Design and synthesis of 2-iminothiazolidin-4-one moiety-containing compounds as potent antiproliferative agents

A new series of 2,5‐diaryliminothiazolidin‐4‐ones were designed and synthesized as potent antiproliferative agents. The antiproliferative activities of the 25 target compounds were evaluated against three cancer cell lines (A549, H460 and HT29) by MTT assay. Pharmacological data indicated that most of the compounds possessed moderate activity, some showed remarkable activity against one or more cell lines. As the most promising compound, 8s (with IC₅₀ values of 1.1, 0.01 and 1.3 µM against the A549, H460 and HT29 cell lines) was 1.1‐ to 270‐fold more potent than the reference drug sorafenib. Furthermore, preliminary structure–activity relationships (SARs) were summarized to provide guidance for further design and discovery of 2‐iminothiazolidin‐4‐one‐based antiproliferative agents.     

Design,synthesis, and biological evaluation of novel 4‐phenoxypyridine derivatives as potential antitumor agents

A series of novel 4‐phenoxypyridine derivatives containing the 4‐oxo‐1,4‐dihydropyridazine‐3‐carboxamide moiety were synthesized and evaluated for their in vitro cytotoxic activity against the A549 cancer cell line, and some compounds were further examined for their cytotoxic activity against the H460, BGC823, MKN45, and HT‐29 cancer cell lines. Most of the compounds exhibited moderate to significant cytotoxicity. The most promising compound 15b (with VEGFR2 inhibitory concentration [IC₅₀] value of 0.23 μM) showed remarkable cytotoxicity against A549, BGC‐823, MKN45, H460, and HT‐29 cells, with IC₅₀ values of 0.75, 1.68, 2.63, 5.08 and 7.22 μM, respectively. Their preliminary structure‐activity relationship studies indicate that electron‐withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Moreover, treatment of A549 cells with compound 15b resulted in cell cycle arrest in the G₀/G₁ phase in a dose‐dependent manner. Further apoptotic studies and acridine orange/ethidium bromide staining were also performed on A549 cells, which showed that compound 15b could induce apoptosis. Wound‐healing assay results indicated that compound 15b strongly inhibited A549 cell motility.     

6-取代亚甲肼基-2，4-双吗啉嘧啶及三嗪类衍生物的合成与抗肿瘤活性研究

目的设计合成一系列6-取代亚甲肼基嘧啶及三嗪衍生物,并对其体外抗肿瘤活性进行初步评价。方法以2,4,6-三氯嘧啶或三聚氯氰、苯胺、苯并咪唑、吡咯为起始原料,经多步反应合成目标化合物;采用MTT法,以BMCL-200908069—1为阳性对照药,以H460、A549和H226为测试细胞株,对目标化合物进行抗肿瘤活性评价。结果合成了20个未见文献报道的6-取代亚甲肼基-2,4-双吗啉嘧啶及三嗪类化合物,其结构经MS、1H-NMR谱确证。结论体外活性实验显示：该系列化合物具有较强的抗肿瘤活性,其中,化合物6a活性最佳,其对H460、A549和H226抑制作用的IC50值分别为3．4、0L75、0．86pxnol·L-1,其活性为阳性对照药的28～16．8倍。     

N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物的合成及其抗肿瘤活性研究

目的设计并合成结构新颖的N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物,并对其抗肿瘤活性进行初步评价。方法通过分析索拉菲尼与B-Raf激酶的共结晶模型,在保留其药效团的基础上,设计了16个目标化合物,以吡啶甲酸为原料,经氯代、酯化、取代、还原、氨解及与取代的氨基甲酸苯酯反应制得9个目标化合物;经氯代、氨解、取代及与取代的氨基甲酸苯酯反应得到7个目标化合物;以索拉菲尼为阳性对照,采用MTT法,评价目标化合物对人肺癌细胞株H460、人结肠癌细胞株HT-29和人胃癌细胞株MKN-45增殖的抑制活性。结果与结论部分目标化合物显示出较好的抗肿瘤活性,活性优于或与索拉菲尼相当,其中化合物9b和12f的活性突出。初步构效关系研究表明,末端苯环上取代基的电性效应和取代位置对化合物的活性具有显著影响。     

Synthesis and Biological Evaluation of Novel 6‐Hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐Triazine Derivatives as Potential Antitumor Agents

A series of 6‐hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐triazine derivatives ( 5a – 5l and 8a – 8o ) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for antiproliferative activity against three cancer cell lines (H460, HT‐29, and MDA‐MB‐231). Several potent compounds were further evaluated against two other cell lines (U87MG, H1975). Most of the prepared compounds, particularly compounds 5c and 5j with IC₅₀ values (0.07 and 0.05 µM, respectively) in the nM range, exhibited moderate to excellent antiproliferative activity and high selectivity against the H460 cancer cell line as compared with compound 1 . The most promising compound 5j , possessing a cyano group at the 3‐position of the benzene ring, showed strong antiproliferative activity against H460, HT‐29, and MDA‐MB‐231 cell lines with IC₅₀ values of 0.05, 6.31, and 6.50 µM, which were 4.6‐ to 190.4‐fold more active than compound 1 (9.52, 29.24, and 36.21 µM), respectively.     

Synthesis and anticancer activity of Indolin-2-one derivatives bearing the 4-thiazolidinone moiety

A novel series of indolin‐2‐one derivatives containing the 4‐thiazolidinone moiety ( 5a—5p ) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT‐29, H460 and MDA‐MB‐231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI‐38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT‐29 and H460 cancer cell lines (IC₅₀ = 0.016 µmol/L, 0.0037 µmol/L, respectively).     

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.     

Anti-tumor activity of new artemisinin-chalcone hybrids

In an attempt to develop potent and selective anti‐tumor agents, three new series of artemisinin–chalcone hybrids 10a – 10g , 11a – 11g and 12a–12h were designed, synthesized and screened for their anti‐tumor activity against five cell lines (HT‐29, A549, MDA‐MB‐231, HeLa and H460) in vitro. Among compounds 10a–g and 11a–11g , most of them displayed enhanced activity and good selectivity toward HT‐29 and HeLa cell lines with IC₅₀ values ranging from 0.12 to 0.85 µM as compared with DHA (dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC₅₀ values of 0.12 and 0.19 µM. The results revealed that the presence of chalcone moiety is beneficial to their activity and selectivity. In addition, compounds 12a ‐ 12h containing a ‘reversed chalcone’ moiety showed only slight improvement in activity than those of DHA.     

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.     

吲哚脲类化合物的设计合成及其体外抗肿瘤活性研究

目的以索拉非尼为先导物,设计并合成一系列吲哚脲类化合物,并对其体外抗肿瘤活性进行初步评价。方法以5-硝基吲哚-2-甲酸为起始原料,采用BOP法合成酰胺,再将硝基还原成胺基,最后与异氰酸酯缩合,共3步反应制备目标化合物;采用MTT法评价目标化合物对4种肿瘤细胞株(MX-1、A375、HepG2、Ketr3)的生长抑制作用。结果与结论合成了28个吲哚脲类新化合物,其结构经1H-NMR和HR-MS确证。体外活性结果表明,与索拉非尼相比多数化合物选择性地作用于MX-1细胞株,显示出较强的抑制肿瘤细胞增殖的活性。其中含甲基哌啶的化合物26、30和31抑制MX-1和A375细胞生长的作用显著强于索拉非尼。尤其是化合物31抑制A375细胞增殖的作用是索拉非尼的10倍,对HepG2的抑制活性与索拉非尼相当,IC50值均达到微摩尔级水平,值得进一步研究。     

Design,synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines (A431, HepG2, A549, HT-29 and HEK-293) were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships (SARs) indicated that compounds containing phenyl (piperazin-1-yl) methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC₅₀ values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, Hep G2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.     

Synthesis,pharmacophore modeling,and cytotoxic activity of 2-thioxothiazolidin-4-one derivatives

A series of 2-thioxothiazolidin-4-one derivatives were efficiently synthesized and evaluated for their cytotoxic activity against four tumor cell lines. The synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data. Compound 5c exhibited notable in vitro anticancer activity against HeLa, HT29, A549, and MCF-7 cell lines with IC₅₀ values of 28.3, 24.5, 26.6, and 28.6 µM, respectively. Common pharmacophore model with H bond donor (2), H bond acceptor (3), Hydrophobic (1), and ring aromatic (2) was developed using phase module, and molecular docking of target compounds into the epidermal growth factor receptor kinase revealed important structural information on the plausible binding interactions.     

新型6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂的设计、合成及生物活性研究

基于卡博替尼(cabozantinib)和foretinib的化学结构,通过改变中间链,设计合成了一系列含有哌嗪酰胺的6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂。这些化合物未见文献报道,其结构通过MS和NMR确证。采用酶联免疫吸附测定(ELISA)法和MTT法测定了目标化合物对c-Met的抑制活性和对人结肠癌细胞(HT-29)、人肺癌细胞(H460)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MKN-45)的细胞毒性。结果表明,4-(4-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1b)、4-(3-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1h)和4-(2-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1j)对HT-29、H460、A549和MKN-45细胞的抑制活性明显优于对照药卡博替尼。其中,化合物1h和1j对c-Met具有较强的抑制活性,其IC50值分别为0.007 2和0.009 8 μmol/L。     

4-(甲基苯胺基)-3-氰基喹啉类衍生物的 合成及抗肿瘤活性

目的 设计合成4-(甲基苯胺基)-3-氰基喹啉类衍生物,并对其体外抗肿瘤活性进行初步评价。 方法 以氰乙酸乙酯为起始原料,经多步反应合成目标化合物。采用MTT法,以吉非替尼（gefitinib）为阳性对照药,以A549、HT-29和MDA-MB-231为测试细胞株对目标化合物的抗肿瘤活性进行了评价。 结果 合成了18个新化合物,经1H-NMR、MS和IR确认其结构。体外活性测试结果显示,多数化合物可在较低浓度抑制肿瘤细胞增殖,其中的Ⅶ2、Ⅶ3、Ⅶ6、Ⅶ12、Ⅶ13、Ⅶ15 和 Ⅶ16共7个化合物有显著的抗增殖活性,优于阳性对照药吉非替尼。 结论 体外活性实验表明：4-(甲基苯胺基)-3-氰基喹啉类衍生物作为新型的酪氨酸激酶抑制剂,其构效关系值得进一步研究。     

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.     

新型微管稳定剂吲哚美辛衍生物的合成与抗肿瘤活性研究

目的设计合成一系列吲哚美辛衍生物并测定其体外抗肿瘤和微管蛋白抑制活性。方法以5-甲氧基-2-甲基-3-吲哚乙酸为起始原料经两步酰化反应合成12个化合物,MTT法检测目标化合物对HT29、A549、Hep-2、MCF-7肿瘤细胞的抑制活性,同时采用浊度法评价其体外微管蛋白的抑制作用。结果 12种目标化合物均呈现了优于吲哚美辛的体外抗肿瘤作用和微管蛋白抑制活性,其中3位羧基侧链苯乙基取代的化合物12作用于人结肠癌细胞HT29的IC_(50)(2.2μmol)为吲哚美辛的400倍,并且可以干扰微管聚合,其作用于微管蛋白的IC_(50)为5.6μmol。结论改变吲哚美辛1位酰胺和3位羧酸侧链所得的系列衍生物是一类新型的以微管为靶点的抗肿瘤候选药物。     

Evaluation of cytotoxicity of new trans-palladium(II) complex in human cells in vitro

Studies of cytotoxicity allow to elucidate the mechanisms by which chemical compounds influence cells and tissues. On the basis of the structural analogy between platinum(II) and palladium(II) complexes, a variety of studies on palladium(II) compounds as potential anticancer drugs have been carried out (1, 2). The cytotoxicity was evaluated by MTT assay. Abilities of trans-palladium(II) complex containing diethyl (pyridin-2-ylmethyl)phosphates as non-leaving ligands (trans-[PdCl2(2-pmOpe 2)]) to induce apoptosis and necrosis in normal lymphocytes, A549 cells and HT29 cell lines were performed by use of fluorochrome staining. The obtained results revealed, that the new trans-palladium(II) complex was more cytotoxic against A549 and HT29 tumor cells than on the normal lymphocytes in vitro. The novel complex induces apoptosis in all tested cells, but in lymphocytes to a lesser degree. The compound tested also induced significant amounts of necrotic cells, which exceeded the level of apoptotic cell fractions. The results demonstrate that the trans-Pd(II) complex showed substantial cytotoxic activity against A549 and HT29 tumor cells and indicate that the new trans-palladium(II) complex effectively inhibited cancer cells growth.     

通过碳碳双键连接的吲哚-2-酮与喹唑啉-4（3H）-酮杂合物的合成与抗肿瘤活性评价

通过2-甲基4-氧代喹唑啉-6-甲醛与不同的吲哚-2-酮的缩合反应,制备了一系列吲哚-2-酮与喹唑啉-4（3H）-酮的杂合物5a-j。MTT法测试结果表明,只有化合物5e对人肿瘤细胞A549、MCF-7、HeLa、HT-29和HCT-116表现出一定的细胞毒活性,50μM浓度下的抑制率为32．0％-62．3％。     

Synthesis of novel thiazolyl-pyrimidines and their anticancer activity in vitro

A series of novel compounds 7-43 were prepared via the condensation of enaminones 4a-h and the guanidines carbonate 6a-f. The structures of these newly synthesized compounds were confirmed by (1) H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9 and 30 exhibited more efficient activity against Ishikawa, A549.     

4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其 抗肿瘤活性研究

目的 设计合成一系列4,6-双苯基-2-氨基-3-氰基吡啶类化合物,并对其体外抗肿瘤活性进行初步评价。方法 以取代苯甲醛、取代苯乙酮、丙二腈和醋酸铵为原料,经一步反应制得目标化合物。采用MTT法,以 MX-58151 为阳性对照药,以 A549、HT-29 和 SMMC-7721为测试细胞株对目标化合物进行体外抗肿瘤活性评价。 结果与结论 合成了13 个未见报道的4,6-双苯基-2-氨基-3-氰基吡啶类化合物, 其结构经¹H-NMR、MS 和 IR 谱确证。体外活性测试结果显示,多数化合物能够在较低的浓度下抑制肿瘤细胞增殖。其中,2-氨基-6-（4-氟苯基）-4-（2,3,4-三甲氧基苯基）-3-氰基吡啶 具有显著的抗肿瘤细胞增殖活性,IC₅₀值达纳摩尔级水平,明显优于阳性对照药MX-58151。