4-Fluoro-3′,4′,5′-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model

Roman, Bart; Ryck, Tine De; Patronov, Atanas; Slavov, Svetoslav; Vanhoecke, Barbara; Katritzky, Alan R.; Bracke, Marc; Stevens, Christian V.

doi:10.1016/j.ejmech.2015.06.029

Cited by 12 publications

(10 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The compound is stable in simulated intestinal and gastric fluid and in PBS. A much higher intrinsic clearance was obtained for rat liver microsomes in comparison with earlier results for humans [ 5 ]. C16 does not significantly inhibit three major drug-drug interaction (DDI)-inducing human cytochromes P450 (CYPs, 1A2, 2D6 and 3A4).…”

Section: Resultssupporting

confidence: 46%

“…Interpretation of the above PK data required the generation of additional in vitro stability and metabolism data ( Table 3 ), and revision of known data [ 5 ]. As illustrated above, solubility and lipophilicity are acceptable for exploratory work in vivo when using suitable vehicles.…”

Section: Resultsmentioning

confidence: 99%

“…C16 was prepared as described earlier [ 5 ]. A tribromoethanol injectable solution (Avertin) was prepared as described in Section E in S1 File .…”

Section: Methodsmentioning

confidence: 99%

“…Our laboratories have been characterizing and validating 4-fluoro-3’,4’,5’-trimethoxychalcone or C16 as a novel invasion inhibitor for the study and potential treatment of metastatic cancer ( Fig 1 ) [ 5 ]. C16 has nanomolar anti-invasive potency in the chick heart [ 6 ] and Matrigel in vitro invasion models against several human cancer cell lines (MCF-7/6 breast cancer, BLM melanoma and SK-OV-3 ovarian carcinoma).…”

Section: Introductionmentioning

confidence: 99%

“…C16 has nanomolar anti-invasive potency in the chick heart [ 6 ] and Matrigel in vitro invasion models against several human cancer cell lines (MCF-7/6 breast cancer, BLM melanoma and SK-OV-3 ovarian carcinoma). The molecule shows a defined structure-activity relationship [ 7 – 9 ] and possesses adequate in vitro absorption, distribution, metabolism, and excretion (ADME) properties ( see section ‘Stability and metabolism’ and [ 5 ]). Given its discovery in a phenotypic model, the biological target of C16 is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3’,4’,5’-trimethoxychalcone in rodents

et al. 2018

Self Cite

View full text Add to dashboard Cite

Effective inhibitors of invasion and metastasis represent a serious unmet clinical need. We have recently identified 4-fluoro-3’,4’,5’-trimethoxychalcone or C16 as a potent anti-invasive molecule. In this paper, we report on the development of an optimized vehicle for oral administration of C16. We also explore its pharmacokinetic and toxicity profile in rodents as a prelude to a broad-scope evaluation as a pharmacological tool in animal models of disease. C16 showed suboptimal pharmacokinetics with limited oral bioavailability and whole blood stability. Rapid metabolism with elimination via glutathione conjugation was observed. An oral dosing routine using medicated gels was developed to overcome bioavailability issues and yielded sustained whole blood levels above the half maximal effective concentration (EC50) in a 7-day study. The compound proved well-tolerated in acute and chronic experiments at 300 mg/kg PO dosing. The medicated gel formulation is highly suitable for evaluation of C16 in animal models of disease.

show abstract

Section: Resultssupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

“…C16 was prepared as described earlier [ 5 ]. A tribromoethanol injectable solution (Avertin) was prepared as described in Section E in S1 File .…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3’,4’,5’-trimethoxychalcone in rodents

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38α Mitogen‐Activated Protein Kinase Inhibitors

Zeid,

El‐Badry,

Elmeligie

et al. 2024

Chemistry & Biodiversity

View full text Add to dashboard Cite

New chalcones were synthesized and evaluated to serve as p38‐α type of mitogen‐activated protein kinase (MAPK) inhibitors. According to the National Cancer Institute, the findings indicated that at a 10 µM dosage, compounds 3a and 6 were the most active among all the compounds examined, with mean growth inhibition% of 94.83 and 58.49, respectively. In 5‐dose testing, they showed anticancer activity in the micro‐molar range with GI50 in the range of 1.41–46.1 and 2.07–31.3 μM, respectively. Besides, powerful activity, especially against the leukaemia cell lines and good selectivity to cancer cells compared to normal PCS‐800‐017 with a selectivity index = 12.41 and 23.77, respectively. Compounds 3a and 6 inhibited p38α MAPK with IC50 values of 0.1462 ± 0.0063 and 0.4356±0.0189 µM, correspondingly. 3a showed good inhibition for HL‐60(TB) cells and induced cell cycle arrest in HL‐60(TB) cells at the G2/M phase. Besides, it elevated the total apoptosis by 14.68‐fold and increased the caspase‐3 level by 3.52‐fold compared with doxorubicin, which raised it by 4.30‐fold, inducing apoptosis by acting as caspase‐dependent inducers. These results suggest that 3a is a promising antiproliferative and p38α MAPK inhibitor, confirmed by molecular docking with high compatibility 3a with the p38α MAPK binding site.

show abstract

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Targanski

Sousa

Pádua

et al. 2020

Pest Management Science

View full text Add to dashboard Cite

BACKGROUND: The expansion of Aedes aegypti (Diptera: Culicidae) population has increased the number of cases of arboviruses, in part due to the inefficiency and toxicity of the chemical control methods available to control this vector. We synthesized 19 chalcone derivatives and examined their activity against Ae. aegypti larvae in order to select larvicidal compounds that are non-toxic to other organisms. RESULTS: Seven chalcone derivatives (3a, 3e, 3f, 6a, 6c, 6d, and 6f) had lethal concentrations of substituted chalcones capable of killing 50% (LC 50) values lower than 100 mg mL −1 at 24 h post-treatment, which is the dose that the World Health Organization recommends for the selection of promising larvicides. The type of substituent added to (E)-1,3-diphenylprop-2-en-1-one (3a) markedly affected the larvicidal activity. Addition of chlorine, bromine and methoxy groups to the aromatic rings reduced the larvicidal activity, while replacement of the Bring (phenyl) by a furan ring significantly increased the larvicidal activity. The furan-chalcone (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) killed Ae. aegypti larvae (LC 50 = 6.66 mg mL −1 ; LC 90 = 9.97 mg mL −1) more effectively than the non-substituted chalcone (3a) (LC 50 = 14.43 mg mL −1 ; LC 90 = 20.96 mg mL −1), and was not toxic to the insect Galleria mellonella, to the protozoan Tetrahymena pyriformis, and to the algae Chorella vulgaris. CONCLUSIONS: The substitution pattern of chalcones influenced their larvicidal activity. In the set of compounds tested, (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) was the most effective larvicide against Ae. aegypti, with no clear signs of toxicity to other animal models. Its mechanism of action and effectiveness under field conditions remain to be determined.

show abstract

4-Fluoro-3′,4′,5′-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model

Cited by 12 publications

References 65 publications

Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3’,4’,5’-trimethoxychalcone in rodents

Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3’,4’,5’-trimethoxychalcone in rodents

Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38α Mitogen‐Activated Protein Kinase Inhibitors

Larvicidal activity of substituted chalcones against Aedes aegypti (Diptera: Culicidae) and non‐target organisms

Contact Info

Product

Resources

About