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95058-81-4

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95058-81-4 Usage

Description

Different sources of media describe the Description of 95058-81-4 differently. You can refer to the following data:
1. Gemcitabine (2’,2’-difluorodeoxycytidine; dFdCyd) is a novel deoxycytidine analogue with both structural and metabolic similarities to cytarabine. It has a broad spectrum of antitumor activity in preclinical murine leukemia and solid tumor models. This drug requires intracellular phosphorylation that results in the accumulation of difluorodeoxycytidine triphosphate (dFdCTP). The dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, which in turn inhibits DNA synthesis and terminates DNA chain elongation. In addition, this drug reduces intracellular deoxynucleoside triphosphate pools, presumably through the inhibition of ribonucleotide reductase. Gemcitabine is used alone or with other treatments/medications to treat certain types of cancer (including breast cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, bladder cancer, bone cancer, Ewing’s sarcoma, mesenchymal chondrosarcoma osteosarcoma, dedifferentiated chondrosarcoma, head and neck cancers-cancer of the nasopharynx, hepatobiliary cancers including gallbladder cancer, Hodgkin lymphoma, kidney cancer, malignant pleural mesothelioma, non Hodgkin lymphoma, non-melanoma skin cancer – dermatofibrosarcoma protuberans (DFSP), occult primary, small cell lung cancer, soft tissue sarcoma, testicular cancer, thymic malignancies, uterine malignancies). It is a chemotherapy drug that works by slowing or stopping the growth of cancer cells. One commercial product of gemcitabine is Gemzar, which is supplied in a sterile form for intravenous use only.
2. Gemcitabine is an anticancer nucleoside analog that inhibits the growth of HL-60 promyelocytic leukemia cells with an LC50 value of 40 nM. It inhibits the growth of MX-1 mammary, CX-1, HC-1, GC3, and VRC5 colon, LX-1, Calu-6, and NCI-H460 lung, and HS766T, PaCa-2, PANC-1, and BxPC-3 pancreatic cancer tumors in mouse xenograft models (45-93% inhibition). Gemcitabine is a prodrug that is metabolized to a diphosphate and triphosphate form in cells. The triphosphate form is incorporated into DNA which induces masked chain termination and cell death. By specifically inhibiting growth arrest and DNA damage inducible protein 45 a (Gadd45a), a key mediator of active DNA demethylation, gemcitabine, at concentrations ranging from 34 to 134 nM, inhibits repair-mediated DNA demethylation in a methylation-sensitive reporter assay. Gemcitabine also has broad antiretroviral activity, decreasing MuLV cell infectivity, a murine AIDS model, in cell culture (EC50 = ~1.5 nM) and inhibits the progression of murine AIDS in vivo at a dose of 1-2 mg/kg per day.

References

[1] H. A. Burris, M. J. Moore, J. Andersen, M. R. Green, M. L. Rothenberg, M. R. Modiano, M. C. Cripps, R. K. Portenoy, A. M. Storniolo, P. Tarassoff, R. Nelson, F. A. Dorr, C. D. Stephens, D. D. Von Hoff (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, 15, 2403-2413 [2] http://www.webmd.com/drugs/2/drug-13451/gemcitabine-intravenous/details

Originator

Gemzar,Lilly Co.

Uses

Different sources of media describe the Uses of 95058-81-4 differently. You can refer to the following data:
1. Gemcitabine is used for breast cancer treatment. First-line treatment for locally advanced pancreatic cancer.
2. Gemcitabine(Gemzar) belongs to the group of medicines called antimetabolites. It is used alone or in combination with other medicines to treat cancer of the breast, ovary, pancreas, and lung. Gemcitabine interferes with the growth of cancer cells, which a

Indications

Gemcitabine (Gemzar), an antimetabolite, undergoes metabolic activation to difluorodeoxycytidine triphosphate, which interferes with DNA synthesis and repair. It is the single most active agent for the treatment of metastatic pancreatic cancer, and it is used as a first-line treatment for both pancreatic and small cell lung cancer. It is administered by intravenous infusion. The dose-limiting toxicity is bone marrow suppression.

Manufacturing Process

Benzyl 4,6-O-benzylidene-2-O-benzyl-3-oxo-α-D-gluco-pyranoside was obtained by 4 steps from glucose. 0.53 ml (4.0 mmol) of DAST (fluorinaiting agent) was added to asolution of 300 mg (0.67 mmol) of benzyl 4,6-O-benzylidene-2-O-benzyl-3-oxo-α-Dgluco-pyranoside in anhydrous dichloromethane (4 ml). The solution was then stirred at room temperature for 2 h, and the excess of DAST was neutralized by careful addition of saturated aqueous NaHCO3. The resulting mixture was extracted with CH2Cl2, and organic phase was dried and evaporated. The residue was purified by CC (Hexane/Ethyl acetate 7:1) to afford benzyl 4,6-Obenzylidene-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-gluco-pyranoside (189 mg, 60%), melting point 118°-119°C. Benzyl 4,6-O-benzylidene-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-glucopyranoside (77 mg, 0.16 mmol) was dissolved in a 0.1 N solution of HCl in ethanol and stirred at room temperature for 40 h. The solution was then neutralized with solid NaHCO3, filtered and evaporated to give an oily product that was dissolved in 2 ml of CH2Cl2 and 0.5 ml of pyridine. After cooling to 0°C, 0.40 ml (1.6 mmol) of benzoyl chloride was added and the solution was stirred for 1 h and poured into ice and water (200 ml) containing NaHCO3, extracted several times with CH2Cl2, dried and evaporated to give 86 mg (0.14 mmol, 90%) of benzyl 4,6-di-O-benzoyl-2-O-benzyl-3-deoxy-3,3- difluoro-α-D-gluco-pyranoside. Benzyl 4,6-di-O-benzoyl-2-O-benzyl-3-deoxy-3,3-difluoro-α-D-glucopyranoside (220 mg, 0.44 mmol) was dissolved in methanol in the presence of 200 mg of palladium on activated charcoal (10% Pd content). The suspension was stirred at room temperature under hydrogen pressure (10 bar) for 16 h. The suspension was then filtered through a thin silica gel pad, and evaporated. The residue was purified by CC to give 105 mg (59%) of 4,6- di-O-benzoyl-3-deoxy-3,3-difluoro-α/β-D-gluco-pyranoside as an inseparable anomeric mixture (ratio α/β = 5:1). To a solution of 46 mg (0.11 mmol) of 4,6-di-O-benzoyl-3-deoxy-3,3-difluoro- α/β-D-gluco-pyranoside in water-dioxane 1:2 (2 ml) was added 120 mg (0.56 mmol) of sodium periodate. This resulting solution was stirred at room temperature for 20 h. Then, more sodium periodate (55 mg, 0.26 mmol) was added and stirring was continued for 6 h. After that, the solvents were evaporated and the solid was repeatedly extracted with ethyl acetate (total volume 70 ml). The solvent was then evaporated to give a solid that was treated for 15 min with a diluted (0.1%) methanolic solution of ammonia. THE solution was evaporated and the crude purified by preparative TLC (hexane/ethyl acetate 2:1) to yield 18 mg (0.04 mmol, 43%) of α-3,5-di-Obenzoyl-2-deoxy-2,2-difluoro-D-ribose.

General Description

The drug is available as the hydrochloride salt in 200- and1,000-mg lyophilized single-dose vials for IV use.Gemcitabine is used to treat bladder cancer, breast cancer,pancreatic cancer, and NSCLC. Gemcitabine is a potent radiosensitizer,and it increases the cytotoxicity of cisplatin.The mechanism of action of this fluorine-substituted deoxycytidineanalog involves inhibition of DNA synthesis andfunction via DNA chain termination. The triphosphatemetabolite is incorporated into DNA inhibiting severalDNA polymerases and incorporated into RNA inhibitingproper function of mRNA. Resistance can occur because ofdecreased expression of the activation enzyme deoxycytidinekinase or decreased drug transport as well as increasedexpression of catabolic enzymes. Drug oral bioavailabilityis low because of deamination within the GI tract, and thedrug does not cross the blood-brain barrier. Metabolism bydeamination to 2', 2'-difluorouridine (dFdU) is extensive.Drug toxicity includes myelosuppression, fever, malaise,chills, headache, myalgias, nausea, and vomiting.

Hazard

Human systemic effects

Clinical Use

Antineoplastic agent: Palliative treatment, or first-line treatment with cisplatin, of locally advanced or metastatic non-small cell lung cancer Pancreatic, ovarian and breast cancer Bladder cancer in combination with cisplatin

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

After intravenous doses gemcitabine is rapidly cleared from the blood and metabolised by cytidine deaminase in the liver, kidney, blood, and other tissues. Clearance is about 25% lower in women than in men. Almost all (99%) of the dose is excreted in urine as 2′-deoxy-2′,2′-difluorouridine (dFdU), only about 1% being found in the faeces. Intracellular metabolism produces mono-, di-, and triphosphate metabolites, the latter two active. The active intracellular metabolites have not been detected in plasma or urine.

references

[1] karnitz lm, flatten ks, wagner jm, et al. gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. mol pharmacol, 2005, 68 (6): 1636-1644. [2] ando t, ichikawa j, okamoto a, et al. gemcitabine inhibits viability, growth, and metastasis of osteosarcoma cell lines. j orthop res, 2005, 23 (4): 964-969. [3] clouser cl, holtz cm, mullett m, et al. analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. plos one, 2011, 6 (1): e15840.

Check Digit Verification of cas no

The CAS Registry Mumber 95058-81-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 9,5,0,5 and 8 respectively; the second part has 2 digits, 8 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 95058-81:
(7*9)+(6*5)+(5*0)+(4*5)+(3*8)+(2*8)+(1*1)=154
154 % 10 = 4
So 95058-81-4 is a valid CAS Registry Number.
InChI:InChI=1/C9H11F2N3O4/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17)/t4-,6-,7?/m1/s1

95058-81-4SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name Gemcitabine

1.2 Other means of identification

Product number -
Other names 3-DEOXY-2,2-DIFLUORO-D-RIBOFURANOSE-3,5-DIBENZOATE

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:95058-81-4 SDS

95058-81-4Synthetic route

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-2-((3-fluorobenzoyloxy)methyl)tetrahydrofuran-3-yl 3-fluorobenzoate
942288-40-6

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-2-((3-fluorobenzoyloxy)methyl)tetrahydrofuran-3-yl 3-fluorobenzoate

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia; water at 20℃; for 3h;100%
With methanol; ammonia; water at 20℃; for 3h;100%
(2'-deoxy-2',2'-difluorocytidine)-3',5'-dibenzoate
134790-39-9

(2'-deoxy-2',2'-difluorocytidine)-3',5'-dibenzoate

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonium hydroxide In methanol at 20℃; for 3h;82.7%
With sodium t-butanolate In methanol at 20℃; for 2h;
1-(2'-deoxy-2',2'-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-β-D-arabinofuranosyl)-4-aminopyrimidine-2-one
896109-84-5

1-(2'-deoxy-2',2'-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-β-D-arabinofuranosyl)-4-aminopyrimidine-2-one

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In methanol at 20℃; for 12h; Product distribution / selectivity;76.9%
1-(5'-O-benzoyl-2'-deoxy-2',2'-difluoro-3-O-(p-phenylbenzoyl)-D-ribofuranosyl)-4-aminopyrimidin-2-one

1-(5'-O-benzoyl-2'-deoxy-2',2'-difluoro-3-O-(p-phenylbenzoyl)-D-ribofuranosyl)-4-aminopyrimidin-2-one

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In methanol at 20℃; Product distribution / selectivity;72.6%
With ammonia In methanol at 20℃; Product distribution / selectivity;72.6%
With ammonia; water In methanol at 20℃; for 12h;71%
With ammonia In methanol at 20℃; Product distribution / selectivity;
(2R,3R)-5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate

(2R,3R)-5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With Amberlite IRA 400, OH-form In methanol at 40 - 45℃; for 36h; Product distribution / selectivity;71%
With ammonia In methanol; water at 20℃; for 24h; Product distribution / selectivity;
C31H25F2N3O7

C31H25F2N3O7

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In methanol Product distribution / selectivity;63%
With ammonia In methanol for 8h; Product distribution / selectivity;63%
With ammonia In methanol
2-amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide trifluoroacetic acid
1018907-93-1

2-amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide trifluoroacetic acid

A

C11H14F2N4O5
1018908-06-9

C11H14F2N4O5

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With sodium hydrogencarbonate In methanolA 51%
B n/a
2'-deoxy-2',2'-difluoro-3',5'-di-O-(triisopropylsilyl)cytidine
1260238-57-0

2'-deoxy-2',2'-difluoro-3',5'-di-O-(triisopropylsilyl)cytidine

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With tetramethylammonium fluoride; acetic acid In N,N-dimethyl-formamide at 20℃; stereoselective reaction;A 42%
B 36%
With tetramethylammonium fluoride; acetic acid In N,N-dimethyl-formamide at 20℃;
C2HF3O2*C14H18F2N4O5
1018908-14-9

C2HF3O2*C14H18F2N4O5

A

C14H18F2N4O5
1018908-15-0

C14H18F2N4O5

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With sodium hydrogencarbonate In methanolA 38%
B n/a
bis(trimethylsilyl)-N-acetylcytosine
18027-23-1

bis(trimethylsilyl)-N-acetylcytosine

3,5-bis-O-(tert-butyldimethylsilyl)-1-O-(methanesulfonyl)-2-deoxy-2,2-difluororibose
103882-89-9

3,5-bis-O-(tert-butyldimethylsilyl)-1-O-(methanesulfonyl)-2-deoxy-2,2-difluororibose

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
Multistep reaction;
1-[2'-deoxy-2',2'-difluoro-3',5'-bis(tert-butyldiphenylsilyloxy)-ribofuranosyl]-cytosine
952408-92-3

1-[2'-deoxy-2',2'-difluoro-3',5'-bis(tert-butyldiphenylsilyloxy)-ribofuranosyl]-cytosine

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonium fluoride In methanol at 65℃; for 3h;
gemcitabine hydrochloride
122111-03-9

gemcitabine hydrochloride

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With potassium carbonate In ethanol; dichloromethane at 20℃;
With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h;
Multi-step reaction with 4 steps
1: 1H-imidazole / N,N-dimethyl-formamide / 2.5 h / 20 °C
2: pyridine / tetrahydrofuran / 1 h / 4 °C
3: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C
4: Pd0-functionalized resin / aq. phosphate buffer / 37 °C / pH 7.4
View Scheme
Multi-step reaction with 4 steps
1: 1H-imidazole / N,N-dimethyl-formamide / 2.5 h / 20 °C
2: pyridine / tetrahydrofuran / 20 °C
3: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C
4: Pd0-functionalized resin / aq. phosphate buffer / 37 °C / pH 7.4
View Scheme
Multi-step reaction with 4 steps
1: 1H-imidazole / N,N-dimethyl-formamide / 2.5 h / 20 °C
2: pyridine / tetrahydrofuran / 48 h / 20 °C
3: tetrabutyl ammonium fluoride / tetrahydrofuran / 3 h / 20 °C
4: Pd0-functionalized resin / aq. phosphate buffer / 37 °C / pH 7.4
View Scheme
N4-benzoyl-2'-deoxy-2',2'-difluorocytidine
142816-70-4

N4-benzoyl-2'-deoxy-2',2'-difluorocytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With pyridine; ammonium hydroxide In water at 37℃; for 18h; Kinetics;
C13H15F2N3O6
861445-90-1

C13H15F2N3O6

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With sodium ethanolate In isopropyl alcohol for 1 - 6h; Heating / reflux;
N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-propylpentanamide
892128-60-8

N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-propylpentanamide

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With water; CD-1 mouse small intestinal homogenate for 6h; pH=7.5; Conversion of starting material; Aqueous acetate buffer; Enzymatic reaction;
With water; CD-1 mouse post-mitochondrial liver (S9) homogenate for 6h; pH=8.0; Conversion of starting material; Aqueous phosphate buffer; Enzymatic reaction;
With water; beagle dog post-mitochondrial liver (S9) homogenate for 6h; pH=8.0; Conversion of starting material; Aqueous phosphate buffer; Enzymatic reaction;
1-(5'-O-benzoyl-2'-deoxy-2',2'-difluoro-3-O-(p-phenylbenzoyl)-D-ribofuranosyl)-4-aminopyrimidin-2-one

1-(5'-O-benzoyl-2'-deoxy-2',2'-difluoro-3-O-(p-phenylbenzoyl)-D-ribofuranosyl)-4-aminopyrimidin-2-one

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In methanol at 20℃; Product distribution / selectivity;
With ammonia In methanol at 20℃;
With ammonia In methanol at 20℃; for 10h; Product distribution / selectivity;
N4-(1-(5-nitrothien-2-yl)ethyl)oxycarbonyl-2',2'-difluoro-2'-deoxycytidine

N4-(1-(5-nitrothien-2-yl)ethyl)oxycarbonyl-2',2'-difluoro-2'-deoxycytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
In water; isopropyl alcohol G-values; Irradiation;
N4-(2-nitro-1-methylimidazol-5-yl)methoxycarbonyl-2',2'-difluoro-2'-deoxycytidine

N4-(2-nitro-1-methylimidazol-5-yl)methoxycarbonyl-2',2'-difluoro-2'-deoxycytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
In water; isopropyl alcohol G-values; Irradiation;
N4-(5-nitrothien-2-yl)methoxycarbonyl-2',2'-difluoro-2'-deoxycytidine

N4-(5-nitrothien-2-yl)methoxycarbonyl-2',2'-difluoro-2'-deoxycytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
In water; isopropyl alcohol G-values; Irradiation;
3',5'-bis(tert-butyldiphenylsilyloxy)-2',2'-difluoro-2'-deoxycytidine

3',5'-bis(tert-butyldiphenylsilyloxy)-2',2'-difluoro-2'-deoxycytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 15 - 30℃; for 5.33333h;
2',2'-difluoro-2'-deoxy-N-acetylcytidine-3',5'-dibenzoate

2',2'-difluoro-2'-deoxy-N-acetylcytidine-3',5'-dibenzoate

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With methanol; ammonia at -5 - 5℃; for 8 - 10h;
(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate hydrochloride
1147119-18-3

(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate hydrochloride

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In methanol Product distribution / selectivity;
With methanol; 2,2,2-trifluoroethanol; potassium carbonate Product distribution / selectivity;
2’-deoxy-2’,2’-difluoro-cytidine
103882-84-4

2’-deoxy-2’,2’-difluoro-cytidine

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With ammonia In water Resolution of racemate;
C23H19F2N3O6
1155863-81-2

C23H19F2N3O6

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
With sodium methylate
2-deoxy-2,2-difluoro-3,5-di-O-(triisopropylsilyl)-D-ribofuranose

2-deoxy-2,2-difluoro-3,5-di-O-(triisopropylsilyl)-D-ribofuranose

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: triethylamine / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere
2.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 0.5 h / 20 °C
2.2: Reflux
3.1: tetramethylammonium fluoride; acetic acid / N,N-dimethyl-formamide / 20 °C
View Scheme
Multi-step reaction with 3 steps
1.1: methanesulfonyl chloride; triethylamine / dichloromethane
2.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 0.5 h / 20 °C
2.2: Reflux
3.1: tetramethylammonium fluoride; acetic acid / N,N-dimethyl-formamide / 20 °C
View Scheme
1-methylsulfonyl-2-deoxy-2,2-difluoro-3,5-di-O-(triisopropylsilyl)-D-ribofuranose
1173700-36-1

1-methylsulfonyl-2-deoxy-2,2-difluoro-3,5-di-O-(triisopropylsilyl)-D-ribofuranose

A

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose
95058-85-8

α-1-(2-oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 0.5 h / 20 °C
1.2: Reflux
2.1: tetramethylammonium fluoride; acetic acid / N,N-dimethyl-formamide / 20 °C
View Scheme
Multi-step reaction with 2 steps
1.1: trimethylsilyl trifluoromethanesulfonate / 1,2-dichloro-ethane / 0.5 h / 20 °C
1.2: Reflux
2.1: tetramethylammonium fluoride; acetic acid / N,N-dimethyl-formamide / 20 °C
View Scheme
C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

A

C4H11N*C72H72N4O12*H(1+)

C4H11N*C72H72N4O12*H(1+)

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
at 20℃; under 9.0009E-09 Torr; Kinetics; Fourier-Transform Ion Cyclotron Resonance mass spectrometer;
C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

A

C4H11N*C72H72N4O12*H(1+)

C4H11N*C72H72N4O12*H(1+)

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
at 20℃; under 9.75098E-09 Torr; Kinetics; Fourier-Transform Ion Cyclotron Resonance mass spectrometer;
C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

C4H11N*C9H11F2N3O4*C72H72N4O12*H(1+)

A

C4H11N*C72H72N4O12*H(1+)

C4H11N*C72H72N4O12*H(1+)

B

gemcitabine
95058-81-4

gemcitabine

Conditions
ConditionsYield
at 20℃; under 3.0003E-08 Torr; Kinetics; Fourier-Transform Ion Cyclotron Resonance mass spectrometer;
1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane
69304-37-6

1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane

gemcitabine
95058-81-4

gemcitabine

4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f] [1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one
1254062-21-9

4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f] [1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one

Conditions
ConditionsYield
With pyridine at 20℃; for 4h;100%
With pyridine at 20℃; for 48h;84%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;82.3%
tert-butyldimethylsilyl chloride
18162-48-6

tert-butyldimethylsilyl chloride

gemcitabine
95058-81-4

gemcitabine

4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
688009-09-8

4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)pyrimidin-2(1H)-one

Conditions
ConditionsYield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Cooling with ice; Inert atmosphere;99%
With 1H-imidazole at 20℃;97.1%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Solvent; Reagent/catalyst;95%
chloroformic acid ethyl ester
541-41-3

chloroformic acid ethyl ester

gemcitabine
95058-81-4

gemcitabine

1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-4-(ethoxycarbonylamino)pyrimidin-2-one
155968-14-2

1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-4-(ethoxycarbonylamino)pyrimidin-2-one

Conditions
ConditionsYield
In ethyl acetate; acetonitrile for 3h; Inert atmosphere; Reflux;98.31%
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

gemcitabine
95058-81-4

gemcitabine

(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl tert-butyl carbonate
250698-51-2

(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl tert-butyl carbonate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 20℃; for 50h;94%
With sodium carbonate In water at 20℃; for 30h;89%
With sodium carbonate In 1,4-dioxane; water at 20℃; for 72h;88%
1,5-pentanedioic acid
110-94-1

1,5-pentanedioic acid

gemcitabine
95058-81-4

gemcitabine

1-hydroxybenzotriazol-hydrate
80029-43-2, 123333-53-9

1-hydroxybenzotriazol-hydrate

5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl)amino)-5-oxo-pentanoic acid

5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl)amino)-5-oxo-pentanoic acid

Conditions
ConditionsYield
With 4-methyl-morpholine94%
gemcitabine
95058-81-4

gemcitabine

gemcitabine hydrochloride
122111-03-9

gemcitabine hydrochloride

Conditions
ConditionsYield
With hydrogenchloride In water; isopropyl alcohol at 20 - 70℃;93.4%
With hydrogenchloride In water; acetone at 20℃; for 2h; Product distribution / selectivity;91.5%
With hydrogenchloride In isopropyl alcohol at 0 - 5℃; for 2h; pH=2;90%
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

gemcitabine
95058-81-4

gemcitabine

3′,5′-O-bis(tert-butoxycarbonyl)-gemcitabine
250698-52-3

3′,5′-O-bis(tert-butoxycarbonyl)-gemcitabine

Conditions
ConditionsYield
Stage #1: gemcitabine With potassium hydroxide In water at 20℃; for 1h;
Stage #2: di-tert-butyl dicarbonate In 1,4-dioxane; water at 20℃; for 1h;
93%
Stage #1: gemcitabine With potassium hydroxide In water for 1h;
Stage #2: di-tert-butyl dicarbonate In 1,4-dioxane; water at 20℃; for 2.67h;
90%
With potassium hydroxide In 1,4-dioxane
benzoyl chloride
98-88-4

benzoyl chloride

gemcitabine
95058-81-4

gemcitabine

(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate
1445381-44-1

(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-yl benzoate

Conditions
ConditionsYield
With pyridine; dmap at 0 - 20℃; for 3.5h; Inert atmosphere;93%
trityl chloride
76-83-5

trityl chloride

gemcitabine
95058-81-4

gemcitabine

5'-Tr-gemcytabine

5'-Tr-gemcytabine

Conditions
ConditionsYield
With triethylamine In pyridine at 20℃; for 6h; Inert atmosphere; Cooling with ice; regioselective reaction;91.2%
Azelaic anhydride
45289-91-6

Azelaic anhydride

gemcitabine
95058-81-4

gemcitabine

5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl)amino)-5-oxo-nonanoic acid

5-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl)amino)-5-oxo-nonanoic acid

Conditions
ConditionsYield
91%
benzyl chloroformate
501-53-1

benzyl chloroformate

gemcitabine
95058-81-4

gemcitabine

4-(benzyloxycarbonylamino)-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-one
138685-83-3

4-(benzyloxycarbonylamino)-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-one

Conditions
ConditionsYield
Stage #1: gemcitabine With pyridine; chloro-trimethyl-silane at 4 - 20℃; for 1.5h; Inert atmosphere;
Stage #2: benzyl chloroformate In methanol at 20℃; Inert atmosphere;
91%
gemcitabine
95058-81-4

gemcitabine

4-amino-1-(2-deoxy-2,2’-difluoro-β-D-erythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one
95058-82-5

4-amino-1-(2-deoxy-2,2’-difluoro-β-D-erythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one

Conditions
ConditionsYield
With hydrogen iodide; iodine In tetrachloromethane; ethanol; water at 45℃; for 16h;90%
gemcitabine
95058-81-4

gemcitabine

p-toluenesulfonyl chloride
98-59-9

p-toluenesulfonyl chloride

N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-methylbenzenesulfonamide
1519060-68-4

N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-4-methylbenzenesulfonamide

Conditions
ConditionsYield
With pyridine; chloro-trimethyl-silane; ammonia In methanol Inert atmosphere;90%
With pyridine; chloro-trimethyl-silane at 20℃; for 2h; Inert atmosphere;83%
vinyl myristate
5809-91-6

vinyl myristate

gemcitabine
95058-81-4

gemcitabine

O5’-tetradecanoyl-2',2'-difluoro-2'-deoxycytidine

O5’-tetradecanoyl-2',2'-difluoro-2'-deoxycytidine

Conditions
ConditionsYield
With pyridine; lipase B Candida antarctica In hexane at 50℃; for 6h; Enzymatic reaction;89%
N-(pyridin-4-carbonyl)-D-Ala-L-Proline

N-(pyridin-4-carbonyl)-D-Ala-L-Proline

gemcitabine
95058-81-4

gemcitabine

C23H26F2N6O7

C23H26F2N6O7

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide87%
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

gemcitabine
95058-81-4

gemcitabine

tert-butyl [1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-carbamate

tert-butyl [1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-carbamate

Conditions
ConditionsYield
In N,N-dimethyl-formamide at 50℃; for 18h;86%
In N,N-dimethyl-formamide at 50℃; for 18h;86%
(R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester

(R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester

gemcitabine
95058-81-4

gemcitabine

C21H27F2N4O8P

C21H27F2N4O8P

Conditions
ConditionsYield
In tetrahydrofuran at 0℃;85%
(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester
1334513-02-8

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester

gemcitabine
95058-81-4

gemcitabine

isopropyl ((S)-(((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

isopropyl ((S)-(((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions
ConditionsYield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 22h; Inert atmosphere; diastereoselective reaction;83%
(fluorenylmethoxy)carbonyl chloride
28920-43-6

(fluorenylmethoxy)carbonyl chloride

gemcitabine
95058-81-4

gemcitabine

(9H-fluoren-9-yl)methyl (1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate

(9H-fluoren-9-yl)methyl (1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate

Conditions
ConditionsYield
Stage #1: gemcitabine With pyridine; chloro-trimethyl-silane for 0.333333h;
Stage #2: (fluorenylmethoxy)carbonyl chloride In water for 2.5h;
80.9%
Stage #1: gemcitabine With 1H-imidazole; dmap; tert-butyldimethylsilyl chloride In N,N-dimethyl-formamide at 20℃;
Stage #2: (fluorenylmethoxy)carbonyl chloride With pyridine In dichloromethane at 20℃;
Stage #3: With pyridine hydrogenfluoride In tetrahydrofuran at 20℃; for 24h;
79.4%
4,4'-dimethoxytrityl chloride
40615-36-9

4,4'-dimethoxytrityl chloride

gemcitabine
95058-81-4

gemcitabine

C30H29F2N3O6
1421929-71-6

C30H29F2N3O6

Conditions
ConditionsYield
With pyridine at 20℃; for 4h;80%
With pyridine at 0 - 20℃; for 4h;64%
With pyridine at 0 - 20℃; for 4h;39%
(2S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)-phenoxy-phosphorylamino]propionic acid benzyl ester

(2S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)-phenoxy-phosphorylamino]propionic acid benzyl ester

gemcitabine
95058-81-4

gemcitabine

benzyl ((S)-(((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

benzyl ((S)-(((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions
ConditionsYield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 20h; Inert atmosphere; diastereoselective reaction;80%
C18H26O13
807370-86-1

C18H26O13

gemcitabine
95058-81-4

gemcitabine

C27H35F2N3O16

C27H35F2N3O16

Conditions
ConditionsYield
Stage #1: C18H26O13 With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;
Stage #2: gemcitabine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
80%
gemcitabine
95058-81-4

gemcitabine

Gemcitabine monophosphate
116371-67-6

Gemcitabine monophosphate

Conditions
ConditionsYield
Stage #1: gemcitabine With trichlorophosphate at 20℃; for 0.15h; Flow reactor; Green chemistry;
Stage #2: With water at 20℃; Temperature; Flow reactor; Green chemistry; chemoselective reaction;
78%
With trimethyl phosphite; trichlorophosphate at -5℃; for 2h;53%
With recombinant deoxyribonucleoside kinase AtdNK from Arabidopsis thaliana (ecotype Columbia); ATP In aq. buffer Kinetics; Concentration; Reagent/catalyst; Enzymatic reaction;
Multi-step reaction with 5 steps
1: pyridine / 4 h / 0 - 20 °C
2: pyridine / 2 h / 0 - 20 °C
3: toluene-4-sulfonic acid / dichloromethane / 2 h / 20 °C
4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 20 °C
5: ammonium hydroxide
View Scheme
Multi-step reaction with 7 steps
1: pyridine / 4 h / 0 - 20 °C
2: pyridine / 2 h / 0 - 20 °C
3: toluene-4-sulfonic acid / dichloromethane / 2 h / 20 °C
4: N-ethyl-N,N-diisopropylamine / dichloromethane
5: 1H-tetrazole; water / acetonitrile
6: pyridine; iodine; triethylamine; water
7: ammonium hydroxide
View Scheme
vinyl laurate
2146-71-6

vinyl laurate

gemcitabine
95058-81-4

gemcitabine

O5'-dodecanoyl-2',2'-difluoro-2'-deoxycytidine

O5'-dodecanoyl-2',2'-difluoro-2'-deoxycytidine

Conditions
ConditionsYield
With pyridine; lipase B Candida antarctica In hexane at 50℃; for 6h; Enzymatic reaction;76.9%
C30H33N2O8S3(1-)

C30H33N2O8S3(1-)

gemcitabine
95058-81-4

gemcitabine

C39H42F2N5O11S3(1-)

C39H42F2N5O11S3(1-)

Conditions
ConditionsYield
Stage #1: C30H33N2O8S3(1-) With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 0.5h;
Stage #2: gemcitabine In dimethyl sulfoxide for 15h;
75%
succinic acid anhydride
108-30-5

succinic acid anhydride

gemcitabine
95058-81-4

gemcitabine

N4-n-butyryl gemcitabine
1374587-08-2

N4-n-butyryl gemcitabine

Conditions
ConditionsYield
With triethylamine In N,N-dimethyl-formamide at 60℃; Inert atmosphere;75%
succinic acid
110-15-6

succinic acid

gemcitabine
95058-81-4

gemcitabine

N-(3-Carboxy-1-oxopropyl)-2'-deoxy-2',2'-difluorocytidine

N-(3-Carboxy-1-oxopropyl)-2'-deoxy-2',2'-difluorocytidine

Conditions
ConditionsYield
Stage #1: succinic acid With thionyl chloride; triethylamine In 1,4-dioxane at 110℃; for 4h; Inert atmosphere;
Stage #2: gemcitabine With triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
75%

95058-81-4Relevant articles and documents

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Fang, Jianguo,Hou, Yanan,Li, Jin,Li, Xinming,Wang, Song,Zhao, Jintao

, p. 3215 - 3222 (2020/04/08)

Cancer cells are vulnerable to reactive oxygen species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine (Gem), Se-Gem, and evaluated its activation and biological effects in cancer cells. Se-Gem was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug Gemvia a carbamate linker. Se-Gem is preferably activated by glutathione (GSH) and displays a remarkably higher potency than Gem (up to a 6-fold increase) to a panel of cancer cell lines. The activation of Se-Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS via redox cycling reactions. Thus Se-Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se-Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

Matsushita, Katsunori,Okuda, Takumi,Mori, Shohei,Konno, Masamitsu,Eguchi, Hidetoshi,Asai, Ayumu,Koseki, Jun,Iwagami, Yoshifumi,Yamada, Daisaku,Akita, Hirofumi,Asaoka, Tadafumi,Noda, Takehiro,Kawamoto, Koichi,Gotoh, Kunihito,Kobayashi, Shogo,Kasahara, Yuuya,Morihiro, Kunihiko,Satoh, Taroh,Doki, Yuichiro,Mori, Masaki,Ishii, Hideshi,Obika, Satoshi

, p. 1384 - 1391 (2019/07/12)

The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.

Difluoronucleoside antimetabolite anticancer drug for destroying cell replication

-

Paragraph 0040; 0053; 0053; 0057; 0065, (2018/09/13)

The invention provides a difluoronucleoside antimetabolite anticancer drug for destroying cell replication as well as preparation and application of pharmaceutical composition of the antimetabolite anticancer drug. The chemical structural formula of the difluoronucleoside antimetabolite anticancer drug for destroying cell replication is shown as (A) in the description. The drug is an important anticancer drug, has the characteristic of wide antitumor spectrum, shows better anticancer activity in various tumors such as non-small cell lung cancer, breast cancer, pancreatic cancer and the like, and is one of the first choices for treatment of the non-small cell lung cancer and also one of the first choices for chemotherapy of pancreatic cancer.

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