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Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties

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...

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Autores principales: Hong, Sungwoo, Fang, Zhenghuan, Jung, Hoi-Yun, Yoon, Jin-Ha, Hong, Soon-Sun, Maeng, Han-Joo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222828/
https://www.ncbi.nlm.nih.gov/pubmed/30314360
http://dx.doi.org/10.3390/molecules23102608
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author Hong, Sungwoo
Fang, Zhenghuan
Jung, Hoi-Yun
Yoon, Jin-Ha
Hong, Soon-Sun
Maeng, Han-Joo
author_facet Hong, Sungwoo
Fang, Zhenghuan
Jung, Hoi-Yun
Yoon, Jin-Ha
Hong, Soon-Sun
Maeng, Han-Joo
author_sort Hong, Sungwoo
collection PubMed
description 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 (1)H-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.
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spelling pubmed-62228282018-11-13 Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties Hong, Sungwoo Fang, Zhenghuan Jung, Hoi-Yun Yoon, Jin-Ha Hong, Soon-Sun Maeng, Han-Joo Molecules Article 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 (1)H-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. MDPI 2018-10-11 /pmc/articles/PMC6222828/ /pubmed/30314360 http://dx.doi.org/10.3390/molecules23102608 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hong, Sungwoo
Fang, Zhenghuan
Jung, Hoi-Yun
Yoon, Jin-Ha
Hong, Soon-Sun
Maeng, Han-Joo
Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title_full Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title_fullStr Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title_full_unstemmed Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title_short Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
title_sort synthesis of gemcitabine-threonine amide prodrug effective on pancreatic cancer cells with improved pharmacokinetic properties
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222828/
https://www.ncbi.nlm.nih.gov/pubmed/30314360
http://dx.doi.org/10.3390/molecules23102608
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