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Open AccessArticle

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

1
Center for Catalytic Hydrocarbon Functionalization Institute for Basic Science (IBS), Daejeon 34141, Korea
2
Department and of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
3
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea
4
College of Pharmacy, Gachon University, Incheon 21936, Korea
*
Authors to whom correspondence should be addressed.
These authors are equally contributed to this work.
Molecules 2018, 23(10), 2608; https://doi.org/10.3390/molecules23102608
Received: 29 August 2018 / Revised: 2 October 2018 / Accepted: 10 October 2018 / Published: 11 October 2018
(This article belongs to the Special Issue Amide Bond Activation)
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 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. View Full-Text
Keywords: amino acid transporters; amide bond; gemcitabine prodrug; metabolic stability; pancreatic cancer cells; pharmacokinetics amino acid transporters; amide bond; gemcitabine prodrug; metabolic stability; pancreatic cancer cells; pharmacokinetics
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MDPI and ACS Style

Hong, S.; Fang, Z.; Jung, H.-Y.; Yoon, J.-H.; Hong, S.-S.; Maeng, H.-J. Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties. Molecules 2018, 23, 2608.

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