Der substitutionsspezifische einfluss von chalkonen auf die anthocyanbiosynthese bei Petunia hybrida

The effect of two chalcones, 3,4,2′,4′,6′-pentahydroxy- and the 4, 2 ′,4′,6′ -tetrahydroxy- 3-methoxy-chalcone- 4′-glucoside, on the synthesis of different flower anthocyanins in isolated petals of Petunia hybrida has been investigated. The results show that the synthesis of those anthocyanins, which have the same substitution pattern as the chalcone used was increased. This suggests that the chalcones are incorporated into the anthocyanins concerned. When the chalcones were fed together with acetic acid-[1-¹⁴C], this specific substitution effect was detectable only for the 3,4,2′,4′,6′-pentahydroxy-chalcone-4′-glucoside.     

Introduction of amino moiety enhances the inhibitory potency of 1-tetralone chalcone derivatives against LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages

The design and synthesis of a series of thirty-two halogenated 1-tetralone or 6-amino-1-tetralone chalcone derivatives was achieved by the Claisen-Schmidt condensation reaction and were evaluated for their inhibitory effects against ROS production in LPS-stimulated RAW 264.7 macrophages. It was observed that the introduction of amino moiety into 1-tetralone skeleton greatly increased the inhibitory potency compared to corresponding 1-tetralone chalcones. Among the synthesized compounds, compound 18 which consists of 6-amino-1-tetralone skeleton together with o-fluorobenzylidene showed the most potent ROS inhibitory effect with IC₅₀ value of 0.25 ± 0.13 µM. SAR analysis revealed that amino moiety at the 6th position of 1-tetralone chalcones have an important role for exerting the greater ROS inhibitory potency in LPS-stimulated RAW 264.7 macrophages than those exhibited by 1-tetralone chalcones alone.     

Synthesis and investigations into the anticancer and antibacterial activity studies of β-carboline chalcones and their bromide salts

A series of sixteen β-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-β-carboline and various aldehydes under basic conditions followed by N²-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N²-Alkylated-β-carboline chalcones 13a-i represented the interesting anticancer activities compared to N²-unsubstituted β-carboline chalcones 12a-g. Off the prepared β-carbolines, 13g exhibited broad spectrum of activity with IC₅₀ values lower than 22.5?µM against all the tested cancer cell lines. Further, the N²-alkylated-β-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared β-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.     

Chalcone synthesis with enzyme extracts from tulip anther tapetum using a biphasic enzyme assay

The in vitro synthesis of chalcones has been demonstrated using a special biphasic enzyme assay. The highly viscous lower phase in this assay stems from a tapetum fraction of anthers of Tulipa cv. “Apeldoorn” which has been used an enzyme source. The upper phase of this system consists of a reaction mixture of the normal “flavanone synthase” assay. It is suggested that chalcone synthesis occurs at the boundary layer between the two phases. To prevent spontaneous as well as enzymatic cyclization of the chalcones formed (phloroglucinyl type), the pH of the upper phase must not be allowed to exceed pH 4.0. Under these pH conditions, chalcone formation by a reverse reaction of chalcone-flavanone isomerase can be excluded. The measured substrate specificity of the “chalcone synthase” corresponds to the conditions of chalcone formation in the natural system. Using p-coumaroyl-CoA, caffeoyl-CoA, and feruloyl-CoA, respectively, as substrates, the enzyme system forms the correspondingly substituted chalcones which are also accumulated in the loculus of tulip anthers. It is suggested that this chalcone synthase is identical to the previously described “flavanone synthase”. The results can be further explained as follows. (i) Not flavanones, but rather chalcones are the first C₁₅ intermediates of flavonoid biosynthesis in tulip anthers. (ii) In this Tulipa system, the substitution pattern of three different hydroxycinnamic acids can be transferred unchanged into the flavonoid C₁₅ stage. (iii) The role of chalcone-flavanone isomerase is to cyclize chalcones to flavanones on the direct biosynthetic pathway to the further accumulated flavonol glycosides. (iv) The sensitivity of the reaction with regard to chalcone production points to the localization of chalcone synthase in a most unstable and, up to now, unknown tapetal compartment. Since purification of the enzyme results in exclusive production of flavanones, it is suggested that certain “chalcone stabilizing factors” must occur in the natural system. (v) The phenomenon of chalcone accumulation in tulip anthers, however, must be caused by a complex system, distinguished by cooperation of certain biochemical and physiological conditions, and, finally, by special compartmentation of the enzymes which are responsible for the biosynthesis of flavonoids.     

Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro

An efficient method for palladium-catalyzed CO cross-coupling of ethyl acetohydroxamate (EAcHO) with 4-bromo-chalcones has been developed to synthesize novel chalcones. The two supporting ligands, namely tBuXPhos (L7), and cataCXium®PIntB (L16) were found to be effective ligands towards the Pd-catalyzed CO cross-coupling reaction to afford the desired product in moderate to excellent yields (50–99%). The coupled products were screened for in vitro blood stage antiplasmodial activity against Plasmodium falciparum (3D7) using the [³H] hypoxanthine incorporation inhibition assay. Of the twenty two compounds screened, eleven showed good antiplasmodial activity with IC₅₀ values ranging from 6–16 μg/mL. The selected active molecules 11, 16, 22, (IC₅₀ 12 μg/mL) and 19 (IC₅₀ 6 μg/mL) were studied for their cytotoxic effect against HepG2 Cells (human hepatocellular liver carcinoma cell lines), showing the selectivity index (SI) values are greater than 4 except chalcone 22. Our result demonstrates a methodology for synthesizing novel chalcones as a new class of antiplasmodial agent.     

The occurrence of aurentiacin and flavokawin B on Pityrogramma triangularis var. pallida and Didymocarpus species

The two chalcones, aurentiacin and flavokawin B, were isolated from the frond exudate of Pityrogramma triangularis var. pallida. In addition, flavokawin B was obtained from the leaf exudate of Didymocarpus corchorifolia.     

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC₅₀ in the range of 6.2–10.98 μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50 μM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.     

Nitrochalcones: Potential in vivo insulin secretagogues

In this study, the in vivo and in vitro anti-hyperglycemic activity of chalcone derivatives of 3,4-methylenedioxy, with a substituent electron-acceptor nitro group in the A or B ring, was investigated. As expected, the second generation sulfonylurea glipizide stimulated insulin secretion and reduced glycemia over the study period. Also, it was demonstrated for the first time that chalcones are able to increase insulin secretion and this event was coincident with serum glucose-lowering in the oral glucose tolerance test. Additionally, the chalcones studied had a similar effect on insulin secretion and serum glucose-lowering as glipizide. The effect of chalcones in terms of inducing insulin secretion was greater than that of glipizide after 30 min. Moreover, chalcones were not able to stimulate glucose uptake in soleus muscle, either in the presence of insulin or in the absence of this hormone. In addition, the oral treatment with chalcones did not alter glycemia in diabetic rats. These reports indicate that the effect of chalcones on serum glucose-lowering in hyperglycemic-normal rats is mainly a consequence of insulin secretion, highlighting these chalcones as novel compounds with strong anti-hyperglycemic properties.     

Direct synthesis of C3-mono-functionalized oxindoles from N-unprotected 2-oxindole and their antileishmanial activity

A novel approach for the synthesis of unprecedented C3-mono-functionalized indolin-2-ones is reported, starting from 2-oxindole and chalcones. The reactions proceed regioselectively under mild conditions, without di- and tri-alkylated side products. The new compounds have been evaluated in vitro for their antiproliferative effects against the protozoan Leishmania infantum. Interestingly, they appear able to kill L. infantum promastigotes and amastigotes, without significant cytotoxic effects.     

Identification of chalcones as in vivo liver monofunctional phase II enzymes inducers

Cancer preventive agents (CPA) are drugs able to suppress the carcinogen metabolic activation or block the formation of ultimate carcinogens. CPA could act through various molecular mechanisms, for example by interfering with the action of procarcinogen. This could be attained by increasing the phase II enzymes levels of quinone reductase (QR) and glutathione S-transferase (GST). New flavonoids, especially chalcones, have been identified as in vivo monofunctional phase II enzymes inducers. Oral administration of chalcone, 4, and both p-methoxy-substituted chalcones, 6 and 14, increased hepatic QR activity with concomitant decrease in CYP1A1 activity, a member of the most important group of phase I enzymes cytochrome P450. Among them, 4 also increased GST activity. While p-bromo-substituted chalcone 8 was the best inducer of QR it decreased hepatic GST expression and cytochrome P450, being the most effective decreasing cytochrome P450-expression. Thienyl-chalcone 20 being the bioisostere of chalcone 4 did not display the same in vivo profile in the phase I level modification. As chalcone 4 its bioisostere, chalcone 20, displayed low DNA strand breakage and absence of mutagenicity. Also, in our preliminary in vivo tumourigenesis/chemopreventive and acute-toxicity studies, chalcones 4, 6 and 8 showed the best behaviours as CPA justifying additional studies that are ongoing.     

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into β-cyclodextrin/cellulose-nanocrystal complexes

This paper describes the preparation of two chalcone/β-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of β-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/β-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.     

Neue chalkon-derivate und humulon-ähnliche verbindungen aus Helichrysum-arten

The investigation of two further Helichrysum species afforded in addition to known compounds three new prenylated chalcones and two humulone-like compounds. The structures were elucidated by spectroscopic methods and some chemical transformations. The chemotaxonomic situation is discussed briefly.     

Flavonoids from the leaves and twigs of Knema elegans

Knema elegans, a tropical evergreen plant, belongs to Myristicaceae family. Phytochemical investigation on the leaves and twigs of K. elegans led to the isolation and identification of two new flavonoids knemavones A and B (1 and 2), along with fifteen known analogues (3–17). These compounds belong to four subtypes of flavonoids, including chalcones, flavanes, flavones, and isoflavones. The structures of 1 and 2 were elucidated by means of spectroscopic techniques, including HRESIMS, 1D, and 2D NMR experiments. Compounds 3–17 are isolated from the title plant for the first time. Moreover, the new chalcones 1 and 2 could serve as chemotaxonomic markers of K. elegans.     

Chalcone cyclase and flavonoid biosynthesis in grapefruit

A chalcone cyclase (CC), which acts unidirectionally upon the chalcone-flavanone equilibrium reaction, was isolated from immature grapefruit. The enzyme required neohesperidose at C-4′ of the chalcone A-ring and a free, unhindered hydroxyl group at C-4 of the B-ring for activity. The CC bound, but did not cyclize, prunin chalcone (K_i= 2.5 × 10^?5 M). The results suggest that the intermediates that form the B-ring of chalcones are hydroxylated prior to chalcone formation, that chalcones are glycosylated during their formation, and that methylation occurs after cyclization of the chalcones to flavanones.     

Chalcone glycosides of Antirrhinum majus

Three chalcones have been found in yellow flowers of A. majus, two of which have been identified as chalcononaringenin 4′-glucoside and 3,4,2′,4′,6′-pentahydroxychalcone 4′-glucoside.     

Novel quinoxalinyl chalcone hybrid scaffolds as enoyl ACP reductase inhibitors: Synthesis,molecular docking and biological evaluation

We report herein, first ever synthesis of series of novel differently substituted quinoxalinyl chalcones using Claisen Schmidt condensation, its molecular docking studies, and potential to be good anti-microbial, anti-tubercular and anti-cancer agents. The antimicrobial studies were carried out against Staphylococcus aureus, Escherichia coli and Candida albicans using disc diffusion procedure. The selected chalcones were tested for anti-cancer and cytotoxicity activity against MCF-7 cancer cell line using MTT assay method. All the synthesized compounds were screened for in vitro anti-tubercular screening against MtbH37RV strains by Alamar blue dye method. These results were compared with molecular docking studies carried out on Mycobacterium tuberculosis enzyme enoyl ACP reductase using Surflex-Dock program that is interfaced with Sybyl-X 2.0. SAR analysis for antimicrobial and antitubercular activity has also been proposed.     

Determination of chemical structure and anti-Trypanosoma cruzi activity of extracts from the roots of Lonchocarpus cultratus (Vell.) A.M.G. Azevedo & H.C. Lima

Trypanosoma cruzi is the agent of Chagas disease, an infection that affects around 8 million people worldwide. The search for new anti-T. cruzi drugs are relevant, mainly because the treatment of this disease is limited to two drugs. The objective of this study was to investigate the trypanocidal and cytotoxic activity and elucidate the chemical profile of extracts from the roots of the Lonchocarpus cultratus. Roots from L. cultratus were submitted to successive extractions with hexane, dichloromethane, and methanol, resulting in LCH, LCD, and LCM extracts, respectively. Characterization of extracts was done using ¹H-RMN, ¹³C-RMN, CC and TLC. Treatment of T. cruzi forms (epimastigotes, trypomastigotes, and amastigotes) with crescent concentrations of LCH, LCD, and LCM was done for 72, 48, and 48 h, respectively. After this, the percentage of inhibition and IC₅₀/LC₅₀ were calculated. Benznidazole was used as a positive control. Murine macrophages were treated with different concentrations of both extracts for 48 h, and after, the cellular viability was determined by the MTT method and CC₅₀ was calculated. The chalcones derricin and lonchocarpine were identified in the hexane extract, and for the first time in the genus Lonchocarpus, the presence of a dihydrolonchocarpine derivative was observed. Other chalcones such as isocordoin and erioschalcone B were detected in the dichloromethane extract. The dichloromethane extract showed higher activity against all tested forms of T. cruzi than the other two extracts, with IC₅₀ values of 10.98, 2.42, and 0.83 µg/mL, respectively; these values are very close to those of benznidazole. Although the dichloromethane extract presented a cytotoxic effect against mammalian cells, it showed selectivity against amastigotes. The methanolic extract showed the lowest anti-T. cruzi activity but was non-toxic to peritoneal murine macrophages. Thus, the genus Lonchocarpus had demonstrated in the past action against epimastigotes forms of T. cruzi but is the first time that the activity against infective forms is showed, which leading to further studies with in vivo tests.     

Synthesis of novel pyrazolic analogues of chalcones and their 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antitumor agents

Novel (E)-1-aryl-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 5/6 (pyrazolic chalcones) were synthesized from a Claisen–Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes 4 with several acetophenone derivatives 1. Subsequently, the microwave-assisted cyclocondensation reaction of chalcones 5/6 with hydrazine afforded the new racemic 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 7 or their N-acetyl derivatives 8 and 9 when reactions where carried out in DMF or acetic acid, respectively. Several of these compounds were screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where 5c and 9g showed remarkable activity mainly against leukemia (K-562 and SR), renal cancer (UO-31) and non-small cell lung cancer (HOP-92) cell lines, with the most important GI₅₀ values ranging from 0.04 to 11.4 μM, from the in vitro assays.     

Synthesis and biological evaluation of a series of tangeretin-derived chalcones

A series of chalcones polyoxygenated on the ring A (with pentamethoxy or 2′-hydroxy-3′,4′,5′,6′-tetramethoxy substitution patterns) was synthesized from tangeretin, a natural Citrus flavonoid. These chalcones were evaluated for their antiproliferative, activation of apoptosis, inhibition of tubulin assembly and antileishmanial activities. Comparison with the reference analogous 3′,4′,5′-trimethoxylated chalcones showed that such peroxygenated substitution patterns on the ring A were less beneficial to these activities.     

Chalcones and bis-chalcones: As potential α-amylase inhibitors; synthesis,in vitro screening,and molecular modelling studies

Despite of a diverse range of biological activities associated with chalcones and bis-chalcones, they are still neglected by the medicinal chemist for their possible α-amylase inhibitory activity. So, the current study is based on the evaluation of this class for the identification of new leads as α-amylase inhibitors. For that purpose, a library of substituted chalcones 1–13 and bis-chalcones 14–18 were synthesized and characterized by spectroscopic techniques EI-MS and ¹H NMR. CHN analysis was carried out and found in agreement with the calculated values. All compounds were evaluated for in vitro α-amylase inhibitory activity and demonstrated good activities in the range of IC₅₀ = 1.25 ± 1.05–2.40 ± 0.09 µM as compared to the standard acarbose (IC₅₀ = 1.04 ± 0.3 µM). Limited structure–activity relationship (SAR) was established by considering the effect of different groups attached to aryl rings on varying inhibitory activity. SMe group in chalcones and OMe group in bis-chalcones were found more influential on the activity than other groups. However, in order to predict the involvement of different groups in the binding interactions with the active site of α-amylase enzyme, in silico studies were also conducted.