- Potential development of Tumor-targeted oral Anti-cancer prodrugs: Amino acid and dipeptide monoester prodrugs of gemcitabine
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One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.
- Tsume, Yasuhiro,Drelich, Adam J.,Smith, David E.,Amidon, Gordon L.
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- Regioselective synthesis of 5′-amino acid esters of some nucleosides via orthogonal protecting protocol
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Amino acid esters of nucleosides at 5′-position, as peptidomimetic prodrugs, which could be actively transported by the intestinal oligopeptide transporters 1 (PepT1), bear improved oral bioavailability. We established here a regioselective synthesis of the 5′-esters of some nucleosides via an orthogonal protecting protocol with triphenylmethyl (Tr) and allyloxycarbonyl (AOC) protecting groups. A series of 5′-esters of cytarabine and gemcitabine were selectively synthesized in over 36.0% total yields. This efficient and robust methodology will be examplified for the further study of the prodrugs of large number of antiviral and anticancer nucleosides.
- Liu, Jia-An,Guo, Xiao-Peng,Liang, Shuang,An, Fei,Shen, Hong-Yan,Xu, You-Jun
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p. 1409 - 1412
(2015/02/19)
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- The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability
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Gemcitabine prodrugs with d- and l-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-prolife
- Tsume, Yasuhiro,Incecayir, Tuba,Song, Xueqin,Hilfinger, John M.,Amidon, Gordon L.
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p. 514 - 523
(2014/05/06)
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