Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized.The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay.Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines.The most potent compound 4-(benzo[d][1,3]dioxol5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50=0.44 M,3.07 M) was 2.0 and 8.4 times more active than gefitinib (IC50=0.89 M,16.81 M) against A549 and H460 cell lines,respectively.     

Design,Synthesis and Antitumor Activity of a Novel Series of PAC-1 Analogues

A novel series of first procaspase activating compound(PAC-1) analogues was designed, synthesized and evaluated for antitumor activity towards two cell lines[human promyelocytic leukemia cell line(HL60) and human embryonic lung fibroblast cell line(HLF)] by the MTT[3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazo-liumromide] method in vitro. The structures of all the compounds were confirmed by ¹H NMR, MS and elemental analysis. Among the compounds synthesized,(E)-2-[(3-{[4-(tert-butyl)benzyl](methyl)amino}propyl)(methyl)amino]-N'-[4-(diethylamino)-2-hydroxybenzylidene]acetohydrazide(compound 6n) exhibits a good anti-proliferative activity to the majority of tumor cells tested, and selectively cleaves cancer cells. Thus, compound 6n was identified as promising lead compound for further structural modification.     

A unique highly oxygenated pyrano[4,3-c][2]benzopyran-1,6-dione derivative with antioxidant and cytotoxic activities from the fungus Phellinus igniarius

[structure: see text] A unique pyrano[4,3-c][2]benzopyran-1,6-dione derivative with an unprecedented carbon skeleton, phelligridin G (1), has been isolated from the fruiting body of the fungus Phellinus igniarius. Its structure was elucidated by detailed spectroscopic analysis. A possible biogenetic origin of 1 mediated by the fungal metabolite precursor 4-hydroxy-6-methyl-2-pyrone was postulated. Phelligridin G (1) showed antioxidant activity inhibiting rat liver microsomal lipid peroxidation and moderate selective cytotoxic activities against human cancer cell lines.     

Synthesis and cytotoxic activity of heterocycle-substituted phthalimide derivatives

<正>A series of heterocycle-substituted phthalimide derivatives were synthesized.Structurally diverse derivatives with heterocyclic rings,including furan,imidazo[1,2-a]pyridine,1,3,4-thiadiazine,imidazo[2,1-b][1,3,4]thiadiazine,pyrazole,1,2,4-triazolo[3,4- b][1,3,4]thiadiazine,thiazole and thiazoline,were obtained by the reactions ofα-bromoketone intermediate with various nucleophiles containing oxygen,nitrogen and sulfur atom.Their cytotoxic activity was also evaluated against five human cancer cell lines in vitro.     

含1,2,3-三氮唑基团的新型四氧杂杯[2]芳烃[2]嘧啶衍生物的合成与抗肿瘤活性研究

以4-氯-2-甲硫基-6-丙炔氧基嘧啶为原料,依次经Williamson醚合成、氧化和聚合反应制得新型四氧杂杯[2]芳烃[2]嘧啶母体(4),并通过点击化学反应合成了4个结构新颖的含1,2,3-三氮唑基团的四氧杂杯[2]芳烃[2]嘧啶衍生物(5a^5d),其结构经1H MNR,13C MNR和HR-MS(ESI)表征。采用MTT法研究了5a^5d对人宫颈癌细胞(Hela),人乳腺癌细胞(MCF-7),人肝癌细胞(HepG2)和人肺癌细胞(A549)的体外抗肿瘤活性。结果表明:化合物5a对MCF-7具有明显的抑制活性,在50μM浓度下抑制率可达82%,优于阳性对照药5-氟尿嘧啶。     

Cytotoxic triterpenoid saponins from the roots of Cephalaria gigantea

Three new oleanane-type saponins, giganteosides L (1), M (2) and N (3) along with eight known ones were isolated from the roots of Cephalaria gigantea. Their structures were established as 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, respectively, by means of spectroscopic methods (1D and 2D NMR, HR-ESI-MS). Cytotoxic activity of monodesmosides was investigated in vitro using three cancer cell lines, namely, human non pigmented melanoma MEL-5 and human leukemia HL-60. Giganteosides D (4) and E (5) showed antiproliferative effect on human cell lines with IC(50) values in the range 3.15-7.5 microM.     

Cucurbit[n]urils (n=7, 8) binding of camptothecin and the effects on solubility and reactivity of the anticancer drug

The interaction between cucurbit[n]uril (n = 7, 8)(Q[n]) with two forms namely lactone modality and carboxylate modality of anticancer drug camptothecin (CPT) was studied. The results revealed that the combination of Q[n] with the lactone form of CPT was observed by electronic absorption spectroscopy, fluorescence spectroscopy and ¹H NMR technique in the acid solution (pH 2) and the total stability constants β were also obtained by Job plot with a host:guest ratio of 2:1; while in the phosphate buffer solution (pH 7.4), only Q[8] bound the carboxylate form of CPT in ratio 1:1, but no obvious interaction between Q[7] and the carboxylate form of CPT was observed. The solubility of CPT was enhanced up to about 70 and 8 times at pH 2 due to the formation of interaction complexes with Q[7] and Q[8], respectively, by using phase solubility method. The cytotoxicity tests revealed that compared with the free CPT, the complexes of Q[n] and CPT had the same cytotoxic activity on the human lung cancer cell line A549 and murine macrophage cell line P388D1 and the moderate depressed activity on human leukaemia cell line K562.     

Preparation of leukotriene B(4) inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells

A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives were prepared, and their leukotriene B(4) inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2-hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2.     

Design,synthesis and biological activity against estrogen receptor-dependent breast cancer of furo[1]benzofuran derivatives

The docking study on a series of furo[1]benzofuran derivatives with ERα has been demonstrated. The synthesis and characterization of a series of furo[1]benzofuran derivatives were described. All the target compounds were conducted to in vitro for the inhibitory activities against human breast cancer strains T-47D, MCF-7 and toxicity against human liver normal cell strains HL7702 via MTT assay. Most of the target compounds possessed anti-estrogen receptor-dependent breast cancer activities with weak toxicity to healthy cell strains. The preliminary structure–activity relationships were discussed.     

Novel 5H-[1,2,4]oxadiazolo[4,5-a]pyrimidin-5-one derivatives as antibacterial and anticancer agents: Synthesis and biological evaluation

A novel class of 5H-[1,2,4]oxadiazolo[4,5-a]pyrimidine derivatives was prepared, characterized, and tested for its antibacterial and anticancer potential against thirteen strains and five human cancer cell lines. The synthetic method was optimized, and a proposed reaction mechanism was also presented. The compounds containing the 5-bromo-pyrimidine moiety exhibited moderate antibacterial potencies against Gram-positive strains. Furthermore, the newly prepared compounds displayed selectively antiproliferative activity against human cancer cell lines. These current results will help us to further optimize and develop new drug candidates for clinical studies as novel antibacterial or anticancer agents.     

同时含α-[Mo8O26]4-和β-[Mo8O26]4-的新型超分子化合物的合成、表征及其抗肿瘤活性

以(NH4)2[Mo4O13]·2H2O, NiCl2·6H2O和2-(1H-吡唑-3-基)吡啶为原料, 通过水热方法合成了一个新颖的[Ni(C8N3H7)3]4[Mo8O26]2·7H2O超分子化合物. 采用元素分析、红外光谱和单晶X射线衍射法表征了该无机-有机杂化配合物的结构. 晶体解析表明, 该化合物同时含有α-[Mo8O26]4-和β-[Mo8O26]4-, 在[Ni(C8N3H7)3]2+阳离子和[Mo8O26]4-阴离子之间通过氢键作用结合, 在[Ni(C8N3H7)3]2+阳离子之间通过芳香环的π-π堆积作用连接, 两种[Mo8O26]4-阴离子作为客体共存于一个具有三维蜂窝状的超分子结构中. 同时研究了该化合物对人卵巢癌细胞SK-OV-3、肺癌细胞A549、宫颈癌细胞Hela和乳腺癌细胞MCF-7等细胞的体外抗肿瘤活性. 结果表明, 该化合物对3种不同来源的肿瘤细胞均有一定的增殖抑制作用, 其中对MCF-7细胞的IC50值为6.48 μmol/L, 具有进一步研究的价值.     

Two novel glycosidic triterpene alkaloids from the stem barks of Machilus yaoshansis

[structure: see text] Two unusual glycosidic triterpene alkaloids, machilaminosides A (1) and B (2), have been isolated from the stem barks of Machilus yaoshansis. Their structures were elucidated by detailed spectroscopic analysis. A possible biogenetic origin of 1 and 2 mediated by the coupling of 2-O-beta-D-glucopyranosyl-cucurbitacin I, respectively, with urea and adenosine was postulated. 1 and 2 showed nonselective cytotoxic activities against several human cancer cell lines as well as TNF-alpha secretion inhibitory activities.     

Phelligridimer A, a highly oxygenated and unsaturated 26-membered macrocyclic metabolite with antioxidant activity from the fungus Phellinus igniarius

[structure: see text] A highly oxygenated and unsaturated 26-membered macrocyclic metabolite, phelligridimer A (1), has been isolated from the Chinese medicinal fungus Phellinus igniarius. Its structure was elucidated by spectroscopic methods. A possible biogenesis of 1 mediated by the fungal metabolite hispidin was postulated. Phelligridimer A showed antioxidant activity (IC50 of 10.2 microM) but was inactive to several human cancer cell lines (IC50 > 50 microM) and enzymes PTP1B (IC50 > 25 microM) and thrombin (IC50 > 10 microM).     

Synthesis and cytotoxic activities of pyrrole[2,3-d]pyridazin-4-one derivatives

1-Methyl-2-phenyl (1) and 1,3-dimethyl-2-phenyl (2)-substituted pyrrole[2,3-d]pyridazinones, as well as their tetracyclic analogues 3-6, were synthesized and evaluated in vitro by the National Cancer Institute against 60 human tumor cell lines derived from nine cancer cell types. Biological results showed that the antitumor activities of these compounds were related to the planarity of their ring systems with potency increasing in the order 2<4 congruent with 5<6<3. Among them, the most potent compound 3 showed significant cell line cytotoxicity, particularly against the renal cancer subpanel [GI(50) (microM) 5.07] and displayed significant potency [GI(50) (microM) 3.04-4.32] against MOLT-4, SR (leukemia), NCI-H460 (non-small cell lung), HCT-116 (colon), and SF-295 (CNS) cancer cells, respectively.     

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.     

Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives

A number of 2,3-diarylquinoline derivatives were synthesized and evaluated for antiproliferative activities against the growth of six cancer cell lines including human hepatocellular carcinoma (Hep G2 and Hep 3B), non-small cell lung cancer (A549 and H1299), and breast cancer (MCF-7 and MDA-MB-231) cell lines. The preliminary results indicated that 6-fluoro-2,3-bis{4-[2-(piperidin-1-yl)ethoxy]phenyl}quinoline (16b) was one of the most active compounds against the growth of Hep 3B, H1299, and MDA-MB-231 with a GI(50) value of 0.71, 1.46, and 0.72 μM respectively which was more active than tamoxifen. Further investigations have shown that 16b induced cell cycle arrest at G2/M phase followed by DNA fragmentation via an increase in the protein expression of Bad, Bax and decrease in Bcl-2, and PARP which consequently cause cell death.     

Synthesis,computational quantum chemical study,in silico ADMET and molecular docking analysis,in vitro biological evaluation of a novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties as a potential human topoisomerase IIα inhibiting anticancer agent

Computational quantum chemical study and biological evaluation of a synthesized novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties namely BTPT [2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-methoxy-4-(thiophen-2-yl) pyridine] was presented in this study. The crystal structure was determined by SCXRD method. For the title compound BTPT, spectroscopic characterization like ¹H NMR, ¹³C NMR, FTIR, UV–vis were carried out theoretically by computational DFT method and compared with experimental data. Druglikeness parameters of BTPT were found through in silico pharmacological ADMET properties estimation. The molecular docking investigation was performed with human topoisomerase IIα (PDB ID:1ZXM) targeting ATP binding site. In vitro cytotoxicity activity of BTPT/doxorubicin were examined by MTT assay procedure against three human cancer cell lines A549, PC-3, MDAMB-231 with IC50 values of 0.68/0.70, 1.03/0.77 and 0.88/0.98 μM, respectively. Our title compound BTPT reveals notable cytotoxicity against breast cancer cell (MDAMB-231), moderate activity with human lung cancer cell (A-549) and less inhibition with human prostate cancer cell (PC-3) compared to familiar cancer medicine doxorubicin. From the results, BTPT could be observed as a potential candidate for novel anticancer drug development process.     

Synthesis of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitriles: in vitro anticancer activity against MCF-7, PC-3 and A2780 cancer cell lines

A series of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitrile (2–9) were designed and synthesized to develop new cancer drugs. The structures of synthesized compounds 2–9 were described by using melting point, mass (MALDI-TOF-MS), FT-IR, elemental analysis, ¹H, ¹³C, ¹³C-APT and 2D NMR spectroscopy. The in vitro anticancer activities of 2–9 against human breast cancer (MCF-7), human prostate cancer (PC-3) and human ovarian cancer cells (A2780) were investigated by [3-(4,5-dimethylthiazol)-2-yl]-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assay method. Additionally, the LogIC₅₀ values of these compounds on A2780, MCF-7 and PC-3 cell lines were calculated by using inhibition % values by the GraphPad Prism 6 program on a computer. The results indicated that these compounds have high anticancer activity against MCF-7, PC-3 and A2780 cell lines (especially A2780 cell lines, p < 0.05).     

First synthesis of an aziridinyl fused pyrrolo[1,2-a]benzimidazole and toxicity evaluation towards normal and breast cancer cell lines

Anionic aromatic ipso-substitution has allowed an aziridine ring to be fused onto pyrrolo[1,2-a]benzimidazole. This diazole analogue of aziridinomitosene, and N-[(aziridinyl)methyl]-1H-benzimidazole are shown to be significantly more cytotoxic towards the human breast cancer cell lines MCF-7 and HCC1937 than towards a human normal fibroblast cell line (GM00637). The aziridinyl fused pyrrolo[1,2-a]benzimidazole is less cytotoxic than the non-ring fused aziridinyl analogue towards all three cell lines. The BRCA1-deficient HCC1937 cells are more sensitive to mitomycin C (MMC) compared to GM00637 and MCF-7 cells. The evidence provided indicates that different pathways may mediate cellular response to benzimidazole-containing aziridine compounds compared to MMC.     

Synthesis and Antiproliferative Activity of Some 1H-Isochromen-1-ones and Their Thio Analogues

A series of 1H-isochromen-1-one derivatives and their thio analogues were synthesized by thionation using Lawesson's reagent for evaluation of their cytotoxic effect on cancer cells. The effect of these derivatives was tested on the growth of human epidermoid carcinoma A431 cell line by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] colorimetric assay. MTT assay revealed that these new compounds are potent inhibitors of cell growth.

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