Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

Pięta, Marlena; Kędzia, Jacek; Kowalczyk, Dorota; Wojciechowski, Jakub; Wolf, Wojciech M.; Janecki, Tomasz

doi:10.1016/j.tet.2019.03.024

Cited by 9 publications

(10 citation statements)

References 25 publications

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“…Synthesis of 5-methylidenedihydrouracils U-236, U-332 and U-359 was performed using Horner-Wadsworth-Emmons methodology according to the described procedure. The purity of compounds established by NMR and analytical HPLC was over 96% [28].…”

Section: Synthetic Uracil Analogsmentioning

confidence: 99%

“…Continuing the search for novel anticancer compounds containing an exo-cyclic methylidene group conjugated with a carbonyl function, we have synthesized a series of 1,3-disubstituted or 1,3,6-trisubstituted 5-methylidenedihydrouracils [28], which all showed significant cytotoxicity against HL-60 leukemia cells (unpublished data). Three most potent analogs from this series, designated U-236, U-332 and U-359 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line

et al. 2019

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Overexpression of ATP-binding cassette (ABC) transporters causing multidrug resistance (MDR) in cancer cells is one of the major obstacles in cancer chemotherapy. The 5-FU resistant subclone (HL-60/5FU) of the human HL-60 promyelocytic leukemia cell line was selected by the conventional method of continuous exposure of the cells to the drug up to 0.08 mmol/L concentration. HL-60/5FU cells exhibited six-fold enhanced resistance to 5-FU than HL-60 cells. RT-PCR and ELISA assay showed significant overexpression of MDR-related ABC transporters, ABCB1, ABCG2 but especially ABCC1 in the HL-60/5FU as compared with the parental cell line. Three novel synthetic 5-methylidenedihydrouracil analogs, U-236, U-332 and U-359, selected as highly cytotoxic for HL-60 cells in MTT test, showed similar cytotoxicity in the resistant cell line. When co-incubated with 5-FU, these analogs were found to down-regulate the expression of all three transporters. However, the most pronounced effect was caused by U-332 which almost completely abolished ABCC1 expression in the resistant HL-60/5FU cells. Additionally, U-332 inhibited the activity of ATPase, an enzyme which catalyzes hydrolysis of ATP, providing energy to efflux drugs from the cells through the cellular membranes. Taken together, the obtained data suggest that acquired 5-FU resistance in HL-60/5FU cells results from overexpression of ABCC1 and that targeting ABCC1 expression could be a potential approach to re-sensitize resistant leukemia cells to 5-FU. The synthetic uracil analog U-332, which can potently down-regulate ABC transporter expression and therefore disturb drug efflux, can be considered an efficient ABCC1 regulator in cancer cells.

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Section: Synthetic Uracil Analogsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line

et al. 2019

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“…The important finding of the research presented here and in our previous papers [31,33] was the identification of the novel uracil analog as a potent inhibitor of NF-κB and ABCC1 transporter expression. The inactivation of NF-κB subunits was shown to correlate with the inhibition of ABC transporter activity which may lead to the increased accumulation of a drug in cancer cells.…”

Section: Discussionmentioning

confidence: 59%

“…Synthesis of (R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil (U-332) was performed using Horner-Wadsworth-Emmons methodology, as described elsewhere [33]. Starting 3-(4-bromophenyl)-5-diethoxyphosphoryl-1-ethyluracil 1 was transformed into 3-(4-bromophenyl)-5-dichlorophosphoryl-1-ethyluracil 2 which was next reacted with (R)-1-phenylethylamine to yield (R,R)-3-(4-bromophenyl)-5-di (1-phenylethylamino)pho sphoryl-1-ethyluracil (R,R)-3.…”

Section: Chemistrymentioning

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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“…Although a large number of quinoline scaffolds are discovered against cancer cell proliferation, the process of anticancer drug discovery is a continuos process to develop more efficient drug molecules. Even though FDA has approved drugs such as sunitinib, daunorubicin, trastuzumab, etc for cancer treatment, severe side effects have been reported including mouth sores, constipation and diarrhea, complete hair loss, [50] neuropathy, [51] bone marrow suppression, [52] and life-threatening issues which cannot be identified easily. Hence in the future, the anticancer drug design must aim at synthesizing anticancer drugs with the least side effects and highest efficiency.…”

Section: Introductionmentioning

confidence: 99%

Report on Recently (2017–20) Designed Quinoline‐Based Human Cancer Cell Growth Inhibitors

Dorababu¹

2020

ChemistrySelect

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Quinoline has been a most essential pharmacophore, derivatization of which led to enticing pharmacological properties. Quinoline is responsible for a wide range of biological potencies such as antibacterial, antifungal, anti-leishmanial, antimalarial, antioxidant and anticancer properties. Out of these clinical importances, the anticancer property of heterocycles is of greatest concern as cancer has become a major threat globally. Since some natural products containing quinoline moiety have displayed cancer inhibition potency, quinoline has been given highest priority in the anticancer drug design and development. In addition, quinoline has got eight positions including nitrogen for substitution which may result in some potential anticancer properties. Ever since, this extraordinary potential is being utilized in anticancer drug discovery. In this review, the various trends in drug design of quinoline moiety anticipating finest anticancer properties through cancer cell growth inhibition are collated comprehensively. The review work is classified based on type of quinoline derivatives. Besides this, with the aid of structure-activity relationship discussion, the importance of structural units that contributed to strongest activity towards cancer inhibition is emphasized. The particular activity would help to bring further advanced anticancer agents in the future.

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Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

Cited by 9 publications

References 25 publications

New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line

New uracil analogs as downregulators of ABC transporters in 5-fluorouracil-resistant human leukemia HL-60 cell line

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

Report on Recently (2017–20) Designed Quinoline‐Based Human Cancer Cell Growth Inhibitors

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