Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
DC Field | Value | Language |
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dc.contributor.author | Hong, Sungwoo | - |
dc.contributor.author | Fang, Zhenghuan | - |
dc.contributor.author | Jung, Hoi-Yun | - |
dc.contributor.author | Yoon, Jin-Ha | - |
dc.contributor.author | Hong, Soon-Sun | - |
dc.contributor.author | Maeng, Han-Joo | - |
dc.date.available | 2020-02-27T09:40:59Z | - |
dc.date.created | 2020-02-06 | - |
dc.date.issued | 2018-10 | - |
dc.identifier.issn | 1420-3049 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/3271 | - |
dc.description.abstract | To investigate the amino acid transporter-based prodrug anticancer strategy further, several amino acid-conjugated amide gemcitabine prodrugs were synthesized to target amino acid transporters in pancreatic cancer cells. The structures of the synthesized amino acid-conjugated prodrugs were confirmed by H-1-NMR and LC-MS. The pancreatic cancer cells, AsPC1, BxPC-3, PANC-1 and MIAPaCa-2, appeared to overexpress the amino acid transporter LAT-1 by conventional RT-PCR. Among the six amino acid derivatives of gemcitabine, threonine derivative of gemcitabine (Gem-Thr) was more effective than free gemcitabine in the pancreatic cancer cells, BxPC-3 and MIAPaCa-2, respectively, in terms of anti-cancer effects. Furthermore, Gem-Thr was metabolically stable in PBS (pH 7.4), rat plasma and liver microsomal fractions. When Gem-Thr was administered to rats at 4 mg/kg i.v., Gem-Thr was found to be successfully converted to gemcitabine via amide bond cleavage. Moreover, the Gem-Thr showed the increased systemic exposure of formed gemcitabine by 1.83-fold, compared to free gemcitabine treatment, due to the significantly decreased total clearance (0.60 vs. 4.23 mL/min/kg), indicating that the amide prodrug approach improves the metabolic stability of gemcitabine in vivo. Taken together, the amino acid transporter-targeting gemcitabine prodrug, Gem-Thr, was found to be effective on pancreatic cancer cells and to offer an efficient potential means of treating pancreatic cancer with significantly better pharmacokinetic characteristics than gemcitabine. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | MDPI | - |
dc.relation.isPartOf | MOLECULES | - |
dc.title | Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000451201400204 | - |
dc.identifier.doi | 10.3390/molecules23102608 | - |
dc.identifier.bibliographicCitation | MOLECULES, v.23, no.10 | - |
dc.identifier.scopusid | 2-s2.0-85054824810 | - |
dc.citation.title | MOLECULES | - |
dc.citation.volume | 23 | - |
dc.citation.number | 10 | - |
dc.contributor.affiliatedAuthor | Yoon, Jin-Ha | - |
dc.contributor.affiliatedAuthor | Maeng, Han-Joo | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | amino acid transporters | - |
dc.subject.keywordAuthor | amide bond | - |
dc.subject.keywordAuthor | gemcitabine prodrug | - |
dc.subject.keywordAuthor | metabolic stability | - |
dc.subject.keywordAuthor | pancreatic cancer cells | - |
dc.subject.keywordAuthor | pharmacokinetics | - |
dc.subject.keywordPlus | ACID TRANSPORTER 1 | - |
dc.subject.keywordPlus | ANTICANCER AGENT | - |
dc.subject.keywordPlus | COMBINATION | - |
dc.subject.keywordPlus | METABOLISM | - |
dc.subject.keywordPlus | EXPRESSION | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Chemistry | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Multidisciplinary | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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