Design,Synthesis and Anticancer Activity of Novel 6-（Aminophenyl）-2,4-bismorpholino-1,3,5-triazine Derivatives Bearing Arylmethylene Hydrazine Moiety

In an attempt to develop potent and selective anticancer agents,we designed and synthesized a series of novel bis（morpholino-1,3,5-triazine） derivatives beating aylmethylene hydrazine moiety and evaluated their cytotoxicity,in vitro,against H460（non-small-cell lung cancer）,HT-29（human colorectal cancer） and MDA-MB-231（human breast cancer） cell lines.The pharmacological results indicate that all the compounds exhibit enhanced cytotoxicity than BMCL-200908069-1,and six target compounds（7e,7h,7j,9a,9b,9c） were superior to PAC-1 against all the tested cancer cell lines.The most active compound 7j,with IC50（inhibitory concentration 50％）values of 0.75,0.34 and 0.60 μ mol/L against HT-29,H460 and MDA-MB-231 cancer cell lines,was 39-,28-,and 60-fold more potent than BMCL-200908069-1 （29.24,9.52 and 36.21 μmol/L）,respectively.     

Design,Synthesis and Antitumor Activity of Novel 6,7-Dimethoxyquinazoline Derivatives Containing Diaryl Urea Moiety

A series of 6,7-dimethoxyquinazoline derivatives connected by diaryl urea scaffolds was designed, synthesized and their in vitro antitumor activities were evaluated. Most of them showed an excellent potency against the four tested cancer cell lines as compared with sorafenib. Particularly, a promising compound 20 was identified, which showed the most potent antitumor activities with IC₅₀ values of 0.08, 0.09, 0.16 and 0.19 μmol/L against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The structure-activity relationship(SAR) analysis indicated that compounds with dimethylamino or diethylamino group at the C4 position of 6,7-dimethoxyquinazoline moiety exhibited superior activities than compounds bearing morpholino groups.     

Synthesis and cytotoxic activity of novel 2, 6-disubstituted-4-mor- pholinothieno[3, 2-d]pyrimidines as potent anti-tumor agents

正A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460,HT-29,MDA-MB-231,U87MG and H1975 cancer cell lines were evaluated in vitro.Most of the target compounds exhibited moderate to excellent activity to the tested cell lines.The most promising compound 23(0.84μmol/L,0.23μmol/L, 2.52μmol/L,1.80μmol/L) was 1.0,2.9,29.3 and 4.3 times more active than GDC-0941(0.87μmol/L,0.66μmol/L,73.8μmol/L, 7.77μmol/L) against H460,HT-29,MDA-MB-231 and U87MG cell lines,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 in vitro cytotoxic evaluation of 2-hydrazinylpyrido[2,3-b]pyrazin-3(4H)-one derivatives

A series of novel 2-hydrazinylpyrido[2,3-b]pyrazin-3（4H）-one derivatives were synthesized and evaluated for their cytotoxic activities against A549,MDA-MB-231 and HT-29 cell lines in vitro.Pharmacological data indicated that compounds 5b,5c,10a and 10g possessed marked cytotoxicity,especially 10a(with IC₅₀ values of 0.81,2.56 and 1.63μmol/L against A549,MDA-MB- 23 1 and HT29 cell lines,respectively),which had emerged as a lead compound.     

Design,Synthesis and Pharmacological Evaluation of Novel 4-Phenoxyquinoline Derivatives as Potential Antitumor Agents

A series of novel 4-phenoxyquinoline derivatives containing 3-amino-2-cyano-acrylamide framework was designed and synthesized, and the in vitro cytotoxic activities of them against five cancer cell lines(HT-29, H460, A549, MKN-45, and U87MG) were evaluated. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines as compared with Foretinib. The studies of their preliminary structure-activity relationships(SARs) indicate that the compounds containing methyl groups, especially methyl groups at 4-position of the phenyl ring(moiety B) are more effective. Among them, compound 36 shows the most potent antitumor activities with IC₅₀ values of 0.04, 0.09, 0.67, 0.39 and 1.10 μmol/L against HT-29, H460, A549, MKN-45 and U87MG cell lines, respectively.     

Design,Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives Bearing Semicarbazone Moiety as Antitumor Agents

A series of novel benzothiazole derivatives bearing semicarbazone as a linker was designed and synthesized, and their in vitro antitumor activities were evaluated against four cancer cell lines(HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 12a―12i with fluoro-substituted benzyl-1H-indole moiety displayed more potent activity than those with phenyl moiety. The most promising compound 12d exhibited excellent antitumor activity with IC₅₀ values of 0.015, 0.28, 1.53 and 0.68 μmol/L against the four tested cell lines respectively.     

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)thiazolyl-diphenyltetrazoliumromide(MTT) assay. Six compounds(7b―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.     

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 IC values of 0.13 mmol/L,0.7 mmol/L and 0.5 mmol/L,respectively.     

Synthesis and Antitumor Activities of Novel 4-Morpholinothieno [3,2-d]pyrimidine Derivatives

A series of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives was designed and synthesized.All of them were screened for their cytotoxic activities against large cell lung cancer（H460）,colon cancer （HT-29） and adenocarcinomic lung cancer（A549） cell lines in vitro.The pharmacological results indicate that most of the target compounds show moderate to significant activities.Especially compound 17 exhibits the most potent antitumor activities against H460,HT-29 and A549 cell lines with IC50 values of 0.57,0.45 and 1.45 μmol/L,respectively.     

Synthesis and in vitro cytotoxic activities of sorafenib derivatives

A series of novel sorafenib derivatives have been designed and synthesized.The cytotoxic activities of these compounds were tested in three tumor cell lines.Most of the compounds showed potent antiproliferative activity against the tested cell lines with IC50= 0–20 mmol/L.Some compounds demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines.Among them,compound 5g demonstrated significant inhibitory activity against A549,ACHN and MDAMB-231 cell lines with IC50values of 1.29,1.99,3.11 mmol/L,respectively.     

Alkaloids from the endophytic fungus Penicillium brefeldianum and their cytotoxic activities

One new indoloditerpene,6,7-dehydropaxilline(1),one new indole-diketopiperazine,spirotryprostatin F(2),and one new 13-membered macrolide,N-demethylmelearoride A(3),as well as 8 known alkaloids(4-11),were isolated from the solid cultures of the endophytic fungus,Penicillium brefeidianum.The structures and absolute configurations of compounds 1-3 were elucidated by comprehensive spectroscopic analysis and the circular dichroism(CD) exciton chirality method.All the metablites were evaluated for their cytotoxic activites against three human tumor cell lines.Compound 2 exhibited cytotoxicities against HepG2 and MDA-MB-231 cells with IC_(50) values of 14.1 μmol/L and 35.5μmol/L,respectively.Compound 3 showed moderate activity against HepG2 cells with IC_(50) values of 36.6 μmol/L.     

Identification of hydrazone moiety-bearing aminopyrimidines as potent antitumor agents with selective inhibition of gefitinib-resistant H1975 cancer cells

Based on our previous work,a series of hydrazone moiety-bearing aminopyrimidines were synthesized.The compounds were evaluated for inhibitory activities against EGFRT790M/L858 R and antiproliferative activities against H1975 and A549 NSCLC cell lines harboring different forms of EGFR.Compounds 7f and7 k exhibited potent and selective activity in inhibition of gefitinib-resistant H1975 cancer cells(IC_(50);0.45,0.2μmol/L) while were much less active on A549 cancer cells(IC_(50);52.83,100μmol/L).Both compounds could be served as promising lead compounds for further investigation.     

Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-<i>d</i>]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety

Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003?μM, 0.42?μM and 0.74?μM, which was 1.6- to 290-fold more potent than GDC-0941.     

Synthesis and Tumor Cytotoxicity of Novel 1, 2, 3-Triazole-substituted 3-Oxo-oleanolic Acid Derivatives

Fifteen novel 3-oxo-oleanolic acid esters bearing aryl substituted 1,2,3-triazolyl methyl moiety were synthesized via the method of Copper(I)-catalyzed Huisgen cycloaddition. The cytotoxicity evaluation results of these compounds against five human tumor cell lines show that most of these compounds presented potent activity and selectivity against A375-S2 and HT1080 cells. Compound 6c, with a p-NO₂ at the bezene ring, possesses the best inhibitory activity against A375-S2(IC₅₀=2.82 μmol/L) and HT1080(IC₅₀=1.69 μmol/L).     

Synthesis and antitumor activities of novel 1,4-substituted phthalazine derivatives

<正>A series of 1,4-substituted phthalazine derivatives were designed and synthesized.All the prepared compounds were screened for their cytotoxic activities against A549.HT-29 and MDA-MB-231 cell lines in vitro.Among them,compounds 7a-7h showed excellent selectivity for MDA-MB-231 cell line with IC_(50) values from 1 nmol/L to 0.92μmol/L.A preliminary SAR study of these derivatives was performed.     

Synthesis and Activity Evaluation of Novel Prenylated Flavonoids as Antiproliferative Agents

Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3',4',7-tetramethoxy-8-prenyl-5-hydroxy flavonoid(16) was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines(HeLa, HCC1954 and SK-OV-3). The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration(IC₅₀) values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3',4',7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid(12) exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC₅₀ values of 0.91-7.08 μmol/L. 3',7-Dimethoxy-5-O-prenyl flavone(6) and 3',4',7-trimethoxy-5-O-prenyl flavone(10) showed selective antiproliferative activity against HCC1954 cells with IC₅₀ value of 0.49 and 5.32 μmol/L, respectively.     

Design,Synthesis, Biological Activity and Molecular Docking Study of Coumarin Derivatives Bearing 2-Methylbiphenyl Moiety

A hybrid pharmacophore approach was used to design and synthesize a series of coumarin derivatives bearing 2-methylbiphenyl moiety, which were evaluated for their in vitro anticancer activities against four cancer cell lines(MCF-75 A549, H460 and HT29) and PD-1/PD-L1 inhibitory activities. Moreover, several compounds with excellent anticancer activities were selected to evaluate the cytotoxicities against one normal cell line(HEK-293). The most promising compound llo showed the best anticancer activities against the four tested cancer cell lines with the IC50 values of 6.45, 8.65, 6,57 and 8.13 gmol/L, respectively, and displayed weak cytotoxicity on the normal cell(HEK-293). Furthermore, screening of PD-1 /PD-L1 inhibitory activity revealed that compound llo could effectively inhibit the binding of PD-1/PD-L1, and the binding interactions of compound llo with PD-L1 protein were explored by molecular docking. All above evidences showed that compound llo might be worthy of further study as a valuable leading compound for the treatment of cancer.     

Design,synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents

In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring（5a-5h）,the isoquinolinium ring（6a-6c） and the quinolinium ring（7a-7e） linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line（H460） by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC₅₀ values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC₅₀ = 0.006μmol/L) was 216.7 times more active than MKT-077(IC₅₀ = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.     

New cytotoxic apigenin derivatives from Selaginella doederleinii

75%aqueous ethanol extract from the whole herbs of Selaginella doederleinii was isolated,and two new apigenin derivatives,doederflavones A(1) and B(2),together with ten known compounds(3-12) were characterized.Their structures were assigned by extensive spectroscopic methods including 1D/2D NMR and HR-ESIMS.Compounds 1-6 bear an aryl substituent at the C-8 or C-6 positions in ring A of apigenin skeleton.Compounds 1 and 2 were evaluated for their in vitro cytotoxicity against four human cancer cell lines A549,MCF-7,SMMC-7721,and LoVo,both of which exhibited significant cytotoxicity against A549 with IC_(50) values of 0.82 μmol/L and 1.32 μmol/L,respectively.