95058-81-4 Usage
Description
Gemcitabine, also known as 2',2'-difluorodeoxycytidine (dFdCyd), is a potent deoxycytidine analog with a broad spectrum of antitumor activity. It is a chemotherapy drug that works by inhibiting the growth of cancer cells through various mechanisms, including DNA chain termination and the reduction of intracellular deoxynucleoside triphosphate pools.
Uses
Used in Oncology:
Gemcitabine is used as an anticancer agent for the treatment of various types of cancer, including breast cancer, ovarian cancer, pancreatic cancer, lung cancer, bladder cancer, bone cancer, Ewing's sarcoma, mesenchymal chondrosarcoma, osteosarcoma, dedifferentiated chondrosarcoma, head and neck cancers, hepatobiliary cancers, Hodgkin lymphoma, kidney cancer, malignant pleural mesothelioma, non-Hodgkin lymphoma, non-melanoma skin cancer, small cell lung cancer, soft tissue sarcoma, testicular cancer, thymic malignancies, and uterine malignancies.
Used in Combination Therapy:
Gemcitabine is used in combination with other medicines to enhance the treatment of cancer. It is particularly effective as a first-line treatment for locally advanced pancreatic cancer and has shown synergistic effects when combined with conventional chemotherapeutic drugs, improving chemo-sensitivity and efficacy in resistant cases.
Used in Radiosensitization:
Gemcitabine is used as a potent radiosensitizer, increasing the cytotoxicity of other chemotherapeutic agents such as cisplatin. This property makes it useful in combination therapies to improve the effectiveness of radiation treatments.
Used in Antiviral Applications:
Gemcitabine has demonstrated broad antiretroviral activity, decreasing cell infectivity in murine AIDS models and inhibiting the progression of the disease in vivo. This suggests potential applications in the treatment of retroviral infections.
Gemcitabine is available as the hydrochloride salt in lyophilized single-dose vials for intravenous use. It is metabolized to its active forms within cells, where it inhibits DNA synthesis and function, leading to cell death. However, resistance to Gemcitabine can occur due to decreased expression of activation enzymes, decreased drug transport, or increased expression of catabolic enzymes. The drug has low oral bioavailability due to deamination within the gastrointestinal tract and does not cross the blood-brain barrier. Common side effects of Gemcitabine treatment include myelosuppression, fever, malaise, chills, headache, myalgias, nausea, and vomiting.
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.
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.
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
95058-81-4Relevant 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.
4-N-Alkanoyl and 4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling
Pulido, Jesse,de Cabrera, Maria,Sobczak, Adam J.,Amor-Coarasa, Alejandro,McGoron, Anthony J.,Wnuk, Stanislaw F.
, p. 5624 - 5630 (2018/10/24)
The conjugation of 4-N-(3-aminopropanyl)-2′-deoxy-2′,2′-difluorocytidine with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1 M Na2CO3 buffer (pH 11) at ambient temperature provided