Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

Tian, Zhiyong; Du, Gangjun; Xie, Songqiang; Zhao, Jin; Gao, Wenyuan; Wang, Chaojie

doi:10.3390/12112450

Cited by 23 publications

(16 citation statements)

References 21 publications

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“…7 A proper drug delivery system can reduce the toxicity of 5-FU and increase its efficacy by facilitating its specific accumulation in the tumor tissue allowing a prolonged exposure of the cells to the drug and improving its pharmacokinetic profile (short biological half life and non-uniform oral absorption as a consequence of its metabolism by the enzyme dihydropyrimidine dehydrogenase or uracil reductase). 5,24 The new 5-FU derivatives were included in liposomes composed of a natural phospholipid, dioleoyl-snglycero-phosphocholine (DOPC, Chart 1), in the presence of a gemini cationic surfactant (2S,3S)-2,3-dimethoxy-1,4-bis(Nhexadecyl-N,N-dimethylammonium) butane bromide, 4 (Chart 1) that had been shown to attribute to phospholipid formulations high efficacy in drug and gene delivery and to be characterized by low toxicity. 21 Liposomes are among the most attractive candidates as drug delivery systems of 5-FU because of their biocompatibility, their long circulation lifetime, their ability, when cationic, to interact with negatively charged cell membrane, the possibility of controlling their biodistribution and pharmacokinetic and of increasing their selectivity for tumor tissue with specific functionalization.…”

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confidence: 99%

Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment

et al. 2015

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5-Fluorouracil (5-FU) is widely employed in the treatment of some of the most frequently occurring malignant tumours such as breast, colon, and skin cancer. Unfortunately, 5-FU exhibits high toxicity and low tumor affinity with the risk of limited effectiveness and severe side effects for the patients. Numerous derivatives have been synthesized to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of 5-FU, diminishing or circumventing some of its disadvantages. Three 4-substituted 5-fluoropyrimidines characterized by the presence of a polyoxyethylene chain of different lengths and a hydrophobic alkyl chain were synthesized and characterized. The new 5-FU derivatives were included in cationic liposomes formulated with a natural phospholipid and a cationic gemini surfactant to be delivered to cancer cells. The cytotoxicity of the formulations was evaluated by MTT assay on the HCT116 cancer cell line in vitro. The investigated liposome formulations showed a higher cytotoxicity compared to the free drug, thus showing great potential in cancer therapy

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confidence: 99%

Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment

et al. 2015

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“…So, the radiopharmaceutical should have high specificity for the target organ, only then it will result in high target to nontarget ratio. If this ratio is not high enough, drug uptake in nontarget areas can damage the healthy tissues . Although the exact reason is not explained, the changes have been observed in obtained cell culture results at some time intervals.…”

Section: Discussionmentioning

confidence: 98%

“…If this ratio is not high enough, drug uptake in nontarget areas can damage the healthy tissues. 4,12,31,32,36,37 Although the exact reason is not explained, the changes have been observed in obtained cell culture results at some time intervals. These changes may be due to the effect of molecule E on the cell.…”

Section: Acetone Salinementioning

confidence: 98%

“…5‐Fluorouracil (5‐FU) is an effective antitumor drug, which has been used either as a single agent or in combination with other chemotherapeutic agents for the treatment of tumors such as breast and colorectal carcinoma . 5‐FU is an antimetabolite drug and works by inhibiting essential biosynthetic processes or by being incorporated into macromolecules, such as DNA and RNA.…”

Section: Introductionmentioning

confidence: 99%

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Radiolabeling and in vitro evaluation of a new 5‐fluorouracil derivative with cell culture studies

İlem-Özdemir

Gündoğdu

Ekinci

et al. 2019

Labelled Comp Radiopharmac

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The clinical impact and accessibility of 99mTc tracers for cancer diagnosis would be greatly enhanced by the availability of a new, simple, and easy labeling process and radiopharmaceuticals. 5‐Fluorouracil is an antitumor drug, which has played an important role for the treatment of breast carcinoma. In the present study, a new derivative of 5‐Fluorouracil was synthesized as (1‐[{1′‐(1′′‐deoxy‐2′′,3′′:4′′,5′′‐di‐O‐isopropylidene‐β‐D‐fructopyranose‐1′′‐yl)‐1′H‐1′,2′, 3′‐triazol‐4′‐yl}methyl]‐5‐fluorouracil) (E) and radiolabeled with 99mTc. It was analyzed by radio thin layer chromatography for quality control and stability. The radiolabeled complex was subjected to in vitro cell‐binding studies to determine healthy and cancer cell affinity using HaCaT and MCF‐7 cells, respectively. In addition, in vitro cytotoxicity studies of compound E were performed with HaCaT and MCF‐5 cells. The radiochemical purity of the [99mTc]TcE was found to be higher than 90% at room temperature up to 6 hours. The radiolabeled complex showed higher specific binding to MCF‐7 cells than HaCaT cells. IC50 values of E were found 31.5 ± 3.4 μM and 20.7 ± 2.77 μM for MCF‐7 and HaCaT cells, respectively. The results demonstrated the potential of a new radiolabeled E with 99mTc has selective for breast cancer cells.

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“…Since its first synthesis in 1957 [9] 5-FU has been widely used as a chemotherapeutic drug in various types of cancer [10]. However, its application is now limited due to the serious side-effects and the development of resistance [11]. Numerous modifications of 5-FU have been proposed so far, and new analogs modified at position 1, such as tegafur, carmofur and floxuridine ( Fig.…”

Section: Introductionmentioning

confidence: 99%

New uracil analog U-332 is an inhibitor of NF-κB in 5-fluorouracil-resistant human leukemia HL-60 cell line

Długosz-Pokorska

Pięta

Kędzia

et al. 2020

BMC Pharmacol Toxicol

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Background: 5-Fluorouracil (5-FU) is an antimetabolite that interferes with DNA synthesis and has been widely used as a chemotherapeutic drug in various types of cancers. However, the development of drug resistance greatly limits its application. Overexpression of ATP-binding cassette (ABC) transporters in many types of cancer is responsible for the reduction of the cellular uptake of various anticancer drugs causing multidrug resistance (MDR), the major obstacle in cancer chemotherapy. Recently, we have obtained a novel synthetic 5-FU analog, U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], combining a uracil skeleton with an exo-cyclic methylidene group. U-332 was highly cytotoxic for HL-60 cells and showed similar cytotoxicity in the 5-FU resistant subclone (HL-60/5FU), in which this analog almost completely abolished expression of the ATP-binding cassette (ABC) transporter, multidrug resistance associate protein 1 (ABCC1). The expression of ABC transporters is usually correlated with NF-κB activation. The aim of this study was to determine the level of NF-κB subunits in the resistant HL-60/5-FU cells and to evaluate the potential of U-332 to inhibit activation of NF-κB family members in this cell line. Methods: Anti-proliferative activity of compound U-332 was assessed by the MTT assay. In order to disclose the mechanism of U-332 cytotoxicity, quantitative real-time PCR analysis of the NF-κB family genes, c-Rel, RelA, RelB, NF-κB1, and NF-κB2, was investigated. The ability of U-332 to reduce the activity of NF-κB members was studied by ELISA test. Results: In this report it was demonstrated, using RT-PCR and ELISA assay, that members of the NF-κB family c-Rel, RelA, RelB, NF-κB1, and NF-κB2 were all overexpressed in the 5-FU-resistant HL-60/5FU cells and that U-332 potently reduced the activity of c-Rel, RelA and NF-κB1 subunits in this cell line. Conclusions: This finding indicates that c-Rel, RelA and NF-κB1 subunits are responsible for the resistance of HL-60/5FU cells to 5-FU and that U-332 is able to reverse this resistance. U-332 can be viewed as an important lead compound in the search for novel drug candidates that would not cause multidrug resistance in cancer cells.

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Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

Cited by 23 publications

References 21 publications

Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment

Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment

Radiolabeling and in vitro evaluation of a new 5‐fluorouracil derivative with cell culture studies

New uracil analog U-332 is an inhibitor of NF-κB in 5-fluorouracil-resistant human leukemia HL-60 cell line

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