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Vig, Balvinder S.; Lorenzi, Philip J.; Mittal, Sachin; Landowski, Christopher P.; Shin, Ho‐Chul; Mosberg, Henry I.; Hilfinger, John M.; Amidon, Gordon L.

doi:10.1023/a:1025745824632

Cited by 63 publications

(52 citation statements)

References 25 publications

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“…1). 3,26) The purity of all prodrugs was more than 90% as determined by HPLC. The impurities were generally the known amino acid ester prodrugs or the parent drug.…”

Section: Resultsmentioning

confidence: 99%

“…3,27) Most nucleoside analogs contain free hydroxyl groups which can be easily esterified to obtain ester prodrugs. Although alkyl ester prodrugs are commonly utilized, the use of amino acids as promoieties offers several advantages: structural diversity, well established peptide chemistry, and potential targetability to carrier-mediated membrane transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Although alkyl ester prodrugs are commonly utilized, the use of amino acids as promoieties offers several advantages: structural diversity, well established peptide chemistry, and potential targetability to carrier-mediated membrane transporters. 3,27) In this regard, the use of intestinal epithelial transporters to facilitate the absorption of amino acid prodrugs of antiviral and antitumoral nucleoside agents is a very viable approach to increase their oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6] Valine prodrugs of acyclovir and ganciclovir, valacyclovir and valganciclovir, respectively, exhibit 3-5 times higher systemic exposure than the parent compounds. [7][8][9] Enhanced bioavailabilities of the amino acid prodrugs is attributed to carrier mediated intestinal absorption via intestinal transporters such as a human peptide transporter hPept1 or an amino acid transporter ATB 0,ϩ .…”

mentioning

confidence: 99%

“…Prodrug Synthesis Amino acid ester prodrugs of FUdR and BDCRB were synthesized as described previously. 3,26) Aromatic amino acids L-Phe and D-Phe, aliphatic amino acids L-Val and D-Val, secondary amino acid Pro, acidic amino acid Asp, and basic amino acid Lys were selected as promoieties for the synthesis of FUdR prodrugs. Phe, L-Val, D-Val, Pro, Asp, and Lys were selected for the synthesis of BDCRB prodrugs.…”

mentioning

confidence: 99%

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Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole

Shin

Kim

Vig

et al. 2006

Biological & Pharmaceutical Bulletin

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Targeting a specific molecule toward transporters by designing its prodrugs may be used to improve oral bioavailability or to reduce systemic toxicity. [1][2][3][4][5][6] Valine prodrugs of acyclovir and ganciclovir, valacyclovir and valganciclovir, respectively, exhibit 3-5 times higher systemic exposure than the parent compounds. [7][8][9] Enhanced bioavailabilities of the amino acid prodrugs is attributed to carrier mediated intestinal absorption via intestinal transporters such as a human peptide transporter hPept1 or an amino acid transporter ATB 0,ϩ . 4,[10][11][12] Nucleoside antiviral and anticancer agents are important class of drugs for the fight against viral diseases and cancer. However, they often exhibit poor pharmaceutical and absorption, distribution, metabolism and excretion (ADME) properties. Prodrug approaches that can potentially improve their pharmaceutical and ADME properties can be of great benefit in realizing the full potential of these agents.Clinically important nucleoside drugs such as cladribine, dideoxyinosine, fludarabine, acyclovir, ganciclovir, and abacavir, gemcitabine, azidothymidine, FUdR, cytarabine, zalcitabine and stavudine are known to interact with nucleoside transporters, which can influence their ADME properties. [13][14][15] A sodium-dependent concentrative nucleoside transporter hCNT2 has been cloned from human intestine. [16][17][18] The hCNT2 is abundantly expressed in the intestinal tissues, and is involved in transport of both naturally occurring nucleosides and clinically relevant nucleoside analogs. 13,18) Of the subtypes of concentrative nucleoside transporter hCNT1-3, hCNT2 exhibits a preference for purine nucleosides over pyrimidine nucleosides. 13,19) FUdR is a fluorinated pyrimidine nucleoside drug extensively used in the treatment of colon cancer. Although the mechanism of action and therapeutic effectiveness of FUdR are well understood, it has various side effects in gastrointestinal and bone marrow tissues. 20) Hence, FUdR is administered parenterally due to its poor oral bioavailability. Recently, benzimidazole nucleosides such as BDCRB, maribavir, and GW275175X have also been developed as a new class of antiviral drugs. [21][22][23] Although BDCRB was found to be a potent and selective inhibitor of human cytomegavirus (HCMV) replication, it had a poor pharmacokinetics profile with a very short plasma half-life and cytotoxicity. 24,25) In this regard, we attempted to develop amino acid ester prodrugs of FUdR and BDCRB to improve their pharmacokinetic properties. Although considerable progress has been made in the development of amino acid or dipeptide nucleoside prodrugs, little is known about the nucleoside transporters involved in the intestinal absorption of the prodrugs. In a previous report, 18) we demonstrated that FUdR and BDCRB were potent inhibitors of intestinal nucleoside transporter hCNT2. This suggests that hCNT2 may play an important role in the uptake of nucleoside compounds from the intestine. Therefore, it is relevant to characterize ho...

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“…1). 3,26) The purity of all prodrugs was more than 90% as determined by HPLC. The impurities were generally the known amino acid ester prodrugs or the parent drug.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole

Shin

Kim

Vig

et al. 2006

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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Synthesis and activity evaluation of 3′‐floxuridinyl 4‐[3‐(3, 5‐di‐t‐butyl‐4‐methoxyphenyl)‐3‐oxo‐propenyl]benzoate: in vitro and in vivo as a potential dual‐acting antitumor prodrug

Jin

et al. 2011

Drug Development Research

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BOBA (4‐[3‐(3, 5‐di‐tert‐butyl‐4‐methoxyphenyl)‐3‐oxo‐propenyl]benzoic acid), a substituted chalcone derivative, exhibits an excellent inducing differentiation on neoplastic cellular differentiation. FUDR (5‐fluoro‐2′‐deoxyuridine, floxuridine) inhibits DNA biosynthesis and has been used extensively to treat various cancers. In our efforts to find a new dual‐action antitumor prodrug, 3′‐floxuridinyl 4‐[3‐(3, 5‐di‐t‐butyl‐4‐methoxyphenyl)‐3‐oxo‐propenyl] benzoate (3′‐O‐BOBA‐ FUDR) was synthesized, and its antiproliferative activity in vitro and antitumor efficacy in vivo were evaluated. Compared with FUDR, the antiproliferative activity of 3′‐O‐BOBA‐FUDR was improved by 3–7‐fold. In rat hepatocellular carcinoma xenografts, 3′‐O‐BOBA‐FUDR‐treated rats had smaller tumors than were found in controls. In addition, the expression of Bcl‐2 protein was significantly downgraded, whereas the expression of Bax protein was upregulated in neoplastic tissues. The early apoptotic ratio of 3′‐O‐BOBA‐FUDR‐treated rat group was increased dose‐dependently. These findings strongly support the concept that 3′‐O‐BOBA‐FUDR may be a novel and effective dual‐action antitumor prodrug. Drug Dev Res 72:1–9, 2011. © 2011 Wiley Periodicals, Inc.

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Regioselective Acylation of Nucleosides Catalyzed by Candida Antarctica Lipase B: Enzyme Substrate Recognition

Zong

2008

Eur J Org Chem

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The substrate recognition of Candida antarctica lipase B (CAL-B) in the acylation of nucleosides was revealed through rational substrate engineering for the first time. CAL-B displayed lower activities and excellent 5Ј-regioselectivities (94 to Ͼ99 %) in the acylation of ribonucleosides 1f-1j as compared to those in the acylation of 2Ј-deoxynucleosides 1a-1e. The excellent regioselectivities might be attributed to the favorable steric hindrance of the 2Ј-hydroxy group present in

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Cited by 63 publications

References 25 publications

Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole

Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole

Synthesis and activity evaluation of 3′‐floxuridinyl 4‐[3‐(3, 5‐di‐t‐butyl‐4‐methoxyphenyl)‐3‐oxo‐propenyl]benzoate: in vitro and in vivo as a potential dual‐acting antitumor prodrug

Regioselective Acylation of Nucleosides Catalyzed by Candida Antarctica Lipase B: Enzyme Substrate Recognition

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