Cerium(Ⅳ) ammonium nitrate(CAN)-mediated regioselective synthesis and anticancer activity of 6-substituted 5,8-dimethoxy-1,4-naphthoquinone

6-Substituted 5,8-O-dimethyl-1,4-naphthoquinones(6-DMNQ),the promising anticancer scaffolds,were selectively generated by oxidative demethylation of 2-substituted 1,4,5,8-tetramethoxynaphthalenes with CAN in EtOAc/H_2O in comparatively high yields.An interesting finding was that apart from the reported electron-withdrawing effects of substituents on position 2 of naphthalene ring,regioselective synthesis of 6-DMNQ was largely dependent on the steric effects in CAN-mediated oxidation.The selective cytotoxicities of 6-DMNQ from the in vitro cell-based assays were exhibited between the cancer cells and normal cells.Moreover,most of sulfur-containing 6-DMNQ derivatives displayed better anticancer activities than the corresponding oxygen-containing ones,which could provide an available strategy for the design of 6-DMNQ derivatives as potential anticancer agents.     

Preliminary investigation of cytotoxic potential of 2-quinolone derivatives using in vitro and in vivo (solid tumor and liquid tumor) models of cancer

2-Quinolone analogs are powerful inhibitors of farnesyl transferase, and are a novel class of anticancer drugs. The present study focused on continual efforts to elucidate the anticancer activity of synthesized 2-quinolone derivatives without N-methyl or 3-aryl substitution. Three derivatives namely JST, JST2 and JST13 were synthesized in our lab and screened for in vitro and in vivo anticancer activities. Significant cytotoxicity was observed in MCF-7 cells treated with JST2 and JST13. Both the derivatives’ treatment showed damage to the DNA. In vivo studies for JST2 and JST13 were performed at two doses 100 and 200 mg/kg using Ehrlich ascites carcinoma (liquid) and Dalton lymphoma ascites (solid) models. Both derivatives showed a significant reduction in the tumor progression by increasing the mean life span and by improving the haematological profile and antioxidant status of the liver in a liquid tumor model. More prominent effect was observed in a solid tumor model by reduction in solid tumor weight and tumor volume.     

Semi-Synthesis and In Vitro Anti-Cancer Evaluation of Magnolol Derivatives

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound 6a exhibited the best cytotoxic activity against four human cancer cell lines, with IC₅₀ values ranging from 20.43 to 28.27 μM. Wound-healing and transwell assays showed that compound 6a significantly inhibited the migration and invasion of MDA-MB-231 cells. In addition, Western blotting experiments, performed using various concentrations of 6a, demonstrated that it downregulates the expression of HIF-1α, MMP-2, and MMP-9 in a concentration-dependent manner. Overall, these results suggest that substituting a benzyl group having F atoms substituted at the C2 position on MAG is a viable strategy for the structural optimization of MAG derivatives as anticancer agents.     

Synthesis and Anticancer Evaluation of Some Novel Quinazolin‐4(3H)‐one Derivatives

A new series of quinazolinone derivatives bearing pyridine, pyrimidine, pyrazole, or pyran moieties were synthesized for the purpose of anticancer cell line evaluation. Synthesis of these derivatives was achieved by the reaction of the ketone 2 with the appropriate aldehydes in the presence of either ethylcyanoacetate or malononitrile and ammonium acetate in one‐pot reaction. Chalcones 6 reacted also with hydrazine hydrate to give the corresponding pyrazolines 7 and reacted with urea or thiourea to give the 2‐oxopyrimidines or the 2‐thioxopyrimidines 8 , respectively. Evaluation of some representative examples of the newly synthesized compounds against cancer cell lines showed promising activity as anticancer agents.     

Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors

Celecoxib, also known as Celebrex (approved by FDA in 1998) and remembered as the fastest-selling drug in history, was used as a cyclooxygenase-2 (COX-2) selective inhibitor having both anti-inflammatory and anticancer activities. Most recent studies have revealed that the apoptotic activity of celecoxib (and its derivatives) is actually independent of the COX-2 inhibitory activity and that celecoxib also inhibits the kinase activity of 3-phosphoinositide-dependent protein kinase-1 (PDK1), suggesting that the well-known anticancer activity of celecoxib is not due to the inhibition of COX-2, but possibly is due to the inhibition of PDK1. It is highly desirable to develop new celecoxib derivatives as PDK1-specifc inhibitors to avoid the side effects of COX-2 inhibitors. To understand how PDK1 binds with celecoxib and its derivatives, we have performed extensive molecular docking and combined molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on eight representative PDK1 inhibitors, leading to the finding of a new, more favorable binding mode which is remarkably different from the previously proposed binding mode. Based on the determined most stable binding structures, the calculated binding free energies are all in good agreement with the corresponding experimental data, and the biological activity data available for celecoxib and its derivatives can be better interpreted. The obtained new insights, concerning both the binding mode and computational protocol, will be valuable not only for future rational design of novel, more potent PDK1-specific inhibitors as promising anticancer therapeutics, but also for rational design of drugs targeting other proteins.     

Anti-allergic agents from natural sources (4): anti-allergic activity of new phloroglucinol derivatives from Mallotus philippensis (Euphorbiaceae)

Two new phloroglucinol derivatives, mallotophilippen A (1). and B (2). were isolated from the fruits of Mallotus philippensis. These compounds were identified, using chemical and spectral data, as 1-[5,7-dihydroxy-2,2-dimethyl-6-(2,4,6-trihydroxy-3-isobutyryl-5-methyl-benzyl)-2H-chromen-8-yl]-2-methyl-butan-1-one and 1-[6-(3-Acetyl-2,4,6-trihydroxy-5-methyl-benzyl)-5,7-dihydroxy-2,2-dimethyl-2H-chromen-8-yl]-2-methyl-butan-1-one, respectively. They inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) gene expression by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma). Furthermore, they inhibited histamine release from rat peritoneal mast cells induced by Compound 48/80. These results suggest that the novel phloroglucinol derivatives have anti-inflammatory effects.     

Synthesis of (-)-arctigenin derivatives and their anticancer activity

The natural dibenzylbutyrolactone type lignanolide (-)-arctigenin, which was prepared from fructus arctii, showed obvious anticancer activity. The synthesis of four new (-)-arctigenin derivatives and their anticancer bioactivities were examined. The structures of the four new synthetic derivatives were elucidated.     

A Facile Synthesis of Substituted 2‐(5‐(Benzylthio)‐1,3,4‐oxadiazol‐2‐yl)pyrazine Using Microwave Irradiation and Conventional Method with Antioxidant and Anticancer Activities

A series of novel substituted 2‐(5‐(benzylthio)‐1,3,4‐oxadiazol‐2‐yl)pyrazine derivatives ( 6a – n ) were synthesized under microwave irradiation and conventional conditions with less reaction time with good to excellent yields. All the synthesized compounds were screened for antioxidant and anticancer activities. Out of the 14 prepared derivatives, compounds 6f and 6m were most potent and active with antioxidant and anticancer activities, respectively. Also, the developed technique was simple, easy, and less time consuming.     

Cytotoxic di(8-quinolyl) disulfides

It has been shown that the nature of the substituent and its position in the quinoline ring markedly affects the antitumor activity and toxicity of di(8-quinolyl) disulfides. The greatest cytotoxicity in the series of methyl derivatives was shown by the 7-, 6-, and 3-isomers towards HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) tumor cells while the 2-methyl derivatives generally have no effect on these cells. High cytotoxicity was also shown (LC₅₀ <1 μg/ml) by other 7-substituted compounds (Cl, PhO, PhS) but they also appear to be highly toxic towards normal NIH 3Y3 mouse embryonic fibroblasts. A similar trend was observed in the series of 5-substituted compounds (NH₂, Cl, OMe, NO₂) which were highly active towards tumor cells but were toxic to normal cells. The best selectivity was found for the 6-substituted quinolines, the 6-methoxy derivative at low concentration brought about the death of tumor cells but appeared much less toxic towards normal fibroblasts (LC₅₀ 100 μg/ml with a corresponding LD₅₀ of 874 mg/kg ). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 750–754, May 2007.     

Design,Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC₅₀ values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.     

Synthesis of Novel 1,2,3‐Triazole/Isoxazole‐Functionalized Imidazo[4,5‐b]pyridin‐2(3H)‐one Derivatives,Their Antimicrobial and Anticancer Activity

A series of novel 1,2,3‐triazole/isoxazole‐functionalized imidazo[4,5‐b]pyridine‐2(3H)‐one derivatives 7 and 8 were prepared starting from pyridin‐2(1H)‐one 1 in a series of steps. Initially, compound 1 was converted into imidazo[4,5‐b]pyridine‐2(3H)‐one 5 via formation of 2‐alkylamino/amino‐6‐phenyl‐4‐(trifluoromethyl)nicotinonitrile 3 followed by hydrolysis 4 and Hoffman type rearrangement 5 . Compound 5 was further reacted with propargyl bromide to form exclusively N‐propargylated derivatives 6 . Compounds 6 were cyclized with arylazides/aryloximes in the presence of CuI and sodium hypochlorite, respectively, and obtained title products 7 and 8 . All the final products 7 and 8 were screened for antimicrobial and anticancer activity.     

Photoreaction pathways for the anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(NH3)2

The photodecomposition of the anticancer complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] in acidic aqueous solution, as well as in phosphate-buffered saline (PBS), induced by UVA light (centred at λ = 365 nm) has been studied by multinuclear NMR spectroscopy. We show that the photoreaction pathway in PBS, which involves azide release, differs from that in acidic aqueous conditions, under which N(2) is a major product. In both cases, a number of trans-{N-Pt(II/IV)-NH(3)} species were also observed as photoproducts, as well as the evolution of O(2) and release of free ammonia with a subsequent increase in pH. The results from this study illustrate that photoinduced reactions of Pt(IV)-diazido derivatives can lead to novel reaction pathways, and therefore potentially to new cytotoxic mechanisms in cancer cells.     

New mononuclear diorganotin(IV) dithiocarboxylates: synthesis,characterization and study of their cytotoxic activities

Since organotin complexes have been reported to show fewer side effects relative to other heavy metal anticancer compounds, in the present study we report for the first time four novel organotin(IV) derivatives with the general formula R₂SnL₂, where R = methyl (1), n‐butyl (2), phenyl (3), benzyl (4) and L = morpholine‐1‐carbodithioate (MCDT). The newly synthesized ligand was monodentate or bidentate, coordinating through a sulfur atom. The complexes were synthesized by directly mixing, refluxing and stirring the ligand, with diorganotin(IV) dichlorides in a suitable solvent. The complexes were found to be pure and their solid and solution phase structural configuration was investigated by FT‐IR, multinuclear NMR (¹ H, ¹³ C, ¹¹⁹Sn) and mass spectrometry. Complex 2 was also studied for its thermal decomposition by thermogravimetry and differential thermal analysis. The results obtained on the basis of these techniques are in full concurrence with the proposed 1:2 (Sn:L) stoichiometry. The cytotoxic activity of the MCDT and diorganotin(IV) complexes (1–4) was tested against tumor cell lines – human cervix carcinoma HeLa and human myelogenous leukemia K562 – and normal immunocompetent cells: peripheral blood mononuclear cells PBMC. Results of bioassay demonstrated that organotin derivatives were in general more active than the anticancer drug cisplatin. Copyright © 2012 John Wiley & Sons, Ltd.     

Lysosomal-targeted anticancer half-sandwich iridium(III) complexes modified with lonidamine amide derivatives

Ten half-sandwich iridium complexes containing lonidamine amide derivatives were synthesized and characterized. Unlike lonidamine, which acts on mitochondria, its iridium complexes successfully targeted lysosomes and induced lysosomal damage. Antiproliferation studies showed that most of the complexes have higher anticancer activity against A549 and HeLa cells than cisplatin. The antitumor activity of complex 6 is 2.69 times that of cisplatin against A549 cells. We also performed antitumor tests on ligands L₁ and L₅, and proved that they exhibit excellent antitumor activity only after binding to the metal center. The bovine serum albumin (BSA) binding test showed that the complexes had the ability to bind to BSA, and they interact with BSA by a static mechanism. The complexes can also cause changes in mitochondrial membrane potential and can produce active oxygen species better than active control. NADH/NAD⁺ transformation experiments were used to determine if the production of ROS was caused by the transformation of NADH/NAD⁺. We also explored the way that the complexes enter cells.     

The coumarin psoralidin enhances anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Coumarins are a very common type of secondary plant metabolites with a broad spectrum of biological activities. Psoralidin is a naturally occurring furanocoumarin isolated from Psoralea corylifolia possessing anticancer and chemopreventive properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in cancer cells with no toxicity toward normal tissues. Endogenous TRAIL plays an important role in immune surveillance and defence against cancer cells. Coumarins can modulate TRAIL-mediated apoptosis in cancer cells. We examined the cytotoxic and apoptotic activities of psoralidin in combination with TRAIL on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining and mitochondrial membrane potential was evaluated using DePsipher staining by fluorescence microscopy. Death receptor (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression was analyzed using flow cytometry. Psoralidin enhanced TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2 death receptor and depolarization of mitochondrial membrane potential. Our study indicated that psoralidin augmented the anticancer effects of TRAIL and confirmed a potential use of coumarins in cancer chemoprevention.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a–9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by ¹H-NMR, ¹³C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.     

聚乙烯胺类修饰萘酰亚胺衍生物的合成、DNA键合行为和活性研究

合成了二乙烯三胺、三乙烯四胺和四乙烯五胺等低分子量聚乙烯胺类修饰的萘酰亚胺衍生物.通过UV-Vis谱、荧光光谱、圆二色谱和热变性试验研究了合成化合物与小牛胸腺DNA的键合行为,同时通过四甲基偶氮唑蓝(MTT)染色法研究了化合物对Bel-7402(人肝癌细胞)、HL-60(白血病细胞)、A549(人肺癌细胞)和Hela(人宫颈癌细胞)等细胞株的体外抗肿瘤活性,化合物NI1对A549细胞显示良好的抑制活性,优于阳性对照顺铂.     

Synthesis and investigation of cytotoxicity of new N- and S,S-substituted-1,4-naphthoquinone (1,4-NQ) derivatives on selected cancer lines

1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharma-cological properties including antibacterial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic, and anticancer effects. In this study, new N- and S,S-substituted-1,4-NQ derivatives were synthesized in excellent yields and were completely characterized by spectroscopic analysis IR, NMR (¹H and ¹³C), MS and microanalysis. The cytotoxic activities of 1,4-NQ derivatives were examined against to A-549, DU145, HCT-116 and MDA-MB-231 cancer cells. Among these compounds, 2-[4-(2-furoyl)piperazine-1-yl]-3-chloro-1,4-NQ 5 and 2,3-bis(cyclobuthylsulfanyl)-1,4-NQ 17 were identified as the most potent anticancer agents with cytotoxic activity against three cell lines (breast (MDA-MB-231), prostate (DU145), colorectal (HCT-116).     

Anticancer Effect of Benzimidazole Derivatives,Especially Mebendazole,on Triple-Negative Breast Cancer (TNBC) and Radiotherapy-Resistant TNBC In Vivo and In Vitro

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.