Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives

A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC(50) = 1.4 μM) compared with sorafenib (IC(50) = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC(50) = 22.6 μM).     

Inhibitory effects of acetylmelodorinol, chrysin and polycarpol from Mitrella kentii on prostaglandin E₂ and Thromboxane B₂ production and platelet activating factor receptor binding

Acetylmelodorinol, chrysin and polycarpol, together with benzoic acid, benzoquinone and stigmasterol were isolated from the leaves of Mitrella kentii (Bl.) Miq. The compounds were evaluated for their ability to inhibit prostaglandin E? (PGE?) and thromboxane B? (TXB?) production in human whole blood using a radioimmunoassay technique. Their inhibitory effect on platelet activating factor (PAF) receptor binding to rabbit platelet was determined using 3H-PAF as a ligand. Among the compounds tested, chrysin showed a strong dose-dependent inhibitory activity on PGE(2) production (IC?? value of 25.5 μM), which might be due to direct inhibition of cyclooxygenase-2 (COX-2) enzymatic activity. Polycarpol, acetylmelodorinol and stigmasterol exhibited significant and concentration-dependent inhibitory effects on TXB? production with IC?? values of 15.6, 19.1 and 19.4 μM, respectively, suggesting that they strongly inhibited COX-1 activity. Polycarpol and acetylmelodorinol showed strong dose-dependent inhibitory effects on PAF receptor binding with IC?? values of 24.3 and 24.5 μM, respectively.     

3-Hydroxymethylglutaryl flavonol glycosides from a Mongolian and Tibetan medicine, Oxytropis racemosa

Three new flavonol 3-O-glycosides, rhamnetin 3-O-[(S)-3-hydroxy-3-methyl-glutaroyl(1→6)]-β-D-glucopyranoside (1), rhamnocitrin 3-O-[(S)-3-hydroxy-3-methylglutaroyl(1→6)]-β-D-glucopyranoside (2), and isorhamnetin 3-O-[(S)-3-hydroxy-3-methylglutaroyl(1→6)]-α-L-rhamnopyranosyl(1→2)-β-D-glucopyranoside (3), along with 13 known compounds, were isolated from Oxytropis racemosa TURCZ. Their structures were deduced by means of spectroscopic methods and chemical evidence. 2 and 6 showed cytotoxic activities against HCT-8 (IC?? 6.38 μM) and A549 (IC?? 5.20 μM), respectively.     

Design, synthesis and antitumor activity of novel artemisinin derivatives using hybrid approach

In an attempt to develop potent and selective anti-tumor agents, two novel series of artemisinin-chalcone hybrids were designed, synthesized and screened for their antitumor activities against HT-29, A549, MDA-MB-231, HeLa and H460 cell lines in vitro. Nearly all of the tested compounds showed significantly increased anti-tumor activity compared with the corresponding dihydroartemisinin (DHA). Most of the title compounds displayed good selectivity toward HT-29 and HeLa cell lines with IC?? values ranging from 0.09 to 0.85 μM. Among them, the most promising compound 9c (IC??) range of 0.09-0.93 μM) was 10.5- to 70-times more active than DHA (IC?? range of 5.6-15.6 μM) respectively.     

Synthesis of N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamides and their inhibitory activities against secretory phospholipase A₂

N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamide derivatives 3-6 were prepared by the reaction of 3-pyridylamines and sulfonyl chlorides. Inhibitory activities of these compounds toward secretory phospholipase A? (sPLA?) were examined and N-[2-(2,4-difluorophenoxy)-5-trifluoromethyl-3-pyridyl]-2-naphthalenesulfonamide (5c) was found to be the most potent against sPLA? with an IC?? value of 90 μM.     

Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents

Several 1,3,4-trisubstituted pyrazole derivatives were synthesized and screened for their cytotoxic effect in a primary 3 tumor cell line test at 10(-4) M drug concentration. Compounds 19 and 20 reduced the growth of one or more of these cell lines to less than 32% and escalated up to evaluation in the full panel of 60 human tumor cell lines at a minimum of 5 concentrations at 10 fold dilutions. Compound N'-(1-[1-[4-nitrophenyl]-3-phenyl-1H-pyrazol-4-yl]methylene)-2-chlorobenzohydrazide 19 proved to be the most active of these derivatives with full panel median growth inhibition (GI50), total growth concentration (TGI) and median lethal concentration (LC50) mean graph mid-point (MG-MID) of 3.79, 12.5 and 51.5 microM, respectively. In addition, compounds 19, 39, 40, 41, 43, 45, 47 were tested for their antiangiogenic properties by testing their ability to inhibit human umbilical vein endothelial cells (HUVECs) proliferation, cord formation and migration in response to chemoattractant. 3-Acetyl-2-(1-(4-nitrophenyl)-3-phenylpyrazol-4-yl)-5-(4-pyridyl)-1,3,4-oxadiazoline 39 showed significant antiangiogenic profile at non-cytotoxic doses, with HUVEC proliferation inhibition IC50 of 7.60 microM, chemotaxis IC50 of 0.86 microM and was superior to the reference celecoxib 2 in both tests. Furthermore, in contrary to the references TNP-470 and celecoxib, all the tested compounds interfered with the migratory function of HUVECs in response to vascular endothelium growth factor (VEGF) rather than the endothelial cells proliferation.     

Benzyl 2-β-glucopyranosyloxybenzoate, a new phenolic acid glycoside from Sarcandra glabra

From the whole plant of Sarcandra glabra, a new phenolic acid glycoside, benzyl 2-β-glucopyranosyloxybenzoate (1), together with seven known compounds including eleutheroside B? (2), 5-O-caffeoylshikimic acid (3), (-)-(7S, 8R)-dihydrodehydrodiconiferyl alcohol (4), (-)-(7S, 8R)-dihydrodehydrodiconiferyl alcohol 9-, 9′- and 4-O-α-D-glucopyranoside (5-7), and (-)-(7S, 8R)-5-methoxydihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside (8) was isolated. Their structures were elucidated by spectral analysis including 1D-, 2D-NMR and HR-ESI-MS. Compound 2 was found to exhibit potent cytotoxic activity against BGC-823 and A2780 cancer cell lines using MTT method with IC?? value of 2.53 and 1.85 μM, respectively.     

Synthesis, Crystal structure and Antioxidant of 3,5-Dihydroxy-N＇-（5-bro-2-hydroxybenzylidene） benzohydrazide Hydrate

A new compound, 3,5-dihydroxy-N′-(5-bro-2-hydroxybenzylidene)benzohydrazide hydrate, has been synthesized and characterized by single-crystal X-ray diffraction. The title compound crystallizes in a monoclinic system, space group P21/c with a = 14.267(6), b = 8.079(4), c = 13.157(6) , β = 108.114(4), Z = 4, V = 1441.4(11) 3, Dc = 1.701 g/cm3, F(000) = 744.0, μ = 2.878 and S = 1.021. The final R = 0.0457 and wR = 0.1149 for 3500 observed reflections with I > 2 (I). The ability with which the compound scavenges free radicals of ABTS and DPPH, IC50, is 34.13 and 101.6 μM, respectively.     

Chemical composition, antimicrobial and antitumor activities of the essential oils and crude extracts of Euphorbia macrorrhiza

The present study aimed to examine the chemical composition and biological activity of essential oils extracted from Euphorbia macrorrhiza collected from Northwest China. The major constituents of the essential oils of aerial parts and roots of E. macrorrhiza are acorenone B (16.72% and 25.80%), (+)-cycloisosativene (14.94% and 12.40%), 3a-hydroxy-5b-androstane (10.62% and 5.52%), copaene (7.37% and 6.29%), l-calamenene (4.13% and 4.65%) and β-cedrene (8.40% and 7.98%), respectively. The minor components of them are thymene, γ-terpinene, thymecamphor, α-cedrene, zingiberene, trans-caryophyllene, β-chamigrene, curcumene, pentadecane, (-)-α-muurolene, cuparene, γ-cadinene, (Z)-3-heptadecene, 1,3,7,7-tetramethyl-2-oxabicyclo(4.4.0)dec-5-en-4-one, hexahydrofarnesyl acetone, γ-elixene and palmitinic acid. The antimicrobial and antitumor activitiy of the E. macrorrhiza essential oil against Staphyloccocus aureus, Escherichia coli, Canidia Albicans and Caco-2 cells were evaluated. Among all the tested microorganisms and Caco-2 cells, the essential oils showed the strongest inhibitory effect on Staphyloccocus aureus (MIC = 2.8 μg/mL) and Caco-2 cell (IC?? = 11.86 μg/mL), whereas no effect on Escherichia coli and Candida albicans. The data of this study suggested that the E. macrorrhiza essential oils have great potential as a natural medicine for microbial infections and cancers.     

A novel series of (S)-2,7-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor α/γ dual agonists with protein-tyrosine phosphatase 1B inhibitory activity

Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARγ (EC50=0.14 μM) and was much higher than in human PPARα (EC50=0.20 μM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC50=1.85 μM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-Ay mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.     

New catechol derivatives of safrole and their antiproliferative activity towards breast cancer cells

Catechols were synthesized from safrole. Nine derivatives were prepared and assessed for antiproliferative effects using different human cell lines. The in vitro growth inhibition assay was based on the sulphorhodamine dye to quantify cell viability. The derivatives 4-allylbenzene-1,2-diol (3), 4 4-[3-(acetyloxy)propyl]-1,2-phenylene diacetate (6) and 4-[3-(acetyloxy)propyl]-5-nitro-1,2-phenylene diacetate (10) showed higher cytotoxicity than the parent compound 2 in tests performed on two breast cancer cell lines (MCF-7 and MDA-MB-231). The IC?? values of 40.2 ± 6.9 μM, 5.9 ± 0.8 μM and 33.8 ± 4.9 μM, respectively, were obtained without toxicity towards dermal human fibroblast (DHF cells).     

5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway

Our previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5-formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5-formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies.     

Phytochemical and cytotoxic investigations of Alpinia mutica rhizomes

The methanol and fractionated extracts (hexane, ethyl acetate and water) of Alpinia mutica (Zingiberaceae) rhizomes were investigated for their cytotoxic effect against six human carcinoma cell lines, namely KB, MCF7, A549, Caski, HCT116, HT29 and non-human fibroblast cell line (MRC 5) using an in vitro cytotoxicity assay. The ethyl acetate extract possessed high inhibitory effect against KB, MCF7 and Caski cells (IC?? values of 9.4, 19.7 and 19.8 μg/mL, respectively). Flavokawin B (1), 5,6-dehydrokawain (2), pinostrobin chalcone (3) and alpinetin (4), isolated from the active ethyl acetate extract were also evaluated for their cytotoxic activity. Of these, pinostrobin chalcone (3) and alpinetin (4) were isolated from this plant for the first time. Pinostrobin chalcone (3) displayed very remarkable cytotoxic activity against the tested human cancer cells, such as KB, MCF7 and Caski cells (IC?? values of 6.2, 7.3 and 7.7 μg/mL, respectively). This is the first report of the cytotoxic activity of Alpinia mutica.     

Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp

Bioassay-guided fractionation of the CH(2)Cl(2)/MeOH extract of the Australian marine sponge Pseudoceratina sp. resulted in the purification of four new bromotyrosine alkaloids, pseudoceramines A-D (1-4), along with a known natural product, spermatinamine (5). The structures of 1-5 were determined by spectroscopic methods. Pseudoceramines A (1) and B (2) feature a rare bromotyrosyl-spermine-bromotyrosyl sequence, and pseudoceramine C (3) is the first example of bromotyrosine coupled with an N-methyl derivative of spermidine. Compounds 1-5 were screened for inhibition of toxin secretion by the type III secretion (T3S) pathway in Yersinia pseudotuberculosis. Compounds 2 and 5 inhibited secretion of the Yersinia outer protein YopE (IC(50) = 19 and 6 μM, respectively) and the enzyme activity of YopH (IC(50) = 33 and 6 μM, respectively).     

Pseuduvarines A and B, two new cytotoxic dioxoaporphine alkaloids from Pseuduvaria rugosa

Pseuduvarines A (1) and B (2), two new dioxoaporphine alkaloids with an amino moiety, were isolated from the stem bark of Pseuduvaria rugosa and their structures were elucidated by combination of 2D-NMR spectroscopic analysis. Pseuduvarines A (1) and B (2) showed cytotoxicity against MCF7, HepG2, and HL-60 (1: IC??, 0.9, 21.7, and >50.0 μM, respectively, 2: IC?? >50.0, 15.7, and 12.4 μM, respectively).     

Selective cytotoxicity of goniothalamin against hepatoblastoma HepG2 cells

Liver cancer has become one of the major types of cancer with high mortality and liver cancer is not responsive to the current cytotoxic agents used in chemotherapy. The purpose of this study was to examine the in vitro cytotoxicity of goniothalamin on human hepatoblastoma HepG2 cells and normal liver Chang cells. The cytotoxicity of goniothalamin against HepG2 and liver Chang cell was tested using MTT cell viability assay, LDH leakage assay, cell cycle flow cytometry PI analysis, BrdU proliferation ELISA assay and trypan blue dye exclusion assay. Goniothalamin selectively inhibited HepG2 cells [IC?? = 4.6 (±0.23) μM in the MTT assay; IC?? = 5.20 (±0.01) μM for LDH assay at 72 hours], with less sensitivity in Chang cells [IC?? = 35.0 (±0.09) μM for MTT assay; IC?? = 32.5 (±0.04) μM for LDH assay at 72 hours]. In the trypan blue dye exclusion assay, the Viability Indexes were 52 ± 1.73% for HepG2 cells and 62 ± 4.36% for Chang cells at IC?? after 72 hours. Cytotoxicity of goniothalamin was related to inhibition of DNA synthesis, as revealed by the reduction of BrdU incorporation. At 72 hours, the lowest concentration of goniothalamin (2.3 μL) retained 97.6% of normal liver Chang cells proliferation while it reduced HepG2 cell proliferation to 19.8% as compared to control. Besides, goniothalamin caused accumulation of hypodiploid apoptosis and different degree of G2/M arrested as shown in cell cycle analysis by flow cytometry. Goniothalamin selectively killed liver cancer cell through suppression of proliferation and induction of apoptosis. These results suggest that goniothalamin shows potential cytotoxicity against hepatoblastoma HepG2 cells.     

Synthesis, and antitumor activity of some N1-(coumarin-7-yl) amidrazones and related congeners

A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, 1H-NMR, 13C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2-oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC?? values of 20.2 and 9.3 μM, respectively.     

Synthesis of new N-containing maltooligosaccharides, alpha-amylase inhibitors, and their biological activities

Fifteen new N-containing maltooligosaccharides were obtained using the chemoenzymatic method. Among these compounds, maltooligosaccharides having 6-amino-6-deoxy-D-sorbitol residue, (3R,4R,5R,6S)-hexahydro-3,4,5,6-tetrahydroxy-1H-azepine residue, and (3R,5R)-3,4,5-trihydroxypiperidine residue at the reducing end showed strong inhibitory activities for human pancreatic alpha-amylase (HPA) (EC 3.2.1.1) and human salivary alpha-amylase (HSA). The administration of (3R,4R,5R,6S)-hexahydro-3,5,6-trihydroxy-1H-azepine-4-yl O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranoside (13, IC50 = 4.3 x 10(-5) M for HPA, IC50 = 8.2 x 10(-5) M for HSA) and (3R,5R)-3,5-dihydroxypiperidine-4-yl O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranoside (18, IC50 = 3.4 x 10(-5) M for HPA, IC50 = 4.6 x 10(-5) M for HSA) to ICR mice suppressed postprandial hyperglycemia.     

(-)-Kunstleramide, a new antioxidant and cytotoxic dienamide from the bark of Beilschmiedia kunstleri gamble

A new dienamide, (2E,4E)-7-(3',4'-dimethoxyphenyl)-N-ethyl-6-(R)-hydroxyhepta- 2,4-dienamide, named (-)-kunstleramide (1), were isolated from the bark of Beilschmiedia kunstleri Gamble together with one neolignan: (+)-kunstlerone (2) and seven known alkaloids: (+)-nornuciferine (3), (-)-isocaryachine (4), (+)-cassythicine (5), (+)-laurotetanine (6), (+)-boldine (7), noratherosperminine (8), (+)-N-demethylphyllocaryptine (9). Their structures were established from spectroscopic techniques, most notably 1D- and 2D-NMR, UV, IR, OR, circular dichroism (CD) spectra and LCMS-IT-TOF. (-)-Kunstleramide (1) exhibited very poor dose-dependent inhibition of DPPH activity, with an IC?? value of 179.5 ± 4.4 μg/mL, but showed a moderate cytotoxic effect on MTT assays of A375, A549, HT-29, PC-3 and WRL-68 with EC?? values of 64.65, 44.74, 55.94, 73.87 and 70.95 μg/mL, respectively.     

Design,Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors

The recent discovery of c‐Jun NH₂‐terminal kinase JNK1 suppression by natural quercetagetin ( 1 ) is a promising lead for the development of novel anticancer agents. Using both X‐ray structure and docking analyses we predicted that 5′‐hydroxy‐ ( 2 ) and 5′‐hydroxymethyl‐quercetagetin ( 3 ) would inhibit JNK1 more actively than the parent compound 1 . Notably, our drug design was based on the active enzyme–ligand complex as opposed to the enzyme’s relatively open apo structure. In this paper we test our theoretical predictions, aided by docking‐model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3 . As calculated, both compounds strongly suppress JNK1 activity. The IC₅₀ values were determined to be 3.4 μM and 12.2 μM , respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC₅₀=4.6 μM ). Compound 2 was also shown to suppress matrix metalloproteinase‐1 expression with high specificity after UV irradiation.