Design, Synthesis, and Evaluation of Doxifluridine Derivatives as Nitroreductase-Responsive Anticancer Prodrugs
Xinmeng Zhang1, Taimin Dong1, Xu Li1
1National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China.
Abstract:
Antimetabolite antitumor drugs interfere with nucleic acid and DNA synthesis, causing cancer cell death. However, they also affect rapidly dividing normal cells and cause serious side effects. Doxifluridine (5'-deoxy-5-fluorouridine [5'-DFUR]), a 5-fluorouracil (5-FU) prodrug converted to 5-FU by thymidine phosphorylase (TP), exerts antitumor effects. Since TP is distributed in tumor and normal tissues, 5'-DFUR features side effects. Here we designed a series of novel 5'-DFUR derivatives based on high nitroreductase (NTR) levels in the hypoxic microenvironment of tumor tissues by introducing nitro-containing moieties into the 5'-DFUR structure. These derivatives exert their antitumor effects by producing 5-FU under the dual action of TP and NTR in the tumor microenvironment. The derivatives were synthesized and their stability, release, and cytotoxicity evaluated in vitro and antitumor activity evaluated in vivo. Compound 2c, featuring nitrofuran fragments, was stable in phosphate-buffered saline and plasma at different pH values and reduced rapidly in the presence of NTR. The in vitro cytotoxicity evaluation indicated that compound 2c showed excellent selectivity in the MCF-7 and HT29 cell lines. Moreover, it exhibited antitumor effects comparable to those of 5'-DFUR in vivo without significant toxic side effects. These results suggest that compound 2c is a promising antitumor prodrug.
Insights
Novel doxifluridine derivatives targeting tumor hypoxia show promise as effective anticancer prodrugs with reduced side effects. Compound 2c demonstrates potent antitumor activity and selectivity, offering a new therapeutic avenue.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Antimetabolite chemotherapy drugs, like 5-fluorouracil (5-FU), are vital for cancer treatment but cause severe side effects due to their impact on normal rapidly dividing cells.
- Doxifluridine (5'-deoxy-5-fluorouridine [5'-DFUR]) is a prodrug of 5-FU, activated by thymidine phosphorylase (TP), but its efficacy is limited by TP's presence in both tumor and normal tissues.
- Tumor tissues often exhibit hypoxic microenvironments with high levels of nitroreductase (NTR), presenting a potential target for selective drug activation.
Purpose of the Study:
- To design and synthesize novel 5'-DFUR derivatives that are selectively activated in hypoxic tumor environments.
- To evaluate the stability, drug release kinetics, in vitro cytotoxicity, and in vivo antitumor activity of these new derivatives.
- To identify a promising candidate with enhanced tumor-targeting and reduced systemic toxicity compared to existing therapies.
Main Methods:
- Synthesis of novel 5'-DFUR derivatives incorporating nitro-containing moieties.
- In vitro assessment of compound stability in various conditions (pH, plasma) and nitroreductase-mediated release.
- Evaluation of in vitro cytotoxicity against cancer cell lines (MCF-7, HT29).
- In vivo studies to assess antitumor efficacy and toxicity in relevant models.
Main Results:
- Compound 2c, featuring nitrofuran fragments, demonstrated stability and rapid reduction in the presence of NTR.
- In vitro studies showed compound 2c possesses excellent selectivity for cancer cell lines.
- In vivo experiments revealed compound 2c achieved antitumor effects comparable to 5'-DFUR with significantly reduced toxic side effects.
Conclusions:
- The designed 5'-DFUR derivatives, activated by both TP and NTR in tumor microenvironments, offer a strategy for targeted cancer therapy.
- Compound 2c represents a promising antitumor prodrug candidate due to its tumor-selective activation, potent efficacy, and favorable safety profile.
- This approach holds potential for developing more effective and safer chemotherapeutic agents for cancer treatment.
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