Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

A series of 3,5‐bis(arylidene)‐4‐piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3‐c]pyridines, pyrido[4,3‐d]pyrimidines, and pyrido[3,2‐c]pyridines, carrying an arylidene moiety, and some pyrano[3,2‐c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in‐vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7 , 9 , 10 , 12, 13, 15, 17 , and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3‐c]pyridine series proved to be more active than those of the pyrido[3,2‐c]pyridine and pyrano[3,2‐c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T‐47D cell line (GI 54.7%). The pyrano[3,2‐c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six‐membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non‐small cell lung cancer Hop‐92 and ovarian cancer OVCAR‐4 cell lines (GI values 63.9 and 48.5%, respectively).     

新型N-取代邻苯二甲酰亚胺类衍生物抗肿瘤血管生成活性评价

目的 对前期合成的邻苯二甲酰亚胺衍生物的抗肿瘤血管生成活性进行评价.方法 应用体外细胞培养模型、体内斑马鱼模型和C57BL/6荷瘤小鼠模型对化合物的抗肿瘤血管生成活性进行考察.结果 N-苄基-4,6-二甲氧基邻苯二甲酰亚胺(7i)和N-苄基-4,6-二-羟基邻苯二甲酰亚胺(8i)能够显著抑制人肺腺癌A549细胞中血管内皮生长因子分泌,同时能够抑制斑马鱼体节间血管生成.两种化合物抑制Lewis肺腺癌移植瘤生长,并优于阳性对照药沙利度胺.结论 所合成的新型邻苯二甲酰亚胺类衍生物具有一定的抗肿瘤血管生成作用,具有进一步合成修饰研究价值.     

N-糖基取代的邻苯二甲酰亚胺新衍生物的合成与肿瘤多药耐药逆转作用研究

沙利度胺（α-N-phthalimido-glutarimide，TLD）是一种具有抗血管生成和抗炎作用的药物，对多种实体瘤有效。本文研究了N-糖基取代的沙利度胺新衍生物（STA-35）对阿霉素（doxorubicin，ADR）引起的多药耐药（multidurg resistance，MDR）的调节作用。采用SRB法检测化合物对癌细胞的增殖抑制作用，应用流式细胞术测定P-糖蛋白（P-glycoprotein，P—gp）的功能，以免疫印迹方法考察P—gP的蛋白表达。实验结果表明，STA-35能够抑制人乳腺癌细胞MCF-7及其ADR耐药细胞MCF-7／ADR生长，耐药指数仅为1．19；并能增强MCF-7／ADR细胞对ADR的敏感性。此外，STA-35可以增加MCF-7／ADR细胞内罗丹明123（rhodamine 123，RH123）的聚积，减弱P—gP的功能，抑制P-gp的蛋白表达。该化合物具有多药耐药逆转作用，其分子机制可能与抑制P—gp的功能和蛋白表达相关。     

Design,Synthesis and Biological Evaluation of Pazopanib Derivatives as Antitumor Agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR‐2, EGFR, AKT1, ALK1, and ABL1. The anti‐angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR‐2 and ABL1 and higher anti‐angiogenic activity compared with Pazopanib, the reference standard. These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents.     

抗肿瘤前药-姜黄素衍生物的设计合成及初步活性测试

目的:为了提高姜黄素的抗癌活性及选择性,考虑将之做成前药形式.方法:从几种氨基酸出发,经过马来酸酐活化后与姜黄素结合,得到四个化合物.利用MTT法对四个目标化合物进行了体外抗肿瘤活性评价.结果与结论:其结构经IR,1HNMR和13CNMR确证.目标化合物对胰腺癌细胞株SW-1990和膀胱癌细胞株T24的抑制试验结果表明,四个化合物对这两种细胞的抑制作用均优于阳性对照药5-Fu.     

Synthesis and Evaluation of Millepachine Amino Acid Prodrugs With Enhanced Solubility as Antitumor Agents

A series of amino acid derivatives of millepachine were designed, synthesized, and evaluated for their solubility and antiproliferation ability against tumor. The glycine derivative compound 7a exhibited the best potency and possessed long‐term inhibitory capability on cell viability. It was also confirmed that 7a could arrest the cell cycle at G₂/M phase and trigger apoptosis. Furthermore, indirect immunofluorescence staining revealed antitubulin property of 7a , which is consistent with the previously reported derivatives of millepachine. In vivo, 7a suppressed tumor growth in an MDA‐MB‐231 xenograft tumor model. In summary, the exploit of 7a was a successful approach directed by the concept of generating amino acid prodrugs with increased bioavailability.     

Synthesis and Pharmacological Evaluation of New Ethyl Esters of N-Acyl Amino Acids as CNS Agents

The ethyl esters 1a-1j and 2a-2j of N-acyl amino acids were synthesized by the DCC method. The compounds were screened for their monoamine oxidase (MAO) inhibitory activity (in vitro) and various CNS activities (in vivo). Some compounds showed promising MAO inhibitory and anti-depressant activities. The compounds did not produce acute neurological deficits and have low toxicity.     

Semi‐Synthesis and Biological Evaluation of 1,2,3‐Triazole‐Based Podophyllotoxin Congeners as Potent Antitumor Agents Inducing Apoptosis in HepG2 Cells

A series of 4β‐[(4‐substituted)‐1,2,3‐triazol‐1‐yl]podophyllotoxin congeners were synthesized by employing click chemistry and further evaluated for their antitumor activity by MTT assay. Among them, six congeners ( 10 , 11 , 12 , 13 , 22 , and 24 ) exhibited approximately 100‐fold more potent inhibitory activity against four tumor cell lines (HepG2, MKN‐45, NCI‐H1993, and B16) than etoposide as positive control. Docking studies on binding in the ATPase domain of topoisomerase II revealed perfect docking of four congeners in the active site. Furthermore, the podophyllotoxin congeners 10 , 11 , 12 , and 13 induced cell cycle arrest of HepG2 cells at the G₂/M phase in a concentration‐dependent manner, assessed by flow cytometric analysis, highlighting that they exert their antitumor activity via HepG2 cell apoptosis.     

Thieno[2,3‐d]pyrimidines in the Synthesis of Antitumor and Antioxidant Agents

Dimethyl acetylenedicarboxylate, ethyl propiolate, and E‐dibenzoylethylene react with thienopyrimidines (cyclo‐pentyl, ‐hexyl, and ‐heptyl) derivatives to form thiazolo[3,2‐a]thieno‐[2,3‐d]pyrimidin‐2‐ylidene) acetates, thieno[2,3‐d]pyrimidin‐2‐ylthioacrylates, and thieno[2′,3′:4,5]pyrimido[2,1‐b][1,3]thiazin‐6‐ones, respectively. Reactions proceed via cyclization and thio‐addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep‐G2 cells with IC₅₀ < 20 μM.     

Phthalimide analogs as probable 15-lipoxygenase-1 inhibitors: synthesis,biological evaluation and docking studies

Background

Recent studies have been explained the role of lipoxygenases (LOX) in the origin of cancer. Among the lipoxygenases, the 5-LOX, 12-LOX and 15-LOX are more important in the cause of neoplastic disorders. In the present investigation, a new series of anticancer agents with 1,3,4-thiadiazole and phthalimide substructures were synthesized and their in vitro cytotoxicity was evaluated by MTT assay. Moreover, enzyme inhibitory potency was also assessed by enzymatic protocol towards 15-LOX-1. Molecular docking was performed to explore in silico binding mode of the target compounds.

Results

Tested compounds showed a better cytotoxic activity against HT29 cell line (colorectal cancer) in comparison with other cell lines (PC3: prostate carcinoma; SKNMC: neuroblastoma). Unfortunately, all of the tested derivatives rendered lower inhibitory potency than quercetin towards 15-LOX-1. Four hydrogen bonds were detected in docking studies for compound 4d as the most potent derivative in enzymatic assay.

Conclusions

The biological results of reported compounds in this research were not so satisfactory. But, further structural modifications are necessary to improve the bioactivity of these derivatives.     

抗肿瘤药伏立诺他的合成

目的伏立诺他的合成方法。方法以辛二酸为原料,通过连续两步混合酸酐法制得抗肿瘤药伏立诺他。结果合成的目标化合物经核磁共振氢谱、核磁共振碳谱、质谱及红外光谱确证。结论本合成通过两步得到目标化合物,收率约为41%。     

哌啶酮类法尼基转移酶抑制药的微波幅射合成与抗肿瘤活性

目的合成设计哌啶酮类法尼基转移酶抑制药，并对其抗肿瘤活性进行初步评价。方法以取代苯甲醛为起始原料，经Perkin反应和Michael加成，最后在微波辐射条件下环合得到目标化合物，并用MTT法测试它们抑制人Hela细胞和ANC-1细胞的IC50值。结果采用微波辐射技术合成哌啶酮类化合物，反应时间为20～45 min，产率为36.0%～67.1%。经1H-NMR、ESI-MS及IR对化合物的结构确证，总共合成11个新化合物。初步抗肿瘤活性测试结果显示11个目标化合物均有抑瘤活性，其中8个化合物IC50值低于氟尿嘧啶。结论哌啶酮类法尼基转移酶抑制药的合成路线可靠，具有显著抗肿瘤活性。     

Design, Synthesis, and Antitumor Evaluation of Novel Pyrazolo[3,4-d]pyrimidine Derivatives

A new series of pyrazolo[3,4-d]pyrimidines has been synthesized. The new compounds were tested for their antitumor activity on 60 different cell lines, and some of the compounds were found to have potent antitumor activity. In particular, 2-hydroxybenzaldehyde [1-(4-chlorophenyl)-3-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]hydrazone (VIIa) was found to be the most effective among the other derivatives, showing IC50 values of 0.326 to 4.31 μM on 57 different cell lines.     

Synthesis and Antitumor Activity of Podophyllotoxin Analogues

在三氟乙酸催化下，由４′去甲基表鬼臼毒素１０和５烷基４氨基３巯基１，２，４三唑９（ａｇ）合成了７个目标化合物１１（ａｇ），并对它们进行了ＨＬ６０、Ｋ５６２细胞株体外活性试验，结果表明：１１（ａｇ）对Ｋ５６２细胞株显示出较强的活性。     

沙利度胺联合甲氨蝶呤与单独沙利度胺治疗类风湿关节炎的临床疗效及安全性观察

目的探讨沙利度胺联合甲氨蝶呤治疗类风湿关节炎的临床疗效及安全性。方法选取2009年10月至2011年4月来我院就诊治疗的类风湿关节炎患者40例,单盲随机分为对照组和治疗组两组,对照组20例采用单纯沙利度胺治疗,治疗组20例采用沙利度胺联合甲氨蝶呤治疗,每位患者均总共治疗6个月,每2周记录患者治疗情况及不良反应状况,并用疼痛模拟评分方法来对患者的疗效进行评分,对比分析两组的总治疗有效率和疗效差异。结果经过6个月的治疗后,对照组的总有效率75.0%,治疗组的总有效率为80.0%,总有效率差异无统计学意义(P>0.05),但两组的治疗疗效差异具有统计学意义(P<0.05),至于不良反应,对照组20例中有6例患者出现不良反应,治疗组20例有7例出现不良反应,差异无统计学意义(P>0.05),但治疗组的不良反应明显较对照组轻微。结论沙利度胺治疗类风湿关节炎效果明显,联合甲氨蝶呤可改善疗效并提高安全性。     

鬼臼类衍生物的合成及抗肿瘤活性

在三氟乙酸催化下，由4′－去甲基－表鬼臼毒素10和5－烷基－4－氨基－3－巯基－1，2，4－三唑9（a-g）合成了7个目标化合物11（a-g），并对它们进行了ＨＬ－６０、Ｋ５６２细胞株体外活性试验，结果表明：１１（a-g）对Ｋ５６２细胞株显示出较强的活性。     

Synthesis and Evaluation of Flavanones as Anticancer Agents

A few flavanones were synthesised by cyclisation of corresponding 3-(heteroaryl)-1(2-hydroxyphenyl) prop-2-en-1-one with sodium acetate in alcohol–water and evaluated for activity. Synthesised compounds were assayed for their in vitro anticancer activity against three human cancer cell lines, mammary adenocarcinoma (MCF7), human colon adenocarcinoma (HT29) and human kidney adenocarcinoma (A498) using sulforhodamine B dye. Results indicated that most of the compounds exhibited significant in vitro anticancer potential. Among them, compound having furan ring showed most potent activity against all the tested cell lines.