Synthesis of gemcitabine-threonine amide prodrug effective on pancreatic cancer cells with improved pharmacokinetic properties

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dc.contributor.authorHong, Sungwooko
dc.contributor.authorFang, Zhenghuanko
dc.contributor.authorJung, Hoi Yunko
dc.contributor.authorYoon, Jin-Hako
dc.contributor.authorHong, Soon-Sunko
dc.contributor.authorMaeng, Han-Jooko
dc.date.accessioned2018-12-20T08:05:40Z-
dc.date.available2018-12-20T08:05:40Z-
dc.date.created2018-12-14-
dc.date.created2018-12-14-
dc.date.issued2018-10-
dc.identifier.citationMOLECULES, v.23, no.10-
dc.identifier.issn1420-3049-
dc.identifier.urihttp://hdl.handle.net/10203/248752-
dc.description.abstractTo 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 1H-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. © 2018 by the Authors.-
dc.languageEnglish-
dc.publisherMDPI-
dc.titleSynthesis of gemcitabine-threonine amide prodrug effective on pancreatic cancer cells with improved pharmacokinetic properties-
dc.typeArticle-
dc.identifier.wosid000451201400204-
dc.identifier.scopusid2-s2.0-85054824810-
dc.type.rimsART-
dc.citation.volume23-
dc.citation.issue10-
dc.citation.publicationnameMOLECULES-
dc.identifier.doi10.3390/molecules23102608-
dc.contributor.localauthorHong, Sungwoo-
dc.contributor.nonIdAuthorFang, Zhenghuan-
dc.contributor.nonIdAuthorYoon, Jin-Ha-
dc.contributor.nonIdAuthorHong, Soon-Sun-
dc.contributor.nonIdAuthorMaeng, Han-Joo-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthoramino acid transporters-
dc.subject.keywordAuthoramide bond-
dc.subject.keywordAuthorgemcitabine prodrug-
dc.subject.keywordAuthormetabolic stability-
dc.subject.keywordAuthorpancreatic cancer cells-
dc.subject.keywordAuthorpharmacokinetics-
dc.subject.keywordPlusACID TRANSPORTER 1-
dc.subject.keywordPlusANTICANCER AGENT-
dc.subject.keywordPlusCOMBINATION-
dc.subject.keywordPlusMETABOLISM-
dc.subject.keywordPlusEXPRESSION-
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