Synthesis and Biological Activity of 2',2'-Difluorodeoxycytidine (Gemcitabine)

Hertel, Larry W.; Kroin, Julian S.; Grossman, C. S.; Grindey, Gerald B.; Dörr, Alexandra; Storniolo, Anna Maria; Plunkett, William; Gandhi, Varsha; Huang, Peng

doi:10.1021/bk-1996-0639.ch019

Cited by 17 publications

(17 citation statements)

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“…[10,13,14] Recently, Gemcitabine 5'-diphosphate (2',2'-difluoro-2'-deoxycitidine-5'-diphosphate) has been approved for the treatment of non-small cell lung cancer in Europe and pancreatic cancer in the United States. [15,16] RNRs are divided in three classes according to the cofactors required for catalytic activity. Evidence that all of them follow a radical mechanism to dehydrate the substrate has been obtained in the last decades.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Studies on the Mode of Inhibition of Ribonucleotide Reductase by 2′‐Substituted Substrate Analogues

Fernandes

Ramos

2003

Chemistry A European J

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Several 2'-substituted-2'-deoxyribonucleotides are potent time-dependent inactivators of the enzyme ribonucleotide reductase (RNR), which function by destructing its essential tyrosil radical and/or by performing covalent addition to the enzyme. The former leads to inhibition of the R2 dimer of RNR and the latter to inhibition of the R1 dimer. Efforts to elucidate the mechanism of inhibition have been undertaken in the last decades, and a general mechanistic scheme has emerged. Accordingly, two alternative pathways lead either to the inhibition of R1 or R2, for which the 2'-chloro-2'-deoxynucleotides serve as the model for the inhibition of R1 and the 2'-azido-2'-deoxynucleotides the model for the inhibition of R2. However, the underlying reason for the different behavior of the inhibitors has remained unknown until now. Moreover, a fundamental mechanistic alternative has been proposed, based on results from biomimetic reactions, in which the 2'-substituents would be eliminated as radicals, and not as anions, as previously assumed. This would lead to further reactions not predicted by the existing mechanistic scheme. To gain a better understanding we have performed high-level theoretical calculations on the active site of RNR. Results from this work support the general Stubbe's paradigm, although some changes to that mechanism are necessary. In addition, a rational explanation of the factors that determine which of the dimers (R1 or R2) will be inactivated is provided for the first time. It has been demonstrated also that the 2'-substituents are indeed eliminated as anions, and not as radicals. Biomimetic experiments have led to different results because they lack a basic group capable of deprotonating the 3'-HO group of the substrate. It has been found here that the chemical character of the leaving group (radical or anionic) can be manipulated by controlling the protonation state of the 3'-HO group.

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Section: Introductionmentioning

confidence: 99%

Theoretical Studies on the Mode of Inhibition of Ribonucleotide Reductase by 2′‐Substituted Substrate Analogues

Fernandes

Ramos

2003

Chemistry A European J

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“…This ratio is optimally greater than the one under in vivo conditions. Gemcitabine-based chemoradiotherapy in pancreatic cancer currently has a very narrow TR, being very close to one [ 35 , 36 ]. The result is substantial toxicity to the GI tract.…”

Section: Discussionmentioning

confidence: 99%

Biodegradable Polymersomes for the Delivery of Gemcitabine to Panc-1 Cells

Sood

Jenkins

Yang

et al. 2013

Journal of Pharmaceutics

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Traditional anticancer chemotherapy often displays toxic side effects, poor bioavailability, and a low therapeutic index. Targeting and controlled release of a chemotherapeutic agent can increase drug bioavailability, mitigate undesirable side effects, and increase the therapeutic index. Here we report a polymersome-based system to deliver gemcitabine to Panc-1 cells in vitro. The polymersomes were self-assembled from a biocompatible and completely biodegradable polymer, poly(ethylene oxide)-poly(caprolactone), PEO-PCL. We showed that we can encapsulate gemcitabine within stable 200 nm vesicles with a 10% loading efficiency. These vesicles displayed a controlled release of gemcitabine with 60% release after 2 days at physiological pH. Upon treatment of Panc-1 cells in vitro, vesicles were internalized as verified with fluorescently labeled polymersomes. Clonogenic assays to determine cell survival were performed by treating Panc-1 cells with varying concentrations of unencapsulated gemcitabine (FreeGem) and polymersome-encapsulated gemcitabine (PolyGem) for 48 hours. 1 μM PolyGem was equivalent in tumor cell toxicity to 1 μM FreeGem, with a one log cell kill observed. These studies suggest that further investigation on polymersome-based drug formulations is warranted for chemotherapy of pancreatic cancer.

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“…Its market was more than $500 million, 2.5 t, in 2001. Gemcitabine, after metabolic phosphorylation, inhibits RDPR, but also interacts with other enzymes involved in the DNA biosynthesis: this explains the great efficiency of gemcitabine [9].…”

Section: Nucleosides and Carbohydratesmentioning

confidence: 99%

“…Condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [9]. However the control of the stereoselectivity of the Reformatsky reaction is difficult (Fig.…”

Section: Nucleosides and Carbohydratesmentioning

confidence: 99%