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Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products (i.e., rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

A novel synthetic method for flavonol from 2′-hydroxyl acetophenone and benzaldehyde promoted by pyrrolidine under an aerobic condition in water is established. This protocol was supported by efficient synthesis of 44 common examples and three natural products. The α, β-unsaturated iminium ion (enimine ion E) was proved to be the key intermediate in the reaction. H218O and 18O2 isotope tracking experiments demonstrated that both water and the aerobic atmosphere were necessary to ensure the transformation. The selectivity for flavonol or aurone was originated from solvent-triggered intermediates, which were determined by UV-visible spectra from isolated enimine. The phenol-iminium E-A is dominant in water and the ketoenamine intermediate E-B is prevalent in acetonitrile. In the presence of pyrrolidine and oxygen, E-A leads to flavonol through E-I, a zwitterionic-like phenoloxyl-iminium ion, following the key steps of cyclization and a [2 + 2] oxidation; E-B proceeds through path II, a radical process induced by photolysis of E-B with both pyrrolidine and oxygen, to afford aurone. Preliminary mechanistic studies are reported.

Herein, we report a synthetic method with improved selectivity for 5-substituted flavonols via the Algar-Flynn-Oyamada reaction (AFO), by using of sodium carbonate/hydrogen peroxide A series of 5-substituted flavonols was obtained with moderate to high yields. The mechanism of the AFO reaction was elucidated. LCMS analysis and in situ 1H NMR analysis indicated that the epoxide was involved in the transformation from chalcone to flavonol and/or aurone under alkaline base/peroxide conditions.

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4′-bromoflavonol (flavonol 3) was the most potent. This compound inhibited proliferation in a concentration-dependent manner, induced apoptosis and blocked cell cycle progression at the S phase. Cell death was found to be associated with the cleavage and activation of multiple caspases, the activation of the mitogen-activated protein kinase pathway and the up-regulation of two death receptors (death receptor 4 and death receptor 5) for tumor necrosis factor-related apoptosis-inducing ligand. Moreover, combined treatments using 4′-bromoflavonol and TRAIL led to an increased cytotoxicity compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR.We synthesized a series of flavones, 7,8-benzofl avones and 5,6-benzo flavones with varying substituents at positions 3, 3′ and 4′ of the (benzo)fl avone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH3 substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3′,4′-OCH3 on phenyl ring lead to increase in activity as compared to other substituents. Compound 24, a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations.

Phytochemical investigation of the leaves of Astragalus beckari yielded four flavonol aglycones, namely kaempferol, quercetin, 5-deoxy kaempferol and fisitin. These isolated compounds were then synthesised in the laboratory using the Algar-Flyn-Oyamad reaction. Antioxidant activity of both the isolated and synthesised flavonoids was compared using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay method. The isolated flavonoids were found to be more active.

The present invention discloses new rocaglaol derivatives and the use of rocaglaol derivatives to prevent or to limit the cardiotoxicity of an antineoplastic agent, in particular to prevent or to limit the apoptosis of cardiomyocytes induced by such agent

Flavonols are an important class of natural products isolated from plants. Some glycosylated flavonols showed very interesting biological activities. A library of flavonols has been made through Algar-Flynn-Oyamada reaction from 2′-hydroxyacetophenones an

Methods of stimulating an immune response and treating patients responsive thereto with 3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-diones, staurosporine analogs, derivatized pyridazines, chromen-4-ones, indolinones, quinazolines, nucleoside analogs, and other small molecules are disclosed.

The present invention relates to a novel flavone derivative, pharmaceutically acceptable salt, hydrate, solvate and isomer thereof which is useful as an inhibitor against Cyclin Dependent Kinase (CDK), a process for preparation thereof, and a composition of anti-cancer agent or agent for treating neurodegenerative disease comprising this compound as an active ingredient.

Alkoxyflavonols were synthesized by the Algar-Flynn-Oyamada (AFO) cyclization of chalcones. Hydroxyflavonols were prepared by dealkylation of methoxyflavonols by refluxing in hydroiodic acid. The alkoxyflavonols 3-hydroxy-2-(2,3,4-trimethoxyphenyl)-4H-chr

Condensation of 4-methoxy- (1) or 5-methoxy- (2) salicylaldehyde with ω-nitrostyrene (3-6) in the presence of triethylamine yields 7-methoxy or 6-methoxy-3-nitro-2H-flavene (7-13), which on treatment with alkaline hydrogen peroxide yields the correspondin

A series of polysubstituted flavones has been prepared with particular emphasis on 3',4',5',5,7-pentahydroxyflavone and its ether derivatives.The preparation of 4-thioflavones has been undertaken to provide intermediates for the preparation of 4-iminoflav