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 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.
Highlights
Gemcitabine (20 -20 -difluorodeoxycytidine, dFdC) is a standard anticancer agent that is used to treat all stages of pancreatic adenocarcinoma [1], and combinations of gemcitabine with other anti-cancer agents, such as erlotinib [2], nab-paclitaxel [3,4] and others have been applied to pancreatic cancer patients
In order to avoid potential problems associated with epimerization when using carbodiimides as coupling reagents, HOBt was used as an additive because it enhances the reactivities of activated ester intermediates by facilitating amine approach via hydrogen bonding
Various amino acid derivatives of gemcitabine were successfully synthesized by forming amide bonds
Summary
Gemcitabine (20 -20 -difluorodeoxycytidine, dFdC) is a standard anticancer agent that is used to treat all stages of pancreatic adenocarcinoma [1], and combinations of gemcitabine with other anti-cancer agents, such as erlotinib [2], nab-paclitaxel [3,4] and others have been applied to pancreatic cancer patients. Molecules 2018, 23, 2608 a metabolically unstable drug and has a half-life of only 9 min in man, probably due to its rapid conversion to 20 -20 -difluorodeoxyuridine (dFdU) by cytidine deaminase (CD), which is abundant in blood and tissues [7]. This poor metabolic stability and poor compliance has created a clinical need for a gemcitabine prodrug. LAT-1 has been suggested to be a versatile target for the development of transporter-based drugs [14]
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