新型吲唑-查尔酮杂合物的合成及抗肿瘤活性（英文）

设计并合成了一系列新型含查尔酮-吲唑杂合衍生物,并对其体外肿瘤活性进行初步研究。先以2,6-二氟苯腈和吗啉为起始原料,经过取代和环合两步反应合成4-吗啉-3-氨基-1H-吲唑。4-吗啉-3-氨基-1H-吲唑与含羧基的查尔酮中间体与经过酰胺化反应制备了9个新型含查尔酮-吲唑杂合衍生物,其结构经傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(NMR)、质谱(MS)和元素分析确证。采用MTT法,以索拉菲尼为阳性对照药,以人胃癌细胞株(MKN45)和人肺癌细胞株(A549)为测试细胞株对目标化合物进行抗肿瘤活性评价。结果表明,大部分目标化合物显示了较好的抗肿瘤活性,其中化合物4a和4d活性较好,其抑制人胃癌细胞株MKN45的IC_(50)分别为2.65和3.55μmol/L,均优于阳性对照药索拉菲尼(IC_(50)=4.69μmol/L)。     

新型吲唑类化合物的合成及其抗肿瘤活性

以2,6-二氟苯腈与吗啉反应制得2-氟-6-吗啉-苯腈(1); 1与水合肼在N-甲基吡咯烷酮中通过环合反应制得3-氨基-4-吗啉-1H-吲唑(2); 2与不同羧酸经缩合反应合成了8个新型吲唑类化合物(4a~4h),其结构经¹H NMR, IR和HR-ESI-MS表征。抗肿瘤活性测试结果表明：3,4,5-三甲氧基-氮-(4-吗啉-1H-吲唑-3-基)苯甲酰胺（4a）的抗肿瘤活性最好,对K-562, SMMC7721和T-47D肿瘤细胞有明显抑制作用,IC₅₀分别为0.056 μmol·L^-1, 0.062 μmol·L^-1和0.078 μmol·L^-1。     

3-腙喹唑啉酮衍生物的合成及抗肿瘤活性研究

通过活性拼接原理在喹唑啉酮3-位引入腙结构,使用简单的合成路线合成了一系列3-腙喹唑啉酮衍生物.目标化合物结构经核磁共振波谱(¹H NMR,¹³C NMR)和高分辨质谱(HRMS)进行了表征确证.抗肿瘤活性测试结果表明,该类化合物对A549、PC-3、Hep G2、K562等肿瘤细胞系均表现出有效的抑制活性;其中(E)-N-((2-氯-1-甲基-1H-吲哚-3-基)亚甲基)-2-(7-氟-4-氧喹唑啉-3(4H)-基)乙酰肼(H1)对Hep G2细胞的IC₅₀值为(9.90±1.13)μmol/L,(E)-2-(7-氟-4-氧喹唑啉-3(4H)-基)-N-((2-吗啉代-1-丙基-1H-吲哚-3-基)亚甲基)乙酰肼(H2)对PC-3细胞的IC₅₀值为(10.70±0.78)μmol/L,抑制活性均优于阳性对照药吉非替尼[IC₅₀=(23.33±4.14)μmol/L,IC₅₀=(12.02±5.39)μmol/L].细胞凋亡、4’,6-联脒-2-苯基吲哚(...     

新型5位与6位取代的吲唑类衍生物的合成及抗肿瘤活性研究

为了寻找高效低毒的新型抗肿瘤药物,设计并合成了新型的5位与6位取代的吲唑类化合物.采用噻唑蓝(MTT)法对目标化合物在PC-3(人前列腺癌细胞)、MCF-7(人乳腺癌细胞)、Hep G-2(人肝癌细胞)和MGC-803(人胃癌细胞)四种人类癌细胞的抗增殖活性进行评价.结果显示大部分化合物对PC-3具有特异性的抗增殖活性.其中,N-(1-苄基-1H-1,2,3-三唑-4-基)甲基)-1-异丙基-1H-吲哚唑-5-羧酰胺(8a)和N-[(1-苄基-1H-1,2,3-三唑-4-基)甲基]-1-异丙基-1H-吲唑-6-甲酰胺(14a)对PC-3细胞的抗增殖活性较好, IC₅₀值分别为6.21和6.43μmol/L,为前列腺癌抗肿瘤药物的研究提供了思路.     

5-苄基-4-叔丁基-2-芳氨基噻唑氢溴酸盐的合成、表征及抗肿瘤活性

以芳香胺和4,4-二甲基-1-芳基-2-溴戊-3-酮为原料, 设计合成了29种新的5-苄基-4-叔丁基-2-芳氨基噻唑氢溴酸盐化合物; 其结构经¹H NMR和元素分析等确证. 体外抗肿瘤活性测试结果表明, 化合物A4, A5, A12和A29对人非小细胞肺癌细胞A549的IC₅₀值分别为0.016, 0.019, 0.019和0.026 μmol/mL, 与阳性对照物紫杉醇(IC₅₀值为0.022 μmol/mL)相当; 化合物A5, A7, A13, A14和A19对肝癌细胞Bel7402的IC₅₀值分别为0.021, 0.021, 0.026, 0.014和0.029 μmol/mL, 与阳性对照物紫杉醇的IC₅₀值(0.030 μmol/mL)相近. 利用倒置显微镜和Hoechst33342-PI双染色法观察了细胞经化合物处理后的形态变化.     

新型异吲哚酮衍生物的合成与活性研究

为了寻找结构新颖,活性较好的抗肿瘤化合物,本文设计并合成了15个未见报道的异吲哚酮衍生物(I₁~I₅, II₁~II₅和III₁~III₅),其结构经¹H NMR和HR-MS(ESI)表征。使用四甲基偶氮唑盐(MTT)法,初步的生物活性测试结果表明：部分化合物对人肺癌细胞A549(II₄, IC₅₀=15.49μM)、人结肠癌细胞Colo205(II₄, IC₅₀=15.54μM)、人胰腺癌细胞PNAC-1(II₄, IC₅₀=37.07μM)和人骨髓瘤细胞U266(II₅, IC₅₀=75.27μM)表现出明显的抑制作用。      

新型苯并[b]氮杂?-查尔酮杂合物的设计、合成及抗肿瘤活性研究

为了寻找高效、低毒的抗肿瘤药物，基于分子杂交的策略，将苯并[b]氮杂?结构引入查尔酮母体结构中，设计了12个未见文献报道的苯并[b]氮杂?-查尔酮杂合物（7a~7l）。并以苯胺为原料，经N-烷基化、羰基化、水解、环化和Claisen-Schmidt缩合反应合成了7a~7l，其结构经¹HNMR, ¹³CNMR和HR-MS(ESI)表征。采用MTT法评估了目标化合物对人胃癌细胞（HGC-27）、人肝癌细胞（HepG2）、人非小细胞肺癌细胞（A549）和人正常胃粘膜上皮细胞（GES-1）的抗增殖活性，并进一步采用流式细胞术和蛋白印迹法实验在细胞和蛋白水平上探究了活性最优化合物的抗肿瘤机制。结果表明：目标化合物对HGC-27细胞表现出较高的抗增殖活性，其中化合物7d对HGC-27细胞的抗增殖活性最强(IC₅₀=0.78 μmol•L^-1)，优于阳性对照顺铂(IC₅₀=7.38 μmol•L^-1)，同时其对人正常细胞GES-1的毒性较低（IC₅₀=22.77 μmol•L^-1, SI=29.19），弱于阳性对照顺铂（IC₅₀=9.51 μmol•L^-1, SI=1.29）。抗肿瘤机制研究表明:化合物7d能够将癌细胞HGC-27的细胞周期阻滞在G2/M期，并通过增加促凋亡蛋白Bax和降低抗凋亡蛋白Bcl-2的表达来诱导HGC-27细胞的凋亡。      

新型吲哚-嘧啶联芳类化合物的设计、合成及抗肿瘤活性研究（英文）

设计合成了一系列新型的吲哚-嘧啶联芳类化合物,并评估了它们对组蛋白去甲基化酶(LSD1)的抑制活性和5种肿瘤细胞系(MGC-803, PC-3, EC-109, PC-12和MCF-7)的抗增殖活性.探讨了22个新型吲哚-嘧啶联芳类骨架衍生物的主要构效关系.在这些化合物中,1-(4-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-((3,4,5-三甲氧基苯基)氨基)乙-1-酮(6i)展示出了潜在的LSD1抑制活性(IC_(50)=1.03μmol/L),而1-(4-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-(间甲苯胺)乙-1-酮(6c),2-((4-丁基苯基)氨基)-1-(4-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6f)和2-((3-氟苯基)氨基)-1-(4-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6k)对PC-3细胞显示出潜在的抗肿瘤活性.其中活性最强的化合物6k的对PC-3细胞系IC_(50)值为2.75μmol/L,可作为生物活性片段和开发更有效抗肿瘤药物的靶点化合物.     

Oncrasin-1类衍生物的合成及其抗肿瘤活性初探

Oncrasin-1类衍生物对来自肺癌、结肠癌等多种癌细胞系都具有高度活性，其中NSC-743380活性最佳。然而，它在结构上存在问题，易形成二聚体而失活，限制了进一步的研究发展。因此，本文以Oncrasin-1为先导化合物，设计了13种衍生物，通过引入氨基和酰胺基，尝试提高化合物稳定性并保留活性。化合物结构经¹H NMR,¹³C NMR, HR-MS(ESI)表征，并通过细胞增殖实验(CCK-8实验)测定其对人胰腺癌细胞(PANC-1)、人宫颈癌细胞(HeLa)和人肝癌细胞(HepG2)的抗肿瘤活性。结果表明，13个Oncrasin-1类衍生物中，有10个表现出更好的活性，其中化合物4((4-(((1-(4-氯苄基)-1H-吲哚-3-基)甲基)氨基)丁基)氨基甲酸叔丁酯)对HeLa的IC₅₀达到了3.98μM。     

基于薯蓣皂苷元催化合成N-甲基吲哚孕烯醇酮化合物及其抗肿瘤活性

利用N-甲基吲哚对类固醇药物的前驱体16-脱氢孕烯醇酮乙酸酯(16-DPA)的D环C16位进行修饰,采用ZrCl₄-乙酸乙酯廉价催化体系,合成了16个3β-乙酰氧基-16α-3’-吲哚孕烯醇酮化合物和6个3β-羟基-16α-3’-吲哚孕烯醇酮衍生物.该方法具有收率高、立体选择性好和底物适应性强等优点.通过噻唑蓝(MTT)比色法测试了22个化合物对三阴性乳腺癌细胞(MDA-MB-231)的抗肿瘤活性.初步测试结果表明, 3β-乙酰氧基-16α-3’-吲哚孕烯醇酮化合物6h和6i对MDA-MB-231癌细胞有较好的抑制活性,其半数抑制浓度(IC₅₀)分别为18.07和23.22μmol/L;而化合物7a～7f均对MDA-MB-231癌细胞有较好的抑制活性,其中化合物7e的抗肿瘤活性最好,其IC₅₀为12.50μmol/L.目标化合物为药物筛选提供了一定的参考.     

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 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.     

Synthesis,Docking and Biological Evaluation of Isoquinolonic Acid Derivatives

A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.     

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.     

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 Antitumor Activity of Novel Indolin-2-one Derivatives Containing 4-Thiazolidinone Moiety

A series of novel indolin-2-one derivatives containing 4-thiazolidinone moiety(7a―7r) were synthesized and evaluated for their in vitro antitumour activities against MDA-MB-231(human breast cancer), H460(human lung cancer) and HT-29(human colon cancer) cell lines by standard 3-(4,5-dimethylthiazae-2-yl)-2,5-diphenyltetrazo- lium bromide(MTT) assay. Representative compounds(7d, 7k, 7m, 7p) with higher cytotoxicity were further examined against one normal cell line(WI-38, human fetal lung fibroblasts). The preliminary investigation shows that most of the compounds display moderate to excellent potency and high selectivity against different human cancer cell lines. In particular, the most potent compound 7m shows promising cytotoxicity against MDA-MB-231, H460 and HT-29 cell lines with IC₅₀ values of 0.78, 0.056 and 0.018 μmol/L, respectively. The potency is much higher than that of Sunitinib(IC₅₀=3.46 μmol/L against MDA-MB-231, IC₅₀=2.59 μmol/L against H460, IC₅₀=1.50 μmol/L against HT-29) by 4.4, 46.3 and 83.3 fold.     

Synthesis of Aminoalkyl-substituted Polymethoxychalcone Derivatives and Their Antiproliferative Activities Against Three Human Cancer Cell Lines

Two novel series of sixteen aminoalkyl-substituted polymethoxychalcone derivatives 2a-2h and 3a-3h were synthesized from 2'-hydroxy-3,4,5,4',6'-pentamethoxy chalcone(1) through extending alkoxy side chain at the 2'-position, and introducing amine hydrogen bond receptor at the end of the side chain. The structures of all the synthesized compounds were confirmed by ¹H NMR, ¹³C NMR and MS techniques. Furthermore, all the compounds were tested for antiproliferative activities in vitro against a panel of three human cell lines(HeLa, HCC1954 and SK-OV-3) via CCK-8 assay. The results show that all the target compounds exhibit antiproliferative activities against the three human cancer cells with IC₅₀ values of 4.62-48.21 μmol/L, except compound 2h against SK-OV-3 cells. Most of these compounds were more active when compared to the positive control cis-Platin.     

Expeditious synthesis,antileishmanial and antioxidant activities of novel 3-substituted-4-hydroxycoumarin derivatives

A series of novel 3-substituted-4-hydroxycoumarin derivatives 6(a–1) were synthesized in high yield using one-pot three component coupling reaction catalyzed by ceric ammonium nitrate. These compounds were evaluated for antileishmanial activity against Leishmania donovani promastigotes and antioxidant activity(DPPH-radical scavenging activity). Two compounds, 6h(IC_(50)= 9.90 μmol/L) and 6i(IC_(50)= 6.90 μmol/L) displayed potent antileishmanial activity when compared with standard antileishmanial agents pentamidine(IC_(50)= 16.15 μmol/L) and miltefosine(IC_(50)= 12.50 μmol/L). Three compounds, 6c(IC_(50)= 10.79 μmol/L), 6h(IC50= 10.60 μmol/L), and 6i(IC_(50)= 10.73 μmol/L) showed significant antioxidant activity favorably with the antioxidant standards butylated hydroxy toluene(IC_(50)= 16.47 μmol/L) and ascorbic acid(IC_(50)= 12.69 μmol/L). A molecular docking study of compounds 6(a–1) suggested a possible mode of binding with the Adenine phosphoribosyltransferase enzyme of L.donovani. ADME properties were predicted in silico and support the potential of 6(a–1) to show favorable drug-like properties.     

Syntheses and Anti-cancer Activities of Derivatives of Tetrandrine and Fangchinoline

A series of derivatives of tetrandrine and fangchinoline was designed and synthesized to find more active anti-cancer compounds. Their anti-cancer activities were tested against human hcpatocellular carcinoma BEL-7402 and PLC/PRF/5 cells, human lung adenocarcinoma A549 cells as well as human leukaemia K562 cells, and the structure-activity relationship（SAR） was also studied. All the compounds except BI exhibited superior inhibitory ac- tivities against PLC/PRF/5 cells with half maximal inhibitory conccntration（ICs0） values of less than 15 μmol/L, and compounds A2, A4, B2 and B4 showed IC50 values of less than 9 pmol/L. Compounds A2, A6, B2 and B4 showed potent anti-cancer activities against all the tested cells with 1C5o values of less than 10 pmol/L. The results show that terandrine and fangchinoline derivatives are potential suppressors to human cancer.     

Synthesis and Anti-leukemia Evaluation of Tetrahydro-4H-pyrano[3,2-c]pyridines and Corresponding Anti-CD14 Monoclonal Antibody Conjugates

A series of novel tetrahydro-4H-pyrano[3,2-c]pyridines（3a-3p） were synthesized and found to possess potent antiproliferative activity against leukemia K562 cells in vitro. Preliminary bioassay indicates that compounds 3a and 3e afford the best activity, the IC50 values of them were 6.93 and 7.51μg/mL, respectively, which were lower than that of the anticancer drug 5-FU（1C50=8.56μg/mL）. To reduce the toxicity of compounds 3a-3p to the prolife- ration of normal bematopoietic cells, a tumor targeted CD14 monoclonal antibody（McAb） was used in conjugation with compounds 3a--3p to get conjugates 4a--4p, respectively. The inhibitory activities of conjugates 4a--4p toward K562 cells were discovered to approach those of compounds 3a--3p. In the presence of CD14 McAb, tumor cells were found to be much more susceptible to conjugates 3a--3p than normal hematopoietic cells. Therefore, the toxicity of conjugates 4a--4p to normal hematopoietic cells declined obviously. For example, as for the toxicity of compound 3a compared with that of compound 4a, the value of ICs0 increased from 35.90 μmol/L to 39.52 μmol/L.