Synthesis and anticancer evaluation of acetylated-lysine conjugated gemcitabine prodrugs
Mengmeng Wang1, Kunyu Qu1, Peipei Zhao1
1Biology Institute, Qilu University of Technology (Shandong Academy of Sciences) Jinan 250103 China lxzhang@ecust.edu.cn xiaxk@sdas.org.
Abstract:
Gemcitabine is an antimetabolite drug approved for the treatment of various cancers. However, its use is limited due to several issues such as stability, toxicity and drug resistance. Herein, we present the design and synthesis of a series of gemcitabine prodrugs with modifications on the 4-N-amino group by employing an acetylated l- or d-lysine moiety masked by different substitutions. Prodrugs 1-3 and 6-8 showed up to 2.4 times greater anticancer activity than gemcitabine in A549 lung cells, while they exhibited potent activity against BxPC-3 pancreatic cells with IC50 values in the range of 7-40 nM. Moreover, prodrugs 2-3 and 7-8 were found to be less potent against CTSL low expression Caco-2 cells and at least 69-fold less toxic towards human normal HEK-293T cells compared to gemcitabine, leading to improved selectivity and safety profiles. Further stability studies showed that representative prodrugs 2 and 7 exhibited enhanced metabolic stability in human plasma, human liver microsomes and cytidine deaminase. Prodrug 1 can be cleaved by tumor cell-enriched CTSL to release parent drug gemcitabine. Overall, these results demonstrated that acetylated lysine conjugated gemcitabine prodrugs could serve as promising leads for further evaluation as new anticancer drugs.
Insights
New gemcitabine prodrugs, modified with acetylated lysine, show enhanced anticancer activity and improved safety profiles. These novel compounds offer greater stability and reduced toxicity, presenting promising leads for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Gemcitabine is a key antimetabolite chemotherapy agent.
- Current limitations include drug resistance, toxicity, and stability issues.
- Novel prodrug strategies are needed to overcome gemcitabine's limitations.
Purpose of the Study:
- To design and synthesize novel gemcitabine prodrugs.
- To enhance anticancer efficacy and improve safety profiles.
- To investigate the stability and drug release mechanisms of these prodrugs.
Main Methods:
- Synthesis of gemcitabine prodrugs via modification of the 4-N-amino group with acetylated lysine.
- In vitro evaluation of anticancer activity in A549 lung and BxPC-3 pancreatic cancer cell lines.
- Assessment of cytotoxicity in HEK-293T normal cells and stability studies in human plasma and liver microsomes.
Main Results:
- Prodrugs 1-3 and 6-8 demonstrated up to 2.4-fold higher anticancer activity than gemcitabine in A549 cells.
- Potent activity against BxPC-3 cells with IC50 values from 7-40 nM.
- Prodrugs 2-3 and 7-8 showed reduced toxicity (69-fold less) in HEK-293T cells and improved selectivity.
- Enhanced metabolic stability and tumor-specific drug release (via CTSL) were observed.
Conclusions:
- Acetylated lysine conjugated gemcitabine prodrugs represent a promising advancement.
- These prodrugs offer improved efficacy, selectivity, and safety over gemcitabine.
- Further evaluation as novel anticancer therapeutics is warranted.
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