Design and synthesis of new tetrandrine derivatives and their antitumor activities

A series of tetrandrine derivatives were designed and synthesized using Suzuki coupling reaction. Eleven targeted compounds with over 50% inhibition against HL60 and A549 human cancer cell lines at 10 μM were further evaluated for the in vitro antitumor activities by MTT or SRB assay. The biological results revealed that some compounds exhibited potent antitumor activities. Thiophene derivative 6 and acetylphenyl derivative 5 were the most active ones against HL60 and A549 cell lines, with IC₅₀ values less than 5 μM, which thus could be considered as useful candidate for further development of new antitumor agents.     

Synthesis and in vitro antitumor activities of lupeol dicarboxylic acid monoester derivatives

Ten lupeol dicarboxylic acid monoester derivatives as new potent antitumor agents were synthesized and evaluated for in vitro antitumor activities against A549, LAC, HepG2 and HeLa cell lines. Among them, compounds 1–5 showed excellent antitumor activities against all tested tumor cell lines and compounds 6–10 exhibited high activities against A549, HepG2 and HeLa cells, exceeded lupeol, lupanol and doxorubicin. Compound 2 displayed the highest potent antitumor activities with IC₅₀ values of 5.78 μM against A549 cell, 2.38 μM against LAC cell, 6.14 μM against HepG2 cell and 0.00842 μM against HeLa cell.     

Design,synthesis, and antitumor activity of oleanolic acid derivatives

Using the techniques of computer-aided drug design, the docking of survivin and known active small molecules was simulated and then the key amino acid residue fragments of the target protein were analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, oleanolic acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, 20 new oleanolic acid derivatives had been designed and synthesized. HepG2 and SGC-7901 cells were used to screen the antitumor activity through the standard MTT method. The compounds, II₃, III₅ and IV_4, exhibited more potent cytotoxicity than positive drugs. Western blot experiment demonstrated that compound II₃ can effectively inhibit the proliferation of HepG2 cells.     

甘草次酸C3、C30衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成甘草次酸C3、C30衍生物,并对其体外抗肿瘤活性进行研究。方法以甘草次酸为先导化合物,对其C3位羟基、C30位羧基进行结构修饰,并采用SRB法对目标化合物进行体外抗肿瘤活性研究。结果设计合成了12个新型甘草次酸衍生物,并利用MS、1H-NMR及元素分析确证了结构;体外实验中,目标化合物对MCF-7和A549肿瘤细胞的抑制活性均明显强于甘草次酸,其中化合物GA-I1、GA-I2和GA-II1对MCF-7和A549两种细胞表现出很好的抑制活性,明显高于对照药吉非替尼。结论甘草次酸衍生物具有良好的抗肿瘤活性,值得进一步研究。     

Antitumor effect of resorcinol derivatives from the roots of Ardisia brevicaulis by inducing apoptosis

Two new resorcinol derivatives 2-methoxy-4-hydroxy-6-(8Z-pentadecenyl)-benzene-1-O-acetate (1) and 2-methoxy-4-hydroxy-6-pentadecyl-benzene-1-O-acetate (2), together with four known compounds 2-methoxy-4-hydroxy-6-tridecyl-benzene-1-O-acetate (ardisiphenol D, 3), 5-(8Z-pentadecenyl)resorcinol (4), 5-pentadecylresorcinol (5), 5-tridecylresorcinol (6), have been isolated from the roots of Ardisia brevicaulis in our previous work. In the present study, the inhibitory effect of 1–6 on the proliferation of human pancreatic PANC-1, human lung A549, human gastrointestinal carcinoma SGC 7901, human breast MCF-7, and human prostate PC-3 cancer cells was evaluated by the methyl thiazolyl tetrazolium method. Compounds 1–6 all showed inhibitory activities against the proliferation of PANC-1, A549, SGC7901, MCF-7, and PC-3 cancer cells. Compound 3, the most active agent and the main constituent with the highest yield, induced apoptosis of PANC-1 cells (the most sensitive cell line among the cell lines screened) via the activation of caspase-3 and caspase-9, up-regulation of the ratio of bax/bcl-2 protein expression.     

Synthesis and antitumor activity evaluation of lamiridosin A derivatives

A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC₅₀ value of 2.36 μmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU).     

3-取代-5-氟-1-2-二氢-3H-吲哚-2-酮类化合物的合成及抗肿瘤活性

5-溴-1H-吲哚经氰基取代、Vilsmeier-Haack反应、水解、缩合制得3-[(Z)-(5-氟-1,2-二氢-2-氧代-3H-亚吲哚基)甲基]-1H-吲哚-5-甲酸,再和相应的胺类化合物反应制得10个3-取代-5-氟-1,2-二氢-3H-吲哚-2-酮类化合物.以舒尼替尼为阳性对照,用MTT法测试目标化合物对人乳腺上皮细胞HMEC的体外抑制活性,其中1c、1f、1g和1h在浓度为10 μmol/L时,对HMEC的抑制活性优丁舒尼替尼.进一步测试1c和1e对SGC7901、A549、HL-60、SK-BR-3、HCT116肿瘤细胞株的抗增殖活性.结果表明,1c和1e对白血病细胞株HL-60的抗增殖活性优丁舒尼替尼.     

Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents

A series of nitrogen-containing derivatives of oleanolic acid and ursolic acid were prepared by a modification at C-28 position via esterification with 2-hydroxyacetic acid followed by amidation with amines, such as piperazine, N-methylpiperazine, and alkane-1, 2-diamines, alkane-1, 4-diamines, alkane-1, 6-diamines. In vitro antiproliferative activities of the compounds prepared towards MCF-7, Hela and A549 cell lines were evaluated by a MTT method to show that OA-5a, OA-5b, OA-5c and UA-5a showed somewhat improved antiproliferative activities against MCF-7, Hela and A549 cells comparing to that of the positive control, gefitinib.     

吲哚-1,3,4-噁二唑类衍生物的合成及其体外抗肿瘤活性研究

目的 合成吲哚-1,3,4-噁二唑类衍生物,并进行体外抗肿瘤活性研究。方法 以吲哚-3-甲酰肼为起始原料,通过[4+1]环加成反应、水解反应、缩合反应得到目标化合物。采用MTT法测试目标化合物对HeLa、SCG-7901和MDA-MB-231细胞的体外抗肿瘤活性。采用克隆形成实验考察化合物6f对SCG-7901细胞增殖的影响。采用Annexin V-APC/PI双染法检测化合物6f对SCG-7901细胞凋亡和坏死的影响。采用DAPI染色法检测化合物6f对SCG-7901细胞凋亡核染色质形态学的影响。采用DCFH-DA染色法检测化合物6f对SCG-7901细胞中活性氧含量的影响。结果 合成了15个吲哚-1,3,4-噁二唑类衍生物,其结构经¹H-NMR、¹³C-NMR和HR-ESI-MS确证。部分化合物表现出良好的抗肿瘤活性,其中化合物6f对HeLa、SCG-7901和MDA-MB-231 3种肿瘤细胞株均表现出明显的抗增殖作用,且具有一定的选择性。进一步研究表明,化合物6f以浓度相关的方式促进细胞产生活性氧,抑制细胞增殖,诱导细胞凋亡。结论 部分吲哚-1,3,4-噁二唑类衍生物表现出良好的抗肿瘤活性,为该类化合物的进一步抗肿瘤活性研究提供思路。     

Antitumor effect of resorcinol derivatives from the roots of Ardisia brevicaulis by inducing apoptosis

Two new resorcinol derivatives 2-methoxy-4-hydroxy-6-(8Z-pentadecenyl)-benzene-1-O-acetate (1) and 2-methoxy-4-hydroxy-6-pentadecyl-benzene-1-O-acetate (2), together with four known compounds 2-methoxy-4-hydroxy-6-tridecyl-benzene-1-O-acetate (ardisiphenol D, 3), 5-(8Z-pentadecenyl)resorcinol (4), 5-pentadecylresorcinol (5), 5-tridecylresorcinol (6), have been isolated from the roots of Ardisia brevicaulis in our previous work. In the present study, the inhibitory effect of 1-6 on the proliferation of human pancreatic PANC-1, human lung A549, human gastrointestinal carcinoma SGC 7901, human breast MCF-7, and human prostate PC-3 cancer cells was evaluated by the methyl thiazolyl tetrazolium method. Compounds 1-6 all showed inhibitory activities against the proliferation of PANC-1, A549, SGC7901, MCF-7, and PC-3 cancer cells. Compound 3, the most active agent and the main constituent with the highest yield, induced apoptosis of PANC-1 cells (the most sensitive cell line among the cell lines screened) via the activation of caspase-3 and caspase-9, up-regulation of the ratio of bax/bcl-2 protein expression.     

Substituent Effects on Cytotoxic Activity,Spectroscopic Property,and DNA Binding Property of Naphthalimide Derivatives

A series of novel naphthalimide derivatives NI 1‐5 containing piperazine moieties (N‐(2‐hydroxyethyl)piperazine and 1‐piperazinepropanol) and piperidine moieties (4‐piperidinemethanol, 4‐hydroxypiperidine and 4‐piperidineethanol) have been synthesized and evaluated for their cytotoxic activity, spectroscopic property, and DNA binding behaviors. It was found that substituents at the 4‐position remarkably influence the various activities of this series of compound. Compounds NI 3‐5 modified with piperidines exhibited potent cytotoxic activities against Hela, SGC‐7901, and A549 cells with the IC₅₀ values from 0.73 μm to 6.80 μm , which are better than NI 1‐2 functionalized with piperazines. Compounds NI 1‐2 showed higher binding capacity with Ct‐DNA than compounds NI 3‐5 based on studies of UV–vis, fluorescence and CD spectra. Furthermore, compounds NI 3‐5 , as DNA intercalators, showed fluorescence enhancement upon binding with Ct‐DNA. More interestingly, fluorescence imaging studies of compound NI 4 with A549 cells showed that the fluorescence predominantly appeared in the cytoplasm. These results provided a potential application of NI 3‐5 as anticancer therapeutic and cancer cell imaging agents.     

Synthesis and crystal structure of chalcones as well as on cytotoxicity and antibacterial properties

Abstract  

A series of chalcones derivatives were synthesized and evaluated for cytotoxic and antibacterial activities in vitro. These modifications changed their bioactivity profile and indicated a combination of SAR analysis toward the substituents in rings A and B of chalcones. Compounds 2, 6–8, 14–17, and 32 exhibited good cytotoxic properties against two human cancer cell lines HT29 and SGC7901. Compounds 16 and 17 showed high antibacterial activity toward 14 clinically isolated multidrug-resistant strains. Subsequently, the structure of bi-bioactive compound 16 was determined using single-crystal X-ray diffraction. This study presents a few novel leading compounds for the development of potential antitumor and antibacterial agents.     

Synthesis and cytotoxicity studies of novel 2-Hydrazonylpyrido[2,3-b]pyrazin-3(4H)-ones

In an attempt to develop potent antitumor agents, a series of novel 2‐hydrazonylpyrido[2,3‐b]pyrazin‐3(4H)‐one derivatives were designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, MDA‐MB‐231 and HT‐29 cell lines in vitro. Pharmacological data indicated that five of the target compounds showed cytotoxicity against A549 cell line below a concentration of 1 µM. Compound 15g was the most potent one with IC₅₀ values of 0.19, 2.11 and 2.15 µM against A549, MDA‐MB‐231 and HT29 cell lines, respectively.     

Suppressive effects of novel derivatives prepared from <Emphasis Type="Italic">Aconitum</Emphasis> alkaloids on tumor growth

Summary  Little information has so far been reported regarding the antiproliferative properties of Aconitum alkaloids against human tumor cells despite of their intense toxicities. In the present study, the antitumor properties and radiation sensitizing effects were investigated by various types of novel derivatives prepared from Aconitum alkaloids. The antitumor properties were investigated against human tumor cell lines, A172, A549, HeLa and Raji, respectively, by a cell growth, a clonogenic assay, cell cycle distribution, cell cycle related molecules and γH2AX expression. The novel compounds derived from C₂₀-diterupenoid alkaloids showed a significantly suppressive effect in all cell lines. In contrast, natural C₁₉-norditerpenoid alkaloids and their derivatives showed either no effect or only a slight effect. One of the compounds also showed radiosensitizing properties on A549 cells. These effects are not related to either the cell cycle distribution, the enhancement of apoptosis or the γH2AX expression. Novel derivatives prepared from Aconitum alkaloids, not but natural alkaloids, clearly showed anti-proliferative activity in human tumor cell lines.     

Synthesis and biological evaluation of 1-cyano-2-amino-benzimidazole derivatives as a novel class of antitumor agents

A series of 1-cyano-2-amino-benzimidazole derivatives were synthesized and evaluated for their cytotoxic activities in vitro against three human cancer cell lines (human lung carcinoma cell line: A549, human leukemia cell line: K562, and human prostate cancer cell line: PC-3). Most of these compounds showed potent activities against these tumor cell lines, especially against A549 and K562 cell lines. The preliminary structure–activity relationships of 1-cyano-2-amino-benzimidazole derivatives were also discussed. The cell cycle analysis was carried out in K562 cells and the results showed that compound 4d caused a marked increase of cells in G ₂/M phase.     

Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3‐d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1

A series of tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, ¹H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure–activity relationship analyses indicated that compounds with an aromatic ring substituted in the C‐2 position or with larger molecules such as 3g , 4c , and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μ m ), was identified to have the most potent antitumor activities, with IC₅₀ values of 7.7, 18.9, and 13.3 μ m against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1‐mediated cancers.     

双(2,6-哌嗪二酮)类抗肿瘤药物的研究:2,3-二乙酰氧基-1,4-二(3′,5′-二酮-N4′-取代哌嗪甲基)苯的合成

Seventeen compounds having the structure of 2,3-diacetoxy-1,4-bis(3′,5′- dioxo-N⁴′-substituted piperazinyl methyl)benzene were designed and synthesized based on chelation hypothesis. Their antitumor activities on P388 cells,Hep cells and SGC 7901 cells in vitro were tested. Preliminary results showed that compound 4e has potent antitumor effect against P388 cells and.Hep cells in vitro.     

Synthesis and cytotoxic activity of two steroids: icogenin aglycone analogs

During the process of icogenin analog research, we obtained two cytotoxic steroids: compound 4 and compound 6 casually. Their in vitro antitumor activities were tested by the standard MTT assay. The results disclosed that compound 4 (IC₅₀ = 3.65–6.90 μM) showed potential antitumor activities against HELA, KB cell lines and compound 6 (IC₅₀ = 2.40–9.05 μM) showed potential antitumor activities against HELA, BGC-823, KB, A549, HCT-8 cell lines.     

6-或7-（取代苯乙烯基）香豆素类化合物的合成及其抗癌活性的研究

目的：设计合成一系列苯乙烯基香豆素类化合物,并通过药理筛选寻找具有抗肿瘤活性的药物。方法：通过相转移Wittig反应得到目的物,利用几种药理模型进行体外抗肿瘤活性筛选。结果：合成了30个（I₁～II_I6）新的苯乙烯基香豆素类化合物并确定其构型。结论：药理筛选结果表明,7个化合物(I₂,I_4,II_2,II_2c,III_1a,III_2a,III_5a)对L-1210,HL-60,HCT-8,KB和Bel-7402细胞株有效,显示了一定的抗肿瘤活性。     

Synthesis of novel tetrandrine derivatives and their inhibition against NSCLC A549 cells

Abstract

A series of novel tetrandrine (Tet) derivatives were synthesized through Suzuki -Miyaura reaction and evaluated for their cytotoxicity against human non-small cell lung carcinoma (NSCLC) A549 cells. Interestingly, most of derivatives showed similar cytotoxicity to Tet against NSCLC A549 cells, and particularly, compounds Y5, Y6, Y9 and Y11 showed the most significant cytotoxic effects with IC₅₀ values ranging from 3.87 to 4.66 mM. The present study is expected to contribute to the future design of more effective anticancer agents in lung cancer chemotherapy.