Involvement of extrinsic and intrinsic apoptotic pathways together with endoplasmic reticulum stress in cell death induced by naphthylchalcones in a leukemic cell line: Advantages of multi-target action

Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.     

Synthesis of some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents

Chalcones of 2a–f and their corresponding products, pyrazolines 3a–f , were synthesized and evaluated for their anti‐inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti‐inflammatory activity. The most active compounds of this series, 2a , 2b , and 2d , were found to be most potent. They showed higher percentage of inhibition of edema than the standard drug indomethacin.     

Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: structure-activity analysis

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79.     

Design, synthesis and cytotoxicity of novel chalcone analogs derived from 1-cyclohexylpyrrolidin-2-one and 2,3-dihydrobenzo[f]chromen-1-one

Two divergent series of novel chalcone analogs, one derived from 1‐cyclohexylpyrrolidin‐2‐one and the other derived from 1‐benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1‐benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC₅₀ values between the range of 5 and 6 µM. With an IC₅₀ value of 3.4 µM, compound 4g was also active against human MDA‐MB‐435 melanoma cells. X‐ray structures of the β‐hydroxy ketone product ( 4a ) and the α,β‐unsaturated ketone ( 4h ) were collected, and confirm the syn‐configuration between the carbonyl moiety and the β‐vinylic proton in 4h . X‐ray structures of two 1‐cyclohexylpyrrolidin‐2‐one derivatives were also obtained, and both showed an E‐configuration for the double bond.     

Biological evaluation of chalcones and analogues as hypolipidemic agents

In order to evaluate the anti-hyperlipidemic effect of synthetic chalcones and some analogues, nineteen compounds with different substituents in both rings were synthesized and hypolipidemic activities were measured in vivo using Triton WR1339 acute and hypercaloric chronic assays. 4',4-dichlorochalcone, 3',4',4-trichlorochalcone, and 4'-chlorochalcone gave an excellent decrease in serum total cholesterol and triglycerides in the acute assay. These compounds also showed significant anti-lipidemic activity in the chronic assay.     

查尔酮类细胞周期蛋白依赖性激酶抑制剂的合成以及抗癌活性研究

目的:寻找活性更好的查尔酮类细胞周期蛋白依赖性激酶(CDKs)抑制剂。方法:经查尔酮路线制备8个查尔酮类类黄酮。结果:目标化合物结构经IR、1H-NMR、ESI-MS确证。活性测定结果显示有2个化合物对A549的抑制活性高于对照Flavopiridol,所有化合物对HCT116有较强的抑制活性。结论:Flavopiridol被结构类似的查尔酮代替后,可得到活性更好的类黄酮。     

Synthesis and Antitumor Activity of Novel Nitrogen Mustard‐Linked Chalcones

A series of nitrogen mustard‐linked chalcones were synthesized and evaluated for their antitumor activity in vitro against the K562 and HepG2 cell lines. The aldol condensation of [N,N‐bis(chloroethyl)‐3‐amino]‐acetophenone ( 2 ) with aromatic aldehydes afforded the nitrogen mustard‐linked chalcones. Among the analogs tested, compounds 5e and 5k exhibited significant anti‐proliferation activities against K562 cells with IC₅₀ values of 2.55 and 0.61 µM, respectively, which revealed higher cell toxicity than the standard drugs cisplatin (IC₅₀ > 200 µM) and adriamycin (IC₅₀ = 14.88 µM). The methoxyl and N,N‐dimethyl groups on the B‐ring of the chalcone frame enhanced the inhibitory activities against both the K562 and HepG2 cell lines. The structure–activity relationship study indicated that the inhibitory activities significantly varied with the position(s) and species of the substituted group(s).     

Synthesis and cytotoxic properties of novel (E)-3-benzylidene-7-methoxychroman-4-one derivatives

Background and the purpose of the study

There has been increscent interest in the field of cancer chemotherapy by discovery and development of novel agents with high efficacy, low toxicity, and minimum side effects. In order to find new anticancer agents, we replaced the pyrazolone part of well-known cytotoxic agent SJ-172550 with 7-methoxychroman-4-one. Thus, a novel series of 3-benzylidene-4-chromanones were synthesized and tested in vitro against human cancer cell lines.

Methods

The title compounds were prepared by condensation of 7-methoxychroman-4-one with suitable aldehydes in appropriate alcohol in the presence of gaseous HCl. The antiproliferative activity of target compounds were evaluated against MDA-MB-231 (breast cancer), KB (nasopharyngeal epidermoid carcinoma) and SK-N-MC (human neuroblastoma) cell lines using MTT assay.

Results

Although the direct analog of SJ-172550 (compound 5d) did not show any cytotoxic activity against tested cell lines, but 2-(2-chloro-6-methoxyphenoxy)acetic acid methyl ester analog 5c showed some activity against MDA-MB-231 and SK-N-MC cells. Further modification of compound 5c resulted in the 3-chloro-4,5-dimethoxybenzylidene derivative 5b which demonstrated better cytotoxic profile against all tested cell lines (IC₅₀ values = 7.56–25.04 μg/ml).

Conclusion

The results demonstrated that the cytotoxic activity of compound 5b against MDA-MB-231 and SK-N-MC cells is more than etoposide. Therefore, compound 5b prototype could be considered as novel cytotoxic agent for further developing new anticancer chemotherapeutics.     

Design, synthesis and cytotoxicity of a new series of isoxazolidines derived from substituted chalcones

A new series of isomeric isoxazolidin-3-yl-3-phosphonates were synthesised from N-methyl-C-diethoxyphosphorylnitrone and substituted chalcones. The respective isoxazolidin-3-yl-3-phosphonic acids were obtained from phosphonates via dealkylation procedure using trimethylsilyl bromide. Selected phosphonates and their respective phosphonic acids were screened for their cytotoxic activity to HeLa and K562 cells with IC₅₀ in the 0.1-0.3 mM range.