormulaC10H11ClFN5O3
  • Average mass303.677 Da
(2R,3R,4S,5R)-5-(6-Amino-2-chlor-9H-purin-9-yl)-4-fluor-2-(hydroxymethyl)tetrahydrofuran-3-ol
(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxyméthyl)tétrahydrofuran-3-ol
CAS 123318-82-1 [RN]
2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine [ACD/IUPAC Name]
762RDY0Y2H
8422
9H-Purin-6-amine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)- [ACD/Index Name]
Cl-F-Ara-A
QA-3028
STOCK1N-71250
UD7473000
UNII:762RDY0Y2H

CENTRAL DRUGS STANDARD CONTROL ORGANIZATION
DIRECTOR GENERAL OF HEALTH SERVICES,
MINISTRY OF HEALTH AND FAMILY WELFARE,
GOVERNMENT OF INDIA

approved

Clofarabine Bulk & Injection 20 mg/20ml vial
For the treatment of patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate
16.01.2018

Clofarabine is a purine nucleoside antimetabolite marketed in the US and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia(ALL) in children after at least two other types of treatment have failed. It is not known if it extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy, if any, for managing other cancers.

Clofarabine is a purine nucleoside antimetabolite that is being studied in the treatment of cancer. It is marketed in the U.S. and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra.

Clofarabine is used in paediatrics to treat a type of leukaemia called relapsed or refractory acute lymphoblastic leukaemia (ALL), only after at least two other types of treatment have failed. It is not known if the drug extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out.

For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.

Approval

Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)

Image result for us flag

Side effects

  • Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
  • Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
  • Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cellswhite blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
  • Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
  • Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
  • Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection. Clofarabine can also cause tachycardia and can affect the liver and kidneys.

Contraindications

  • pregnancy or planned pregnancy
  • breast-feeding
  • liver problems
  • kidney problems

Drug interactions

  • nephrotoxic drugs
  • hepatotoxic drugs

Delivery

  • By intravenous infusion.
  • Dosage is a 2-hour infusion (52 mg/m²) every day for five days. The cycle is repeated every 2 to 6 weeks.
  • Regular blood tests to monitor his or her blood cells, kidney function, and liver function.

Biology

Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.[1] A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.[2]

Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibits ribonucleotide reductase, resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.[3]

Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.[4] ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.[5] Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.[6]

Image result for clofarabine synthesis

Synthesis

Production of Clofarabine
The reaction flask was added 2-chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D arabinose yl) adenine 1.5g (3mmol) and methanol 40ml,mixed with stirring. Then it was added sodium methoxide, 0.05g (content> 50%), the reaction was stirred for 40min. Then the mixture was cooled to room temperature, adjusted to pH 7 with acetic acid, filtered, and the filter cake was washed with an ice-methanol 10ml, added to the methanol 40ml, and heated to 63 °C, and then cooled to -10 o C. Still 1h, filtered, and the filter cake was washed with an ice-methanol 10ml, drained, dried under reduced pressure to give an off-white powdery solid clofarabine 0.48g. The yield is 54%.

Image result for clofarabine synthesis

CLIP

Image result for clofarabine synthesis

http://pubs.rsc.org/en/content/articlehtml/2017/ra/c6ra27790j

CLIP

Image result for clofarabine synthesis

SYN 1

JP 1993502014; US 5034518; WO 9014352

Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol

Carbohydr Res 1975,42(2),233

Drugs Fut 2004,29(2),112

J Med Chem 1992,35(2),397

US 2003114663; WO 0311877

CA 2400470; EP 1261350; WO 0160383

References

  1. Jump up^ Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR (Jan 2003). “Antitumor activity of 2-fluoror-2’deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase”. Cancer Gene Ther10 (1): 23–29. doi:10.1038/sj.cgt.7700520PMID 12489025.
  2. Jump up^ Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S (Feb 2014). “Discovery and development of clofarabine: a nucleoside analogue for treating cancer”. nat Rev Drug Discov5 (10): 855–63. doi:10.1038/nrd2055PMID 17016426.
  3. Jump up^ Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). “Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs”. Chem Rev116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209PMID 27960273.
  4. Jump up^ Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F (1999). “Biochemical pharmacology and resistance to 2-chloro-2′-arabino-fluoro-2’deoxyadenosine, a novel analogue of cladribine in human leukemic cells”. Clin Cancer Res5 (9): 2438–44. PMID 10499616.
  5. Jump up^ Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD (Mar 2011). “Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity”Cancer Res75 (1): 1781–91. doi:10.1158/0008-5472.CAN-10-1919PMC 3531552Freely accessiblePMID 21245102.
  6. Jump up^ Arnold LH, Kunzelmann S, Webb MR, Taylor IA (Jan 2015). “A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1”Antimicrob Agents Chemother59 (1): 186–92. doi:10.1128/AAC.03903-14PMC 4291348Freely accessiblePMID 25331707.

External links

Clofarabine
Clofarabine.svg
Clinical data
Trade names Clolar, Evoltra
AHFS/Drugs.com Monograph
MedlinePlus a607012
License data
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.159.663
Chemical and physical data
Formula C10H11ClFN5O3
Molar mass 303.677 g/mol
3D model (JSmol)

//////////////////ind 2018, Clofarabine, Nucleotides

C1=NC2=C(N1C3C(C(C(O3)CO)O)F)N=C(N=C2N)Cl

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