Synthesis and In‐Vitro Antitumor Activities of Some Mannich Bases of 9‐Alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones

A novel series of 2‐substituted aminomethyl‐9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 5a – q was synthesized via aminomethylation of 9‐alkyl‐1,2,3,4‐tetrahydrocarbazole‐1‐ones 4a – e with hydrochlorides of the respective amines 6a – m . The structures of these newly synthesized compounds were characterized by ¹H‐NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non‐small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi‐drug resistant subline (KB‐VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2‐diethylaminomethyl‐9‐methyl‐1,2,3,4‐tetrahydrocarbazole‐1‐one 5c , exhibited a potential inhibitory effect against microtubule.     

Comparative cytotoxicity of 2,3,9-trimethoxypterocarpan in leukemia cell lines (HL-60, Jurkat,Molt-4, and K562) and human peripheral blood mononuclear cells

The purpose of this study was to investigate the antiproliferative activity of 2,3,9-trimethoxypterocarpan, a known pterocarpan with cytotoxic activity against many tumor cell lines, in a panel of four leukemia cell lines (HL-60, Molt-4, Jurkat, and K562) and on human peripheral blood mononuclear cells (PBMC). The pterocarpan showed IC₅₀ ranging from 0.1 to 0.5 μg/ml at leukemic cells after 72 h of incubation, with K562 being the most resistant cell line. This compound seemed to be selective to tumor cell lines, since at a concentration of 10 μg/ml after 72 h, it only reduced 19% of viable peripheral mononuclear cells.     

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.     

磷酰胺类化合物的合成及抗K562细胞活性研究

目的 合成并评价磷酰胺类化合物体外对白血病细胞株K562生物活性的抑制作用。方法 以芳氨基为药效基团,羟脯氨酸为载体设计目标物,通过几步亲核取代反应合成一系列新化合物,并表征其结构。MTT法测定它们对人慢性髓性白血病细胞株K562细胞的抑制作用。结果 发现了10个新化合物有一定的生物活性。结论 发现了一类新的具有一定抗肿瘤活性的磷酰胺类先导化合物。     

氨基噻唑(噁唑)类化合物的合成及抗K562细胞活性研究

目的 设计、合成一系氨基噻唑（噁唑）类似物,并测试新衍生物对人类慢性粒细胞白血病细胞系K562的体外抑制作用。方法 以dasatinib为先导化合物设计新衍生物,通过亲核取代和关环缩合得到目标化合物,其结构通过¹H-NMR、¹³C-NMR、IR和MS测定。结果 发现5个目标化合物抑制活性高于对照药伊马替尼。4个化合物抗K562细胞活性高于dasatinib。结论 保持药效基团不变,用五元噻唑环取代芳香苯环,活性能得以改善。     

Synthesis and biological evaluation of novel AM80 derivatives as antileukemic agents

A series of novel AM80 derivatives as antileukemic agents were synthesized and their structures were confirmed by IR, ¹H-NMR, and HR-MS spectra. All the target compounds were evaluated for in vitro antiproliferative activities against human leukemic HL-60, NB4, and K562 cell lines. Among these derivatives, compound 4g showed much stronger antiproliferative activities against all the three human leukemic cell lines than the positive control AM80, and compound 4b exhibited more active antiproliferative effects against HL-60 and K562 cells than AM80. Furthermore, the preliminary SAR analysis suggested that AM80 conjugating with HDAC inhibitors with small steric hindrance could give more effective antileukemic agents. These results would be helpful to design more potent antileukemic drugs for the treatment of human leukemia.     

Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors

Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. The synthesized compounds were screened for DDR1 and DDR2 kinase inhibitory and cancer cell proliferation inhibitory activities. Some of the compounds showed the potent inhibitory activities against both DDR1 and DDR2, as well as anticancer activity in low nanomolar range against K562 cell line; especially, compound 3j demonstrated significantly better inhibitory potency than the parental dasatinib against both DDRs and also demonstrated the potent inhibitory activity against K562 cell lines (IC₅₀ values of 2.26±0.46 nm for DDR1, 7.04±2.90 nm for DDR2, and 0.125±0.017 nm for K562 cell line).     

Synthesis and identification of a new class of <Emphasis Type="Italic">(S)</Emphasis>-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a–i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by ¹H NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC₅₀ value less than 60 μM. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC₅₀ ~15 μM) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.     

Apoptosis of leukemia K562 and Molt-4 cells induced by emamectin benzoate involving mitochondrial membrane potential loss and intracellular Ca2+ modulation

Leukemia threatens millions of people's health and lives, and the pesticide-induced leukemia has been increasingly concerned because of the etiologic exposure. In this paper, cytotoxic effect of emamectin benzoate (EMB), an excellent natural-product insecticide, was evaluated through monitoring cell viability, cell apoptosis, mitochondrial membrane potential and intracellular Ca²⁺ concentration ([Ca²⁺]_i) in leukemia K562 and Molt-4 cells. Following the exposure to EMB, cell viability was decreased and positive apoptosis of K562 and Molt-4 cells was increased in a concentration- and time- dependent fashion. In the treatment of 10 μM EMB, apoptotic cells accounted for 93.0% to K562 cells and 98.9% to Molt-4 cells based on the control, meanwhile, 63.47% of K562 cells and 81.15% of Molt-4 cells exhibited late apoptotic and necrotic features with damaged cytoplasmic membrane. 48 h exposure to 10 μM EMB increased significantly the great number of cells with mitochondrial membrane potential (MMP) loss, and the elevation of [Ca²⁺]_i level was peaked and persisted within 70 s in K562 cells whilst 50 s in Molt-4 cells. Moreover, a stronger cytotoxicity of EMB was further observed than that of imatinib. The results authenticate the efficacious effect of EMB as a potential anti-leukemia agent and an inconsistency with regard to insecticide-induced leukemia.     

天南星果实对4株人白血病细胞株的体外抑瘤作用研究

目的观察天南星果实提取物对体外培养4株人白血病细胞生长的抑制作用,探讨天南星果实提取物对人白血病细胞的体外抗肿瘤活性。方法采用Alamar Blue法观察天南星果实提取物对4株人白血病细胞的生长抑制作用。结果果实总醇提取物对K562、HL-60、Raji、Jurkat细胞增殖均具有抑制作用,果实石油醚部分对K562、Raji、Jurkat细胞增殖具有抑制作用,果实乙酸乙酯、水部分对K562、HL-60、Jurkat细胞增殖具有抑制作用。结论天南星果实的提取物中具有抑制肿瘤生长的活性物质,值得进一步研究。     

Induction of cell death and modulation of Annexin A1 by phytoestrogens in human leukemic cell lines

BackgroundPhytoestrogens are polyphenolic plant compounds which are structurally similar to the endogenous mammalian estrogen, 17β-estradiol. Annexin A1 (ANXA1) is an endogenous protein which inhibits cyclo-oxygenase 2 (COX-2) and phospholipase A2, signal transduction, DNA replication, cell transformation, and mediation of apoptosis.ObjectiveThis study aimed to determine the effects of selected phytoestrogens on annexin A1 (ANXA1) expression, mode of cell death and cell cycle arrest in different human leukemic cell lines.MethodsCells viability were examined by MTT assay and ANXA1 quantification via Enzyme-linked Immunosorbent Assay. Cell cycle and apoptosis were examined by flow cytometer and phagocytosis effect was evaluated using haematoxylin-eosin staining.ResultsCoumestrol significantly (p < 0.05) reduced the total level of ANXA1 in both K562 and U937 cells and genistein significantly (p < 0.05) reduced it in K562, Jurkat and U937 cells, meanwhile estradiol and daidzein induced similar reduction in U937 and Jurkat cells. Coumestrol and daidzein induced apoptosis in K562 and Jurkat cells, while genistein and estradiol induced apoptosis in all tested cells. Coumestrol and estradiol induced cell cycle arrest at G2/M phase in K562 and Jurkat cells with an addition of U937 cells for estradiol. Genistein induced cell cycle arrest at S phase for both K562 and Jurkat cells. However, daidzein induced cell cycle arrest at G0/G1 phase in K562, and G2/M phase of Jurkat cells. Coumestrol, genistein and estradiol induced phagocytosis in all tested cells but daidzein induced significant (p < 0.05) phagocytosis in K562 and Jurkat cells only.ConclusionThe selected phytoestrogens induced cell cycle arrest, apoptosis and phagocytosis and at the same time they reduced ANXA1 level in the tested cells. The IC50 value of phytoestrogens was undetectable at the concentrations tested, their ability to induce leukemic cells death may be related with their ability to reduce the levels of ANXA1. These findings can be used as a new approach in cancer treatment particularly in leukemia.     

白杨素Mannich碱衍生物的合成及其抗癌活性

目的设计合成新型白杨素Mannich碱衍生物,并寻求具有抗癌活性的新化合物。方法利用Baker-Venkataraman重排法完成白杨素的全合成,再与甲醛、胺类进行Mannich缩合反应得到目标化合物。采用MTT法,以5-氟尿嘧啶为阳性对照,评价目标化合物对人宫颈癌细胞(Hela)、人肺腺癌细胞(A549)、人胃癌细胞(SGC-901)、人结肠癌细胞(HCT-116)、人白血病细胞(K562)5种肿瘤细胞的抗癌活性。结果与结论合成了10个未见文献报道的新化合物,其结构经1H-NMR、IR和MS确证。体外抗癌活性实验表明,部分化合物显示出较好的抗癌活性。     

Synthesis and biological evaluation of 4α/4β-imidazolyl podophyllotoxin analogues as antitumor agents

A series of 4α/4β-imidazolyl podophyllotoxin analogues have been designed and synthesized. All of the compounds were evaluated for their anticancer activity against a panel of three human cancer cell lines. Within the cell lines tested, some of the synthesized compounds showed promising anticancer activity. Compound 12, in particular, exhibited remarkable cytotoxicity, demonstrating effects against all tumor cell lines, including the K562/ADM cell line.     

Synthesis and biological evaluation of novel podophyllotoxin analogs as antitumor agents

A series of 4β N-indole-substituted podophyllotoxin derivatives were synthesized. Nine target compounds were evaluated against human cancer cell lines (HeLa, K562, and K562/A02) using MTT assay including three imine derivatives 8, 9, and 10in vitro. The result showed that the three compounds had higher antitumor activity than their reduced forms. Among them, compounds 8, 9, 11, and 16 were superior to the positive control VP-16.     

Synthesis,Antifolate and Anticancer Activities of N5‐Substituted 8,10‐Dideazatetrahydrofolate Analogues

Based on our previous work, seven N⁵‐substituted 8,10‐dideazatetrahydrofolate analogues and one 8‐deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N¹⁰ with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4‐amino and N⁵‐formyl showed great antitumour activities against HL‐60, Bel‐7402 and BGC823 which were much better than MTX.     

薯蓣皂苷元抗肿瘤衍生物的设计、合成与抗肿瘤活性

薯蓣皂苷元对A375、K562等细胞株具有抑制生长并诱导其凋亡的作用。其作用靶点之一是线粒体中的Bcl-2亚家族蛋白。本文以Bcl-2为靶点,运用Autodock设计并合成了一系列全新的薯蓣皂苷元衍生物,希望完善相关化合物的构效关系及提高其抗肿瘤活性。MTT法体外抗肿瘤活性研究结果表明,所设计的化合物大多对K562、A375、A549等3种肿瘤细胞株有较好的抑制作用,而对H293、L02等2种正常细胞株无明显作用。其中,化合物1、6～8对K562表现出了较好的活性(IC50值为1.96～4.35μmol.L-1)。     

Novel Hybrids of Natural Oridonin-Bearing Nitrogen Mustards as Potential Anticancer Drug Candidates

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新的肿瘤耐药相关基因ERGIC-53的研究

目的:研究ERGIC-53基因表达与肿瘤细胞耐药的关系,寻找肿瘤耐药逆转可能的新靶点。方法:采用Northern Blot检测ERGIC-53基因在K562和K562/A02中的表达差异;应用逆转录聚合酶链反应(RT-PCR)检测11种肿瘤敏感及耐药细胞系中ERGIC-53基因的表达;设计合成针对ERGIC-53基因的siRNAs,用脂质体法转染K562和K562/A02细胞,用MTT比色法和流式细胞仪检测其干扰耐药细胞中ERGIC-53基因表达后的细胞对阿霉素的敏感性。结果:ERGIC-53在K562/A02细胞中的表达明显高于亲代K562细胞(P<0.05);6种耐药细胞株中ERGIC-53基因表达的平均值约为亲代敏感细胞的2倍。siRNA转染组与对照组相比,K562/A02细胞对阿霉素的敏感性均有不同程度的提高,且在转染后72h时细胞内阿霉素积累接近其亲代敏感细胞水平。结论:ERGIC-53基因与肿瘤细胞耐药相关,明确该基因参与耐药肿瘤细胞表型的形成。     

Mannich bases of 1,2,4‐triazole‐3‐thione containing adamantane moiety: Synthesis,preliminary anticancer evaluation,and molecular modeling studies

A series of 18 novel N‐Mannich bases derived from 5‐adamantyl‐1,2,4‐triazole‐3‐thione was synthesized and characterized using NMR spectroscopy and X‐ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL‐60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC‐5 compared to cancer cells. The effects of compounds 5b , 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase‐dependent apoptosis, while the anti‐angiogenic effects of 5b , 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.     

Design,Synthesis, and In Vitro Evaluation of Novel 3, 7‐Disubstituted Coumarin Derivatives as Potent Anticancer Agents

Twenty‐seven 3, 7‐disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate‐to‐potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI₅₀) against SN12C, OVCAR, BxPC‐3, KATO‐III, T24, SNU‐1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3‐position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents.