Design,synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds. The structures were confirmed by ^1H NMR and MS. Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro. Three of compounds （1e, 1g, and 1h） exhibited potent antiproliferative activities, especially compound lh （with IC50 values of 5.2 μmol/L and 1.9 μmol/L against Bel-7402 and HT-1080, respectively）. The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.

Design,synthesis and antiproliferative activities of diaryl urea derivatives bearing N-acylhydrazone moiety

A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their antiproliferative activities against human leukemia cell line （HL-60）, human lung adenocarcinoma epithelial cell line （A549） and human breast cancer cell line （MDA-MB-231） in vitro by standard MTT assay. The pharmacological results indicated that some compounds exhibited promising antitumor activities. Compound 1j showed the most potent antiproliferative activity against the tested three cell lines with IC50 values of 0.13 μmol/L, 0.7 μmol/L and 0.5μmol/L, respectively.

Design, Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents

Two new series of diaryl thiourea containing sorafenib derivatives 9a-9t were designed and synthesized, and their antiproliferative activities against PC-3, HCT116 and MDA-MB-231 cell lines were evaluated. All compounds generally showed antiproliferative activity to PC-3 cells, most of the analogs exhibited potent antiproliferative ac- tivity to HCT116 cells, and compounds 9e, 9f, 9o and 9p demonstrated inhibitory activities against all three cell lines. The structures of all the newly synthesized compounds were determined by JH NMR, 13C NMR and HRMS.

Syntheses and Antiproliferative Activities of Novel Diarylthiosemicarbazide Derivatives

A series of novel N-methylpicolinamide-moiety containing diarylthiosemicarbazide derivatives was prepared and evaluated for their in vitro antiproliferative activity against three cancer cell lines（human alveolar epithelial cell A549, human lung cancer cell H460 and human colorectal cancer cell HT-29） by 3-（4,5-dimethyl）thiazolyldiphenyltetrazoliumromide（MTT） assay. Six compounds（Tb--7g） with halogen substituents exhibited preferable cytotoxicity against one or more cell lines in a low micromolar range. Especially, the most promising compound 7g exhibited remarkable antiproliferative activity with the IC50 values of 2.2, 1.8 and 5.2 μmol/L against A549, H460 and HT-29 cell lines respectively, which is comparable to sorafenib.

Improved Antiproliferative Activities of a New Series of 1,3,4-Thiadiazole Derivatives Against Human Leukemia and Breast Cancer Cell Lines

Twenty-two novel 1,3,4-thiadiazole derivatives were synthesized using different aromatic acids as starting materials, followed by cyclization, coupling and deprotection reaction. The structures of all the target compounds were identified by means of IH nuclear magnetic resonance（NMR）, laC NMR and high resolution mass spectrometer（HRMS）. Further biological evaluations were performed for chronic myelogenous leukemia cell and breast cancer cell. The results suggest that most of the target compounds exhibit potent anti-proliferative activities. Especially, compound 5b shows better antiproliferative activities against MDA-MB-231 and K562 cell lines compared with gossypol.

Synthesis,Crystal Structure and Antiproliferative Activity of Ethyl 1-(Phenylcarbamoyl)-2-3,4,5-trimethoxyphenyl)cyclopropanecarboxylae

Many small-molecule compounds have been evaluated with potential antiproliferative activities. Ethyl 1-（phenylcarbamoyl）-2-（3,4,5-trimethoxyphenyl）cyclopropanecarboxylate, one novel cyclopropylamide analogue of combretastatin-A4（CA-4）, has been synthesized and its crystal structure was characterized by X-ray single-crystal diffraction. The crystal belongs to monoclinic, space group P21/n, with a = 15.0263（3）, b = 7.6574（2）, c = 19.4117（4）, β = 111.9010（10）o, V = 2072.36（8）3, Z = 4, C22H24NO6, Mr = 398.42, Dc = 1.277 Mg/cm3, F（000） = 844, λ（MoKα） = 1.54178 , μ = 0.770 mm–1, R = 0.0546 and wR = 0.1889 for 3319 observed reflections（I 〉 2σ（I））. Meanwhile, the compound revealed potential antiproliferative activities in several cancer cells in vitro.

Crystal Structure and Antiproliferative Activity of Ethyl 3,9-Dihydroxy-9-methyl-7-phenyl-7,8,10-trihydro-6Hdibenzo[b,d]pyran-6-one-8-carboxylate

Ethyl 3,9-dihydroxy-9-methyl-7-phenyl-7,8,10-trihydro-6H-dibenzo[b,d]pyran-6-one-8-carboxylate（C（23）H（22）O6,Mr = 394.42） has been synthesized and its structure was determined by ~1H and ^（13）C NMR,ESI-MS,elemental analysis,and X-ray single-crystal diffraction.The crystal belongs to the triclinic system,space group P1,with a = 8.8220（17）,b = 9.881（2）,c = 12.157（2） A,α= 90.488（3）,β= 102.664（4）,γ= 98.799（3）°,V= 1020.8（3） A^3,Z= 2,Dc = 1.342 g/cm^3,μ= 0.099mm^（-1）,F（000） = 436,R = 0.0615 and wR = 0.2501 for 2592 observed reflections with（I2σ（I））.In the crystal structure,the coumarin ring system is planar and the 3：4 fused cyclohexane ring adopts distorted half-chair conformation.Rich hydrogen bonding interactions are formed between compound 2 and lattice water molecules.These interactions assemble molecules of 2 into 2D layered networks in an AB stacking sequence.Its in vitro antiproliferative activities against three human cancer cell lines were evaluated by MTT assay.

Synthesis, Crystal Structure and Antiproliferative Activity of 2-(((5-(((5,7-Dimethyl-[1,2,4]triazolo-[1,5-a]pyrimidin-2-yl)thio)methyl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)methyl)-4Hchromen-4-one Methanol Solvate

The novel crystal of the title compound 2-（（（5-（（（5,7-dimethyl-[1,2,4]triazolo-[1, 5-a]-pyrimidin-2-yl）thio）methyl）-4-phenyl-4H-1,2,4-triazol-3-yl）thio）methyl）-4H-chromen-4-one methanol solvate（C27H25N7O3S2, Mr = 559.66） has been prepared and its structure was determined by single-crystal X-ray diffraction. The crystal belongs to the monocline system, space group P21/c with a = 11.9879（9）, b = 14.0743（10）, c = 15.9706（11）A, β = 98.509（2）°, V = 2664.9（3）A3, Z = 4, Dc = 1.395 g/cm^3, F（000） = 1168, μ = 0.116 mm-1, MoKa radiation（λ = 0.71073）, R = 0.0652, and wR = 0.1425 for 5220 observed reflections with I 〉 2σ（I）. X-ray diffraction analyses reveal that the molecule adopts a C-shape. The planes of the benzopyrone and triazolopyrimidine were nearly parallel to each other, with a dihedral angle of 1.21（3）°. Intramolecular and intermolecular hydrogen bonds together with π-π interations are found to exist in the structure. The results of MTT assay indicate that the title compound displays excellent antiproliferative activity against two human cancer cell lines.

Synthesis, Crystal Structure and Antiproliferative Activity of 2,2-Dimethyl-4-oxochroman-3-ylmorpholine-4-carbodithioate

The crystal structure of the new title compound 2,2-dimethyl-4-oxochroman-3-ylmorpholine-4-carbodithioate（C16H19NO3S2,Mr = 337.44） has been prepared and determined by single-crystal X-ray diffraction.The crystal is of triclinic,space group P1 with a = 9.5518（7）,b = 9.7172（7）,c = 11.0220（8）,α = 67.08（1）,β = 74.66（1）,= 61.31（1）°,V = 822.72（10）3,Z = 2,Dc = 1.362 g/cm3,F（000） = 356,μ = 0.092 mm-1,MoKa radiation（λ = 0.71073）,R = 0.0515 and wR = 0.1389 for 2623 observed reflections with I 2（I）.X-ray diffraction analysis reveals that the chroman ring adopts a half-chair conformation while the morpholine ring shows a chair conformation.Intramolecular and intermolecular C–H···S and C–H···O hydrogen bonds together with π-π interations are found in the structure.The result of MTT assay shows the title compound displays good antiproliferative activity against two human cancer cell lines.

Design,synthesis and antiproliferative activity of novel 2,7-disubstituted triazolo[1,5-a]pyrimidines

In our efforts to identify novel potent anticancer agents, we synthesized a series of 2,7-disubstituted triazolo[1,5-a]pyrimidines （6-16）. Their antiproliferative activity against Bel-7402, HT- 1080 and WI-38 cell lines was tested by MTT assay in vitro. Four of the compounds （9-11 and 16） displayed promising antiproliferative activity superior to gefitinib, especially compound 9. A preliminary SAR study of these derivatives was performed.

Synthesis and Antiproliferative Activity of Novel [1,2,4]Triazolo[1,5-a]pyrimidine-7-amine Derivatives

A series of novel N-anilino-2-substituted-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine derivatives was prepared and evaluated for their in vitro antiproliferative activity against two cancer cell lines,Bel-7402 and HT-1080.Most of the compounds inhibited the cell proliferation at a low concentration.Seven compounds,VI5,VI7,VI10,and VI12―VI15,possessed marked antiproliferative activity superior to that of cisplatin.Of these seven initial hits,compound VI10 was the most active.

Antiproliferative Triterpenoid Saponins from Leptaulus citroides Baill. from the Madagascar Rain Forest

Bioassay-guided fractionation of EtOH extracts obtained from the roots and wood of the Madagascan plant Leptaulus citroides Baill.(Cardiopteridaceae)led to the isolation of ethyl esters of three new triterpenoid saponins(1–3)and the known sesquiterpenoid cinnamosmolide(4).The structures of 1–3 were elucidated by extensive 1D and 2D NMR experiments and mass spectrometry.Compounds 1,2,and 4 showed moderate cytotoxicity against the A2780 human ovarian cancer cell line with IC50 values of 2.8,10.2 and 2.0 lM,respectively.

A critical review on Nepal Dock(Rumex nepalensis):A tropical herb with immense medicinal importance

Rumex nepalensis Spreng.(Polygonaceae) commonly known as Nepal Dock has wide-spectrum therapeutic potencies and is extensively used for centuries in traditional medicine systems. The leaves of this plant are edible and a rich source of natural antioxidants. They act as a possible food supplement and are largely used in pharmaceutical industry. Extracts and metabolites from this plant exhibits pharmacological activities including anti-inflammatory, antioxidant, antibacterial, antifungal, antiviral, insecticidal, purgative, analgesic, antipyretic, anti-algal, central nervous system depressant, genotoxic, wound healing and skeletal muscle relaxant activity. Due to its remarkable biological activities, it has the potential to act as a rich source of drug against life threatening diseases. However, more studies are needed to scientifically validate the traditional uses of this plant, beside isolating and identifying their active principles and characterizing the mechanisms of action. We present herein a critical account of its botany, ecology, traditional uses, phytoconstituent profile and major pharmacological activities reported in recent years and therefore will provide a source of information on this plant for further studies.

Antioxidant and antitumor potential of wild and IMT-Acultivated Osmundea pinnatifida

Osmundea pinnatifida is a red edible seaweed known as pepper dulse.O.pinnatifida was cultivated in the farm of ALGAplus(ílhavo,Portugal).This farm is integrated with a seabream and seabass commercial aquaculture and uses the nutrient-enriched water resultant from the fish production as its cultivation medium in the integrated multi-trophic aquaculture(IMTA)manner.Wild and IMTA-cultivated samples of O.pinnatifi da were screened for antioxidant and antitumor activities.The antioxidant capacity of solvent extracts from wild and IMTA cultivated samples was assessed in two methods(2,2-diphenyl-1-picrylhydrazyl(DPPH)and oxygen radical absorbance capacity(ORAC)),and their total phenolic contents(TPC)were estimated.Antitumor activity was evaluated in three different tumor cell lines(HepG-2,MCF-7,and SH-SY5Y)through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Among the solvents used for extraction,dichloromethane was the most eff ective to extract phenolic compounds and presented higher ORAC.A significant correlation was found between TPC and ORAC,which was also sustained by the principal components analysis(PCA).Dichloromethane extracts induced a cytostatic eff ect on MCF-7 cells and showed weak cytotoxicity to SH-SY5Y cells and weak impact on cell proliferation.Overall,there were no statistically signifi cant differences in the biological activities shown by the wild and IMTA-cultivated samples.Hence,O.pinnatifida can be obtained in an economical and environmentally sustainable way through IMTA,maintaining bioactive properties in a high potential for further nutraceutical purposes.

Synthesis,Biological Evaluation and Molecular Modeling of Cyclic Tetrapeptide Based Inhibitors HDAC

Histone deacetylases（HDACs） are considered to be among the most promising targets for the development of anti-cancer drugs,and HDAC inhibitors（HDACIs） have become a promising class of anti-cancer drugs.To explore whether thioacetyl group as the zinc binding group（ZBG） and a slight change in the hydrophobicity of the recognition domain of HDACIs could alter their activities,we synthesized a series of cyclo[-L-Am7（SAc）-Aib-L-Phe（n-Cl）D-Pro-] and evaluated their HDAC-inhibitory and antiproliferative activities.The results show that these peptides could inhibit HDAC at 10-9 mol/L level,and could selectively inhibit the proliferation of three human cancer cell lines with IC 50 at 10-6 mol/L level.Docking study was conducted to examine the mechanisms by which these peptides interact with HDAC2.It appeared that a zinc ion in the active site of HDAC was coordinated by the carbonyl oxygen atom of the ZBG in the inhibitor.Both the ZBG domain of all the peptides and the surface recognition domain of cyclo[-L-Am7（SAc）-Aib-L-Phe（o-Cl）-D-Pro-] and that of cyclo[-L-Am7（SAc）-Aib-L-Phe（m-Cl）-D-Pro-] interacted with HDAC2 via hydrogen bonding.Hydrophobic interaction has been considered to provide favorable contributions to stabilizing the complexes,and the introduction of a chlorine atom at the aromatic ring on the L-Phe position of these peptides affected the interaction between each of these inhibitors and the enzyme,resulting in slight change in the structure of the surface recognition domain of the peptides.

Synthesis,Crystal Structure and Bioactivity of a Pd(Ⅱ) Complex with Demethylcantharate and 2,2′-Bipyridine

A novel crystal with the molecular formula [Pd（DCA）（bipy）]2 [Pd（bipy）Cl2 ]·6.75H2O was formed by PdCl2 with disodium demethylcantharate （Na2 （DCA）,DCA2= 7-oxa-bicyclo[2.2.1]heptane-2,3-bicarboxylate） and 2,2-bipyidine （bipy） through the hydrothermal method.The complex was characterized by elemental analysis and infrared spectroscopy.The structure of the complex was determined by single-crystal X-ray diffraction,which is of triclinic system,space group P1 with a=13.6818（7）,b=14.8426（8）,c=15.0043（8）,α=97.319（3）,β=92.521（3）,γ=105.776（2）°,V=2898.4（3） 3,Dc=1.545 g·cm-3,Z=1,F（000）=1420,S=0.852,the final R=0.0525 and wR=0.1777 for 13634 observer reflections （I〉2σ（I））.The binding reaction of the complex with ct-DNA and bovine serum albumin （BSA） was studied by fluorescence spectroscopy.The results indicated that the complex binds to ct-DNA via the partial intercalation.The binding constant K A of the complex interaction with BSA was 3.98×10 5 L·mol-1 and one binding site would be formed.The antiproliferative activity of the complex against human hepatoma cells （SMMC7721） in vitro is much higher than that of Na 2 （DCA）.

Study of the Potential Value of flex affinis （Aquifoliaceae） as a Novel Source for the Food and Pharmaceutical Industries

llex paraguariensis St. Hilaire （Aquifoliaceae） is processed industrially to produce the commercial product ＂yerba mate＂ which is used as a tea-like beverage. It is one of the most commercialized plants of South America. It is exported to the US, Europe and Asia as vegetal drug or extracts used in complementary and alternative medicine and in formulations for functional foods due to its properties as a CNS stimulant, diuretic, weight reducing, antioxidant and antihypercholesterolemic, among others, llex affinis grows in the same habitat and is used as substitute or adulterant ofI. paraguariensis. This species was never investigated before. The objective of this work was to assess the phytochemical composition and to determine the pharmacological activity, according with the major compounds present in it. The results showed small quantities of caffeine and theobromine, but a considerable amount of polyphenols, especially chlorogenic acid and isochlorogenic acid. I. affinis extracts presented scavenging activity on free radical DPPH in a concentration-dependent manner. Antiproliferative action on lymphoma cell line exerting both cytostatic and cytotoxic activities was also demonstrated.

Pyridapeptides F–I,cyclohexapeptides from marine sponge-derived Streptomyces sp.OUCMDZ-4539

Four new cyclohexapeptides,pyridapeptides F–I(1–4),were isolated from the fermentation broth of marine sponge-derived Streptomyces sp.OUCMDZ-4539.The pyridapeptides F–H(1–3)are composed ofβ-hydroxyleucine,alanine,O-methylthreonine,hexahydropyridazine-3-carboxylic acid,5-hydroxytetrahydropyridazine-3-carboxylic acid,and(2S,3R,4E,6E)-2-amino-3–hydroxy-4,6-dienoic acid residues.Pyridapeptide I(4)contains(2S,3R,4E,6E)-2-amino-3–hydroxy-8-methylnona-4,6-dienoic acid residue and a very rare glycose residue,aculose.Their structures were determined based on spectroscopic analysis and chemical methods.Pyridapeptides G–I(2–4)have the 2,3,6-trideoxyhexose units glycosylated at theγ-OH-TPDA residue,displayed significant antiproliferative activity against four(PC9,MKN45,Hep G2,K562)or two(PC9,MKN45)human cancer cell lines.

Constituents from leaves of Macaranga hemsleyana

Objective:To study constituents of the leaves of Macaranga hemsleyana,and evaluate their inhibitory effects against NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome activation,and antiproliferative activity.Methods:The constituents were isolated and purified by column chromatography on MCI gel CHP20P/P120,silica gel,Sephadex LH-20,and HPLC.The structures of compounds were determined by 1D,2D NMR,and HR-ESI-MS data.The inhibitory effect of compounds on inflammasome activation was determined by lactate dehydrogenase(LDH)procedure.The antiproliferative activity was evaluated using MTT assay.Results:The study led to the isolation of 23 compounds,including one new compound,identified as(2Z)-3-[4-(β-D-glucopyranosyloxy)-2′-hydroxy-5′-methoxyphenyl]-2-propenoic acid(1),together with 22 known compounds recognized as 1,4-dihydro-4-oxo-3-pyridinecarbonitrile(2),methyl 4-methoxynicotinate(3),4-methoxynicotinonitrile(4),1-(3-O-β-D-glucopyranosyl-4,5-dihydroxyphenyl)-ethanone(5),neoisoastilbin(6),isoastilbin(7),aromadendrin(8),neoastilbin(9),astilbin(10),quercitrin(11),neoschaftoside(12),apigenin 6,8-bis-C-α-L-arabinoside(13),vitexin(14),bergenin(15),scopoletin(16),glucopyranoside salicyl(17),koaburside(18),benzylβ-D-glucoside(19),icariside B5(20),roseoside(21),loliolide(22),and adenosine(23).The tested compounds did not show LDH inhibition nor antiproliferative activity.Conclusion:Compound 1 was a new glycoside.Compounds 2 and 3 were obtained for the first time from natural source.The 22 known compounds constituted of alkaloids(2–4,23),phenolics(5,15,17,18),flavonoids(6–14),coumarin(16),benzyl glycoside(19),and norsesquiterpenes(20–22).All the compounds,1–23,were revealed from M.hemsleyana for the first time.This is the initial uncovering of molecules 1–10,12,13,17–19,and 23 from the genus Macaranga.The isolated compounds,11,14–16,and 20–22 established taxonomic classification of M.hemsleyana in Euphorbiaceae family.Flavonoids were outstanding as chemosystematic markers of Macaranga genus.

Total synthesis of cajanine and its antiproliferative activity against human hepatoma cells

Cajanine,a constituent of Cajanaus cajan L.,used in traditional Chinese medicine,is a promising drug candidate because of its broad range of bioactivities.However,the total synthesis of cajanine and its derivatives has never been reported.Herein,we report the total synthesis of cajanine in nine steps with an overall yield of 10%together with its analog,longistyline A,in 8%yield.The antiproliferative activity of the two compounds against a human hepatoma cell line is also reported.