Design, synthesis and biological evaluation of novel curcumin-fluorouracil hybrids as potential anti-cancer agents
Xiaotong Wang1, Xin Li1, Xu Zhang1
1State Key Laboratory for Macromolecule Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng 252059, China.
Abstract:
The latest global cancer data statistics report shows that cancer poses a serious threat to human life and health; The number of new cancer and death cases worldwide is severe. Molecular hybridization is considered an effective strategy for developing new anti-cancer drugs. Curcumin (Cur) is a natural active compound containing Michael receptors that target thioredoxin reductase (TrxR). Fluorouracil (5-FU) is the first anti-metabolic drug synthesized based on certain assumptions for tumor treatment, acting on thymidylate synthase (TS). This study synthesized a series of novel hybrid derivatives of Cur and 5-FU, and evaluated their anti-tumor cell proliferation effects. Several compounds with good cytotoxic activity against tumor cells were discovered; and they exhibited high selectivity towards A549 cells, compared to normal THLE cells. Among them, the hybrid derivative F-4 has the best anti-proliferative activity in tumor cells. F-4 can target TrxR, increase reactive oxygen species levels in tumor cells, and lead to tumor cell apoptosis, which may be related to the Michael receptor structure in the chemical structure of F-4; F-4 can also target TS, leading to cell cycle arrest in G0/G1 phase, which may be related to the 5-FU structure in the chemical structure of F-4. Moreover, F-4 can effectively exert anti-tumor activity in mice, significantly reduce tumor volume and weight, and has low toxic side effects. These results indicate that Cur-5-FU hybrid derivative F-4 is a novel lead compound with in vivo anti-tumor activity and minimal side effects, which deserves further investigation.
Insights
Novel Curcumin-Fluorouracil hybrid F-4 shows potent anti-cancer activity. This compound effectively reduces tumor growth in mice with minimal side effects, targeting key cancer pathways.
Area of Science:
- Oncology
- Medicinal Chemistry
- Drug Discovery
Background:
- Cancer remains a significant global health threat, necessitating novel therapeutic strategies.
- Molecular hybridization offers a promising approach for developing new anti-cancer agents.
- Curcumin (Cur) and Fluorouracil (5-FU) are established anti-cancer compounds with distinct mechanisms of action.
Purpose of the Study:
- To synthesize and evaluate novel hybrid derivatives of Curcumin and 5-Fluorouracil for anti-tumor activity.
- To identify compounds with enhanced efficacy and selectivity against cancer cells.
- To investigate the molecular mechanisms and in vivo efficacy of promising hybrid derivatives.
Main Methods:
- Synthesis of a series of Curcumin-5-FU hybrid derivatives.
- In vitro evaluation of cytotoxic activity against various tumor cell lines and normal cells.
- Assessment of anti-proliferative effects, targeting mechanisms (TrxR, TS), and apoptosis induction.
- In vivo efficacy studies in mouse tumor models to evaluate anti-tumor activity and toxic side effects.
Main Results:
- Several Cur-5-FU hybrid derivatives demonstrated significant cytotoxic activity against tumor cells.
- Hybrid derivative F-4 exhibited superior anti-proliferative effects, with high selectivity for A549 cancer cells over normal THLE cells.
- F-4 was found to target thioredoxin reductase (TrxR), increasing reactive oxygen species and inducing apoptosis.
- F-4 also targeted thymidylate synthase (TS), leading to G0/G1 cell cycle arrest.
- In vivo studies showed that F-4 effectively reduced tumor volume and weight in mice with low toxicity.
Conclusions:
- The novel Cur-5-FU hybrid derivative F-4 is a potent anti-cancer lead compound.
- F-4 demonstrates significant in vivo anti-tumor efficacy and a favorable safety profile.
- F-4's dual targeting of TrxR and TS contributes to its anti-cancer activity.
- Further investigation of F-4 as a potential therapeutic agent is warranted.
More Related Videos
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...