Potential of Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine in Facilitating Enhanced Delivery of Active Drug to Interior Sites of Tumors: A Two-Tier Monolayer In Vitro Study

Tsume, Yasuhiro; Hilfinger, John M.; Amidon, Gordon L.

doi:10.1007/s11095-011-0485-7

Cited by 18 publications

(18 citation statements)

References 59 publications

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“…The mono-amino acid prodrugs of gemcitabine appeared to be relatively stable in pH 7.4 buffers and exhibited more stable in acidic pH, SGF and SIF (pH 6.5), which agreed with our previous results [30]. The enzymatic stability of 5′-D-phenylalanyl-gemcita-bine and 5′-D-valyl-gemcitabine was significantly enhanced compared to ones of 5′-L-phenylalanyl-gemcitabine and 5′-L-va-lyl-gemcitabine suggesting that the recognition of enzymes to their substrates is specific and, hence, the unnatural form of amino acids such as D-valine and D-phenylalanine decelerates enzyme-catalyzed hydrolysis of the ester linkage.…”

Section: Discussionsupporting

confidence: 92%

“…A variety of amino acid, dipeptide and tripeptide have been investigated to improve the oral absorption via intake transporters as a part of prodrug approaches [16,17,22–24,46–49]. We have synthesized mono-amino acid and dipeptide prodrugs of floxuridine, gemcita-bine and 2-bromo-5,6- dichloro-1-(beta-d-ribofuranosyl) benz-imidazole (BDCRM) and characterized their stability and membrane permeability [5,6,9–11,13,14,30,50]. These studies revealed that mono-amino acid/dipeptide ester prodrugs in general enhance the PEPT1-mediated transport and glycosidic bond resistance to metabolic enzymes such as thymidine phosphorylase and cytidine deaminase.…”

Section: Discussionmentioning

confidence: 99%

“…PEPT1 is predominantly expressed in the small intestine and can transport dipeptides, trip-eptides, amino acid monoester prodrugs and β-lactam antibiotics [10,11,16,22–28]. PEPT1 has broad substrate specificity and recognizes D-enantiomers of amino acid as a substrate even though PEPT1 is stereoselective and exhibits greater affinity for L-enantio-mers of amino acids than D-enantiomers [10,29,30]. Amino acid ester prodrugs may facilitate enhanced delivery to pancreatic cancer cells such as AsPC-1 due to the high expression of oligopeptide transporters [31].…”

Section: Introductionmentioning

confidence: 99%

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The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Tsume

Incecayir

Song³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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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-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3–17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2–10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of D-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gem-citabine prodrugs. In general, the 5′-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5′-D-valyl-gemcitabine and 5′-D-phenylalanyl-gem-citabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Tsume

Incecayir

Song³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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“…Reportedly, amino acid monoester prodrugs as well as dipeptide monoester prodrugs are substrates for intake transporters such as PEPT1, PEPT2, and ATB 0,+ , and the carrier-mediated mechanism with those transporters improves their oral bioavailability [19,20,21,22,23,24]. PEPT1 has broad substrate specificity and is expressed in the GI tract [25,26]. This transporter can transport dipeptides, tripeptides, amino acid monoester prodrugs and β-lactam antibiotics [11,27,28,29,30,31,32,33].…”

Section: Introductionmentioning

confidence: 99%

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

2014

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Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5′-l-phenylalanyl-l-tyrosyl-floxuridine and 5′-l-phenylalanyl-l-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

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“…1) for anticancer therapy. [6][7][8][9] Dipeptides represent attractive pro-moieties for generating dipeptide prodrugs also of other drugs containing hydroxyl-, [10][11][12] thiol- 4 and amino groups. [13][14][15] Variation of the dipeptide carrier structure allows fine adjustment of the lipophilicity, prodrug stability and pharmacological activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structure and biological activity screening of novel N-(α-bromoacyl)-α-amino esters containing valyl moiety

Yancheva

Cherneva

Quick

et al. 2015

ACSi

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Three novel N-(α-bromoacyl)-α-amino esters: methyl 2-(2-bromo-3-methylbutanamido)pentanoate (1), methyl 2-(2-bromo-3-methylbutanamido)-2-phenylacetate (2) and methyl 2-(2-bromo-3-methylbutanamido)-3-phenylpropanoate (3) were synthesized. Single crystal X-ray diffraction data are reported for compounds 1 and 2. The cytotoxicity, antiinflammatory and antibacterial activity of compounds 1-3 were investigated. Additionally, the physico-chemical properties of studied compounds were calculated and an in silico toxicological study of compounds 1-3 was performed. The low level of cytotoxicity and absence of antibacterial and anti-inflammatory activity of 1-3 in tested concentrations might be a beneficial prerequisite for their incorporation in prodrugs.

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Potential of Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine in Facilitating Enhanced Delivery of Active Drug to Interior Sites of Tumors: A Two-Tier Monolayer In Vitro Study

Abstract: Although a tentative general overall correlation between intact prodrug and uptake or cytotoxic action was obtained, it appears that a mixture of floxuridine prodrugs with varying beneficial characteristics may be more effective in treating tumors.

Cited by 18 publications

References 59 publications

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

Synthesis, crystal structure and biological activity screening of novel N-(α-bromoacyl)-α-amino esters containing valyl moiety

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