大黄酸-氨基酸缀合物的合成及初步抗肿瘤活性研究

以大黄酸为原料,经过酯化、醚化、水解、缩合等步骤,合成了20个大黄酸-氨基酸缀合物.所有目标化合物经~1H NMR,~(13)C NMR和HRMS进行结构确证.以顺铂和阿霉素为阳性对照药,采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Hela,MCF-7,HepG2,KB和HEK293T等5株细胞)活性.结果显示2-(4,5-双(苄氧基)-9,10-蒽醌-2-甲酰氨基)-4-甲基戊酸钠(6eb)显示出较好的抗肿瘤活性,DNA对2-(4,5-二丁氧基-9,10-蒽醌-2-甲酰氨基)-4-甲基戊酸钠(6db)和6eb作用的荧光光谱均表现出荧光猝灭现象,推测6db可能仅是静电结合或分子部分嵌入DNA.     

双-β-咔啉衍生物的设计、合成及抗肿瘤活性

以去氢骆驼蓬碱为原料,经过脱甲基、烷基化等步骤,合成了一系列双-β-咔啉衍生物.目标化合物均经核磁共振谱(NMR)和质谱(MS)进行结构确证.以顺铂为阳性对照药,采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Bel-7402,786-0,BGC-823,A375,769-P和MCF7等6株细胞)活性.结果表明,化合物4g和4o与阳性对照药相比具有良好的抗肿瘤活性,其半抑制浓度(IC_(50))值均小于10μmol/L.初步构效关系研究表明,当桥链亚甲基数目为8~10,β-咔啉环上9-丁基或9-异丁基取代时,化合物的抗肿瘤活性较强.     

双-(1-杂环-β-咔啉)-3-烷氨基衍生物的合成与抗肿瘤活性（英文）

为寻找高效、低毒的抗肿瘤候选化合物,以1-杂环取代-β-咔啉-3-羧酸乙酯为原料,合成了一系列的双-(1-杂环-β-咔啉)-3-烷氨基衍生物.所有目标化合物经~~1H NMR、~(13)C NMR和HRMS进行结构确证.以顺铂为阳性对照药,采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(22RV1,SK-OV-3,MCF-7,BGC-823,A375和769-P等10株细胞)活性.结果显示化合物5a~5h与阳性对照药和单取代β-咔啉衍生物相比具有很好的抗肿瘤活性,其IC_(50)值均小于10μmol·L~(-1),特别是化合物5d对769-P的抑制活性达到0.8μmol·L~(-1),化合物5h对22RV1的抑制活性达到0.6μmol·L~(-1).     

4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类化合物的设计、合成及抗肿瘤活性研究

设计、合成了19个未见文献报道的4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类衍生物,所有化合物结构均经~1H NMR、~(13)C NMR及HRMS确认。采用噻唑蓝(MTT)法测试了目标化合物对人结肠癌细胞(HCT116)、人乳腺癌细胞(MD-MBA-231)、大鼠神经胶质瘤细胞(C6)、人非小细胞肺癌细胞(A549)、人乳腺癌细胞(MCF-7)的体外抗肿瘤活性。所有化合物均表现出较好的抗肿瘤活性,其中5a、5b、5c、5e、5i、5p和5r对多个细胞株的抑制活性为阳性对照药品5-氟尿嘧啶的20～100倍;其中,以5b的抗肿瘤活性最为突出,对肿瘤细胞HCT116、MD-MBA-231、C6、A549、MCF-7的IC_(50)分别为3. 26、3. 06、0. 63、0. 68、2. 32μmol/L。初步研究结果表明,此类化合物对肿瘤细胞增殖有明显抑制作用,为新型抗肿瘤化合物的设计、合成提供了思路。     

4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类化合物的设计、合成及抗肿瘤活性研究

设计、合成了19个未见文献报道的4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类衍生物,所有化合物结构均经~1H NMR、~(13)C NMR及HRMS确认。采用噻唑蓝(MTT)法测试了目标化合物对人结肠癌细胞(HCT116)、人乳腺癌细胞(MD-MBA-231)、大鼠神经胶质瘤细胞(C6)、人非小细胞肺癌细胞(A549)、人乳腺癌细胞(MCF-7)的体外抗肿瘤活性。所有化合物均表现出较好的抗肿瘤活性,其中5a、5b、5c、5e、5i、5p和5r对多个细胞株的抑制活性为阳性对照药品5-氟尿嘧啶的20～100倍;其中,以5b的抗肿瘤活性最为突出,对肿瘤细胞HCT116、MD-MBA-231、C6、A549、MCF-7的IC_(50)分别为3. 26、3. 06、0. 63、0. 68、2. 32μmol/L。初步研究结果表明,此类化合物对肿瘤细胞增殖有明显抑制作用,为新型抗肿瘤化合物的设计、合成提供了思路。     

2-取代苯氨基喹唑啉衍生物的合成及抗肿瘤活性研究

以2,4-喹唑啉二酮为起始原料,通过氯代、Suzuki偶联和芳环亲核取代反应得到一系列2-取代苯氨基喹唑啉衍生物,并经~1H NMR,~(13)C NMR和HRMS进行结构确证.应用溴化噻唑蓝四氮唑(MTT)法对目标化合物进行了初步体外抗肿瘤细胞增殖活性研究.结果表明,部分化合物具有较好的体外抗肿瘤细胞增殖活性,其中活性化合物4u和4v对Hela,A549和MCF-7三种肿瘤细胞株的增殖均有明显抑制作用.     

新型4'-(N-取代-1-哌嗪基)查尔酮衍生物的合成及其抗肿瘤活性

为了寻找活性较高的抗肿瘤新型分子,采用活性亚结构拼接的方法,将查尔酮和哌嗪连接起来,并通过衍生化,设计合成了10个未见文献报道的新型4'-(N-取代-1-哌嗪基)查尔酮衍生物3a~3j,其结构经~1H NMR、~(13)C NMR和HRMS确证.采用溴化噻唑蓝四氮唑(MTT)法测试了目标化合物体外抗肿瘤活性(Hela,A549和SGC7901),结果表明化合物3f、3i和3j均表现出良好的细胞毒活性,可做进一步研究.     

藤黄酸氰基衍生物的合成及抗肿瘤活性

以藤黄酸为原料,经过酯化反应或酰胺化反应,在C-30位的羧基上引入不同的烷氰基或芳香氰基,设计合成了7个藤黄酸氰基衍生物,其中6个为新化合物,其结构经MS和¹H NMR确证。 采用四氮唑蓝(MTT)法测试了合成化合物对肝癌细胞(HepG2)、结肠腺癌细胞(RKO)和卵巢腺癌细胞(OVCAR-3)的体外抗肿瘤活性,结果表明,所合成的化合物均具有一定的抗肿瘤活性,其中化合物4和6的抗肿瘤活性明显优于阳性对照物藤黄酸。     

噻二唑类肽衍生物的合成及抗肿瘤增殖活性研究

以取代的苯乙酸、2-氨基硫脲为起始原料,经多步反应制备了一系列结构新颖的噻二唑类肽衍生物,其结构经~1H NMR,~(13)C NMR,HRMS确证.目标化合物应用3-(4,5-二甲基-2-噻唑基)-2,5-二苯基溴化四唑(MTT)法初步测试了抑制人白血病细胞(K562细胞)及前列腺癌细胞(PC-3细胞)增殖的活性,结果表明大部分目标化合物具有良好的抗肿瘤细胞增殖活性.针对5个活性目标化合物又进行了三株肿瘤细胞的深入活性评价,发现目标化合物(S)-(2-((1-((5-(1,1'-联苯-4-基甲基)-1,3,4-噻二唑-2-基)氨基)-1-氧亚基-3-苯基丙-2-基)氨基)-2-氧亚基乙基)氨基甲酸叔丁酯(6d)的活性最好,其抑制前列腺癌细胞(PC-3细胞)增殖的活性优于阳性药AT-101.     

17-(2′,5′-二取代噁唑基)-雄甾-4,16-二烯-3-酮的合成及抗肿瘤活性研究

以4-雄烯二酮1为原料,用金催化甾炔法设计并合成了一系列17-(2′,5′-二取代噁唑基)-雄甾-4,16-二烯-3-酮衍生物4a~4k.所合成产物通过1H NMR,13C NMR,IR和HRMS方法进行了结构表征.以阿比特龙为阳性对照,通过3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)法测试了目标化合物对MCF-7(人乳腺癌细胞)、A549(人肺癌细胞)、Bel-7402(人肝癌细胞)、Hela(人宫颈癌细胞)和PC-3M-1E8(人前列腺癌细胞)的体外抗肿瘤活性.结果表明大多数化合物表现出了较好的抗肿瘤活性,其中化合物4c,4g,4i和4j的抗肿瘤活性与阳性对照物阿比特龙相当,且所测化合物对MCF-7有较好选择性作用,其IC50值在3.0~25.5μmol/L之间.     

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 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.     

氟代索拉非尼的合成及其抗肿瘤活性研究

以N-甲基-4-氯-2-吡啶甲酰胺为原料,经过4步共合成4个化合物(S-1,S-2,R-1和R-2),其中2个为新的化合物(S-1和R-2)。经过1H NMR,13C NMR,HR-MS等方法对其结构表征。最后通过CTG法,测试4种化合物对四种人肝癌细胞(PLC/PRF/5,Hep3B,HepG2,BEL-7402)的抑制活性。结果表明:S-1,S-2,R-1和R-2均表现较明显的对4种细胞的抑制活性,且呈现出浓度依赖关系。IC50值从1304nM到11228nM。其中化合物R-1(瑞格非尼)对PLC/PRF/5和HepG2细胞,S-1对Hep3B细胞的抑制活性,R-2对HepG2的细胞活性均较高于原药索拉非尼。     

双-β-咔啉衍生物的设计、合成及抗肿瘤活性

以去氢骆驼蓬碱为原料, 经过脱甲基、 烷基化等步骤, 合成了一系列双-β-咔啉衍生物. 目标化合物均经核磁共振谱(NMR)和质谱(MS)进行结构确证. 以顺铂为阳性对照药, 采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7等6株细胞)活性. 结果表明, 化合物4g和4o与阳性对照药相比具有良好的抗肿瘤活性, 其半抑制浓度(IC₅₀)值均小于10 μmol/L. 初步构效关系研究表明, 当桥链亚甲基数目为8~10, β-咔啉环上9-丁基或9-异丁基取代时, 化合物的抗肿瘤活性较强.     

Syntheses of 2- or 6-Substituted Chromones and Chromone Ring-opening Reaction in Polyphosphoric Acid

In an attempt to find new antitumor agents, a novel class of chromone compounds with a benzimidazoleor a benzoxazole ring in positions 2 or 6 were synthesized νia condensation in polyphosphoric acid(PPA) byusing chromone acids as the starting materials. During the preparation process, it was found that PPA couldcleave the chromone ring to produce a ring-opening compound(6). The molar ratio of the chromone com-pound (5) to the ring-opening compound (6) varied with the change of reaction temperature and time. Basedon MTT protocol, the antitumor activity of each of the compounds obtained was evaluated against three hu-man cancer cell lines: KB(oral epidermal), A2780(ovary) and Be17402 (liver). The IC50 varied from 54.7μmol/L to more than 180 μmol/L.     

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.     

Synthesis,Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).     

N,N-二(8-黄酮甲基)香叶胺类化合物的合成及生理活性

设计合成了4个N,N-二（8-黄酮甲基）香叶胺类化合物,所有目标化合物的结构均经1H NMR、MS和元素分析测试技术确证。采用MTT法考察了目标化合物对K562（白血病细胞）和SMMC7721（肝癌细胞）2种肿瘤细胞的体外抑制活性,结果表明,所测化合物对2种肿瘤细胞都有体外抑制活性,其中N,N-二(3′,4′-二甲氧基-8-黄酮甲基）香叶胺(1c)的活性最好,IC50值分别为5.78和3.85 μmol/L,N,N-二（4′-氟-8-黄酮甲基）香叶胺(1a)和化合物1c对K562（白血病细胞）的体外抑制活性明显优于商品药物美法仑(Melphalan)。以溴化乙锭(EB)为荧光探针测定了化合物1c与鲱魚精DNA有较强的相互作用。     

Synthesis,Cytotoxic Activity Evaluation of Novel 1,2,3‐Triazole Linked Quinazoline Derivatives

A series of novel 1,2,3‐triazole‐quinazoline derivatives were synthesized in five steps starting from anthranilamide by conventional methods. All the title compounds 10a — 10r were evaluated for cytotoxic activity against four human cancer cell lines (MGC ‐803, EC ‐109, MCF ‐7 and HGC ‐27) using MTT assay in vitro . Some of the synthesized compounds exhibited moderate to potent activity against tested cancer cell lines. Among them, compounds 10 h and 10q exhibited excellent growth inhibition against HGC ‐27 and compound 10 m also possessed excellent activity against MCF ‐7, with IC₅₀ values less than 1 µmol/L. Especially, compound 10 h was more cytotoxic than 5‐fluorouracil against all tested four human cancer cell lines.