Synthesis,cytotoxic activity,and 2D‐ and 3D‐QSAR studies of 19‐carboxyl‐modified novel isosteviol derivatives as potential anticancer agents

Two series of novel acylthiosemicarbazide and oxadiazole fused‐isosteviol derivatives were synthesized based on the 19‐carboxyl modification. The target compounds were evaluated for their cytotoxicities against three cancer cell lines (HCT‐116, HGC‐27, and JEKO‐1) using an MTT assay. Lead compounds from the acylthiosemicarbazides ( 4 ) showed IC₅₀ values in the lower micromolar range. For example, compounds ( 4i , 4l , 4m , 4r, and 4s ) exhibited significant inhibitory activities against the three cell lines with IC₅₀ values of 0.95–3.36 μm . Furthermore, 2D‐HQSAR and 3D‐topomer CoMFA analyses were established, which could be used to develop second generation of isosteviol derivatives as anticancer agents.     

Design,synthesis, and cytotoxic evaluation of novel scopoletin derivatives

A series of scopoletin derivatives were designed and synthesized by introducing α‐aminoacetamide, acrylamide and β‐aminopropamide, respectively, to 3‐position of scopoletin, and their chemical structures were confirmed by ESI‐MS, IR, ¹H NMR, and ¹³C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (MDA‐MB‐231, MCF‐7, HepG2, and A549) by MTT method. Cytotoxic assay showed that compounds 7a , 7b , 7e , 7f , 8a , and 8e exhibited more potent cytotoxicities compared to scopoletin. Besides, we have further evaluated the growth inhibitory activities of these selected compounds against normal tissue cell lines HFL‐1. Although compound 8a showed the strongest antiproliferative activity in vitro, it exhibited strong cytotoxicity on normal cells HFL‐1, which limited its further study. Compound 7a and 7b exhibited higher antiproliferative activity against MDA‐MB‐231 and HepG2 cells and weak cytotoxicity on HFL‐1, which suggested that 7a and 7b might be ideal anticancer candidates. The SARs showed that the introduction of the acrylamide and its analogues β‐aminopropamide could significantly improve activity, while the α‐aminoacetamide failed to enhance potency obviously. Therefore, the mechanism of compound 7a and 7b is worthy of further research and the structure of compound 8a should be further optimized.     

3‐Aminomethyl pyridine chalcone derivatives: Design,synthesis, DNA binding and cytotoxic studies

Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j . Compounds 6a–f were designed based on 3‐aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF‐7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3‐aminomethyl pyridine and 4‐amino chalcones. A series of chalcone derivatives of 3‐aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA‐binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT‐DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA‐EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC₅₀ 0.0067 ± 0.0002 μm , against MCF‐7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.     

Design,synthesis, and cytotoxic evaluation of novel furo[2,3‐b]quinoline derivatives

A number of novel furo[2,3‐b]quinoline derivatives were designed and synthesized by introducing benzyl ether, benzoate, and benzenesulfonate to 6‐position of furo[2,3‐b]quinoline and their chemical structures were confirmed by ESI‐MS, ¹H NMR, and ¹³C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (HCT‐116, MCF‐7, U2OS, and A549) by MTT method. Cytotoxic assay showed that compounds 8a , 8e , 10a , 10b, and 10c exhibited more potent cytotoxicities compared to 2‐bromine‐6‐hydroxy‐furo‐[2,3‐b]quinoline ( 7 ). Compound 10c exhibited higher antiproliferative activity (IC₅₀ values ranging from 4.32 to 24.96 μm ) against four human cancer cell lines (HCT‐116, MCF‐7, U2OS, and A549) and weak cytotoxicity on normal cell HL‐7702, which suggested that 10c might be an ideal anticancer candidate. Compounds 8a , 10a , 10b showed good selectivities to MCF‐7 and HCT‐116, which could be considered as ideal selective candidates for further study. The SARs showed that the introduction of the benzyl ether and benzenesulfonate could significantly improve cytotoxicities, while the benzoate failed to enhance potency obviously.     

Design,synthesis, and antitumor evaluation of quinoline‐imidazole derivatives

A series of compounds bearing quinoline‐imidazole ( 8a–e , 9a–e , 10a–e , 11a–e , and 12a–e ) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC‐3, HepG2, and MCF‐7 cells by the MTT method, with NVP‐BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC‐3 cells, with half‐maximal inhibitory concentration (IC₅₀) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP‐BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC₅₀ value of 12a against the cell line WI‐38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K‐Akt‐mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP‐BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C‐6 of the quinoline ring was replaced by a bromine atom.

     

Synthesis and evaluation of cytotoxic activities of artemisinin derivatives

Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a – 5d were evaluated by MTT assay against ten cell lines. The results showed that 5a – 5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC‐PRF‐5 cells and presented no cytotoxicity on L‐02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC‐PRF‐5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential (MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase‐3 kit, 5d could significantly increase the content of p53, bax, Apaf‐1, and caspase‐3 and decrease the protein level of bcl‐2, pro‐caspase‐9, and pro‐caspase‐3 in HepG2 cells. These findings indicate that 5d activates the mitochondria‐mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma.     

Design,synthesis, and biological evaluation of chrysin derivatives as potential FabH inhibitors

New series of chrysin derivatives ( 4a – 4t ) were designed and synthesized by introducing different substituted piperazines at C‐7 position. Their inhibitory effects on FabH were evaluated using two Gram‐negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram‐positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC₅₀ values of 5.78 ± 0.24 μm inhibiting E. coli FabH and potent antibacterial activity against S. aureus and E. coli with MIC of 1.25 ± 0.01, 1.15 ± 0.12 μg/mL, respectively, comparing to the control positive drugs penicillin G (7.56 ± 0.30 μm ). Docking simulation was performed to position compound 4s into the FabH active site, and the result showed that compound 4s could bind well with the FabH as potent FabH inhibitor.     

Design,synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, ¹H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC₅₀ values (0.25–1.7 µM) were lower than that of indomethacin (IC₅₀ = 9.47 µM) and somewhat higher than that of celecoxib (IC₅₀ = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC₅₀ values of 0.02–74.03 µM, while the IC₅₀ of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

     

Design,synthesis, and biological evaluation of novel 4‐phenoxypyridine derivatives as potential antitumor agents

A series of novel 4‐phenoxypyridine derivatives containing the 4‐oxo‐1,4‐dihydropyridazine‐3‐carboxamide moiety were synthesized and evaluated for their in vitro cytotoxic activity against the A549 cancer cell line, and some compounds were further examined for their cytotoxic activity against the H460, BGC823, MKN45, and HT‐29 cancer cell lines. Most of the compounds exhibited moderate to significant cytotoxicity. The most promising compound 15b (with VEGFR2 inhibitory concentration [IC₅₀] value of 0.23 μM) showed remarkable cytotoxicity against A549, BGC‐823, MKN45, H460, and HT‐29 cells, with IC₅₀ values of 0.75, 1.68, 2.63, 5.08 and 7.22 μM, respectively. Their preliminary structure‐activity relationship studies indicate that electron‐withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Moreover, treatment of A549 cells with compound 15b resulted in cell cycle arrest in the G₀/G₁ phase in a dose‐dependent manner. Further apoptotic studies and acridine orange/ethidium bromide staining were also performed on A549 cells, which showed that compound 15b could induce apoptosis. Wound‐healing assay results indicated that compound 15b strongly inhibited A549 cell motility.     

一氧化氮供体型塞曲司特衍生物的设计、合成和抗哮喘活性

目的寻找新型抗哮喘药物。方法以抗哮喘药塞曲司特(SD)为母核，将不同类型的一氧化氮(NO)供体, 包括噁三唑类、n-羟基胍类和呋咱氮氧化合物类与其相偶联；通过对乙酰胆碱-组胺所致豚鼠哮喘的抑制作用来评价偶联物的抗哮喘活性；研究偶联物的NO释放作用。结果合成了9个未见文献报道的目标化合物I1~9，结构经IR，NMR，MS及元素分析确证。初步药理试验表明，目标化合物I2~7和I9具有显著的抗哮喘活性(引喘潜伏期由SD的10 s延长到26~62 s)，其中I₄,I₆,I₇的活性强于SD(_P<0.05,_P<0.01)，体外释放NO的C_max分别为0.187 8,0.139 3和0.247 3 mg·L^-1。结论NO供体型塞曲司特衍生物具有进一步研究的价值。     

Design,synthesis, and anti-tumor activity of novel betulinic acid derivatives

Seventeen new derivatives of betulinic acid (BA) with potential anti-tumor activity have been synthesized. In order to improve the bioactivity of BA, we connected BA and nitric oxide donors together via different linkers. The results of the biological activity of these derivatives showed that four compounds exhibited obvious cytotoxicity against human hepatocellular carcinoma cells in vitro.     

Synthesis and cytotoxic evaluation of some new phthalazinylpiperazine derivatives

A new series of 1,4‐disubstituted phthalazinylpiperazine derivatives 7a–f , 12a–f and 20a–f were designed and synthesized in order to develop potent and selective antitumor agents. The target compounds were screened for their cytotoxic activities against A549, HT‐29 and MDA‐MB‐231 cancer cell lines in vitro. Among them, compounds 7a–f exhibited excellent selectivity for MDA‐MB‐231 with IC₅₀ values ranging from 0.013 µM to 0.079 µM. The most promising compound, 7e (IC₅₀ = 2.19 µM, 2.19 µM, 0.013 µM), was 9.3, 10, and 4.9 × 10³ times more active than vatalanib (IC₅₀ = 20.27 µM, 21.96 µM, 63.90 µM), respectively.     

Design,synthesis and biological evaluation of imidazo[1,2‐a]pyridine analogues or derivatives as anti‐helmintic drug

The Albendazole was used as the lead compound, which was modified by structural transformation and with alkyl groups. A total of 18 compounds ( 4a – 4r ) were designed and synthesized. The in vitro experiment results showed that compounds 4e , 4f , 4k , 4l , 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC₅₀ of compound 4l to anti‐egg of roundworm was 0.65 ± 0.01 μmol/L and to anti‐imago of roundworm was 1.04 ± 0.01 μmol/L. At the same time, it showed that compound 4l had the best effect in vivo, and the rate of anti‐helmintic could reach more than 99%. The results of acute toxicity tests indicated that these compounds were with LD₅₀ > 2100 mg/kg by oral administration, so they were low toxicity compounds. In a word, compound 4l was most likely to be a new anti‐helmintic drug through screening in vitro and in vivo.     

Design,synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate

A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF‐7, and HT‐29 were evaluated. Compared with colchicine (1.04 × 10^?2 μm ), 17d and 17e exhibited outstanding activity on MCF‐7 with IC₅₀ values 0.26 × 10^?2 μm and 0.89 × 10^?3μm in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate. In the MCF‐7‐xenograft mouse model that was treated with 17d and 17e by intraperitoneal injection, the tumor weight was decreased at same rate with tamoxifen, and relative tumor proliferation rates were 59.48% and 41.33%, while tamoxifen was 45.08% with a daily dose of 20 mg/kg, which were demonstrated potent in vivo efficacy.     

Bis‐2(5H)‐furanone derivatives as new anticancer agents: Design,synthesis, biological evaluation,and mechanism studies

New bis‐2(5H)‐furanone derivatives containing a benzidine core were synthesized via a one‐step transition‐metal‐free reaction of benzidine with 5‐substituted 3,4‐dihalo‐2(5H)‐furanones. Their antitumor activities against various tumor cells have been evaluated by MTT assay. Among them, compound 4e exhibits significant inhibitory activity against C6 glioma cells with an IC₅₀ value of 12.1 μm and low toxicity toward HaCaT human normal cells. Studies on the antitumor mechanism reveal that cell cycle arrest at S‐phase in C6 cells is induced by compound 4e . Furthermore, investigations with electronic, fluorescence emission and circular dichroism spectra show that compound 4e can significantly interact with C6‐DNA. These data indicate that DNA may be one of the potential targets for bis‐2(5H)‐furanone derivatives as anticancer drugs.     

Synthesis,X-ray crystal structure and biological properties of acetylenic flavone derivatives

The reactions of iodoflavone with 3-methyl-3-hydroxybut-1-yne and 3-methylbut-3-en-2-yne are described and the antimicrobial and cytotoxic activities of the obtained compounds have been tested. The molecular structures of 6-(3-hydroxy-3-methylbut-1-ynyl)-flavone (1a) and 6-(3-methylbut-3-en-1-ynyl) flavone (1b) have been determined by X-ray crystallography. The planar configuration of the two compounds has been attributed to intramolecular hydrogen bond interactions. In 1a, the presence of the hydroxyl group determines a dimeric arrangement of the molecules. In both compounds in the crystal state, molecular stacking has been observed.     

Synthesis and cytotoxic activity of certain benzothiazole derivatives against human MCF‐7 cancer cell line

A new series of benzothiazole has been synthesized as cytotoxic agents. The new derivatives were tested for their cytotoxic activity toward the human breast cancer MCF‐7 cell line against cisplatin as the reference drug. Many derivatives revealed good cytotoxic effect, whereas four of them, 4, 5c, 5d, and 6b , were more potent than cisplatin, with IC₅₀ values being 8.64, 7.39, 7.56, and 5.15 μm compared to 13.33 μm of cisplatin. The four derivatives’ cytotoxic activity was accompanied by regulating free radicals production, by increasing the activity of superoxide dismutase and depletion of intracellular reduced glutathione, catalase, and glutathione peroxidase activities, accordingly, the high production of hydrogen peroxide, nitric oxide, and other free radicals causing tumor cell death as monitored by reduction in the synthesis of protein and nucleic acids. Most of the tested compounds showed potent to moderate growth inhibitory activity; in particular, compound 6b exhibited the highest activity suggesting it is a lead compound in cytotoxic activity.     

茚酮氨基甲酸酯衍生物的设计合成及其对乙酰胆碱酯酶抑制活性的研究

目的设计合成茚酮氨基甲酸酯衍生物并进行乙酰胆碱酯酶(AChE)抑制活性测试。方法以羟基苯丙酸为起始原料,经分子内Friedel-Crafts酰化、羟基的氨基甲酸酯化和羟醛缩合3步反应合成目标物;采用Ellman法,以拉多替吉(ladostigil)为阳性对照,测试目标化合物对AChE的抑制活性。结果合成了8个未见文献报道的新化合物,其结构和纯度均经1H-NMR、MS谱测定。结论目标化合物对AChE均表现出一定的抑制活性,可作为先导化合物做进一步的改造和修饰。