Design,Synthesis and Antitumor Activity of Novel 6,7-Dimethoxyquinazoline Derivatives Containing Diaryl Urea Moiety

A series of 6,7-dimethoxyquinazoline derivatives connected by diaryl urea scaffolds was designed, synthesized and their in vitro antitumor activities were evaluated. Most of them showed an excellent potency against the four tested cancer cell lines as compared with sorafenib. Particularly, a promising compound 20 was identified, which showed the most potent antitumor activities with IC₅₀ values of 0.08, 0.09, 0.16 and 0.19 μmol/L against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The structure-activity relationship(SAR) analysis indicated that compounds with dimethylamino or diethylamino group at the C4 position of 6,7-dimethoxyquinazoline moiety exhibited superior activities than compounds bearing morpholino groups.     

Identification of novel thiourea-stilbene-triazine conjugates as persuasive lymphoid tyrosine phosphatase inhibitors

A library of novel thiourea-based symmetrical stilbene-triazines ( 5a-i ) was synthesized in an effort to develop new protein tyrosine phosphatase LYP inhibitors. The versatile nature of 2,4,6-trichloro-1,3,5-triazine allows considerable scope for derivatization and hence exploration of structure activity relationships. A convenient and versatile three-step synthetic approach involved the successive replacement of the two chloro groups of 2,4,6-trichloro-1,3,5-triazine by a variety of substituents for structural modification. The newly synthesized derivatives were subjected to tyrosine phosphatase LYP inhibition studies. The results for the in vitro bioassays were promising with the identification of compound 5k and 5l having a 4-methyl and 4-methoxy substituent on phenyl ring, as the lead and selective candidate for LYP inhibition with an IC₅₀ value of 2.1 ± 0.05 μM and 28 ± 3.3 μM, respectively. Moreover, docking studies were carried out to determine the possible interaction sites of thiourea-based stilbene-triazine compounds with Lymphoid Tyrosine Phosphatase. Results of docking computations further ascertained the inhibitory potential of compound 5k and 5l . The results indicated that the compound 5k may serve as a structural model for the design of most potent LYP inhibitors.     

N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺的合成及抗肿瘤活性

为进一步发现氟喹诺酮药物向抗肿瘤活性转化的结构修饰新策略,用酰氨基为左氧氟沙星(1)C-3羧基的电子等排体,5-芳苄叉基饶丹宁为其功能修饰基,设计合成了N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺类目标化合物(6a-6n)。 体外抗肿瘤活性结果表明,所合成的14个化合物的活性均强于母体左氧氟沙星,且对正常细胞表现出较低的细胞毒性作用。 构效关系表明,增大芳基取代基的体积或供电性均导致抗肿瘤活性的明显降低,反之,吸电子取代苯基或芳香杂环类目标化合物的抗肿瘤活性强于其他取代基类。 其中,硝基化合物6l、呋喃6m和吡啶6n对人胰腺癌细胞株(Capan-1)的半数抑制浓度(IC₅₀) 与对照抗肿瘤药阿霉素(1.6 μmol/L)相当,分别为1.8、0.8和1.3 μmol/L。 因此,芳苄叉基饶丹宁修饰的酰氨基替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。     

Synthesis,Characterization and Biological Evaluation of Magnolol and Honokiol Derivatives with 1,3,5-Triazine of Metformin Cyclization

Herein, we sought to evaluate the contribution of the 1,3,5-triazine ring through the metformin cyclization unit to the biological activity of magnolol and honokiol-conjugates. One of the phenolic OH groups of magnolol or honokiol was replaced by a 1,3,5-triazine ring to further explore their synthesis and medicinal versatility. In this study, a robust procedure of three steps was adopted for the synthesis of magnolol and honokiol derivatives by alkylation of potassium carbonate with a 1,3,5-triazine ring. To our knowledge, this is the first report to connect one of the phenolic OH positions of magnolol or honokiol to a 1,3,5-triazine ring cyclized by metformin. The structural characterization of three new compounds was carried out via spectroscopic techniques, i.e., ¹³C NMR, ¹H NMR, and HRMS. Surprisingly, these compounds showed no cytotoxicity against RAW 264.7 macrophages but significantly inhibited the proliferation of MCF-7 (human breast cancer cells), HepG2 (human hepatoma cells), A549 (human lung carcinoma cells), and BxPC-3 (human pancreatic carcinoma cells) tumor cell lines. Furthermore, the compounds also significantly inhibited the release of inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in the lipopolysaccharide (LPS)-activated mouse cells (RAW 264.7). Among them, compound 2 demonstrated promising broad-spectrum antiproliferative potential with half inhibitory concentration (IC₅₀) values ranging from 5.57 to 8.74 µM and it significantly decreased caspase-3 and Bcl-2 expression in HepG2 cells. These interesting findings show that derivatization of magnolol and honokiol with 1,3,5-triazine affects and modulates their biological properties.     

sym-triazine derivatives. 9. Reaction of sym-triazines containing trichloromethyl and ethoxycarbonyl groups with phenylhydrazine

Using the example of the reaction of 1,3,5-triazines simultaneously containing trichloromethyl and ethoxycarbonyl substituents with phenylhydrazine, it was shown that the presence of even one ester group leads to ring transformation. Depending on the number of the ester groups in the initial 1,3,5-triazine, the reaction products are either 1,2,4-triazole or 1,2,4-triazine derivatives.For Communication 8, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1655–1664, December, 1990.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

N9位芳基取代嘌呤-8-酮类衍生物的合成及抗肿瘤活性

合成了一系列N9位芳基取代嘌呤-8-酮类衍生物, 利用核磁共振氢谱(¹H NMR)、 核磁共振碳谱(¹³C NMR)和高分辨质谱(HRMS)进行了结构确证. 采用四甲基偶氮唑盐(MTT)法测定了目标化合物的体外抗肿瘤细胞增殖活性. 结果表明, 嘌呤酮环的C2位及N9位的取代对活性有较大影响, C2位引入对位由含氮六元环取代的苯胺, N9位引入对三氟甲基苯均有利于提高抗肿瘤活性. 化合物12c对人白血病细胞(K562)、 人前列腺癌细胞(PC-3)、 人乳腺癌细胞(MDA-MB-231)及人结肠癌细胞(HCT116)的抑制效果明显优于阳性对照药R-Roscovitine.     

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives

Novel pyrimidinyl pyrazole derivatives were synthesized and examined for cytotoxic and antitumor activity. Mannich reaction was employed to construct this scaffold. Among the compounds synthesized, a series of propene derivatives exhibited a potent cytotoxic activity against some tumor cell lines including multidrug resistant cell lines due to the overexpression of P-glycoprotein. The vinyl bond moiety in the scaffold was believed to be required for the cytotoxic activity. Among them, compound 14 g, when administered intraperitoneally, showed potent antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice. This compound also showed high activity against a solid tumor Meth A mouse fibrosarcoma when administered both intraperitoneally and orally.     

Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.     

Synthesis,Characterization and Biological Activity of Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine Derivatives as Epidermal Growth Factor Receptor Inhibitors

Based on the molecular docking studies, which were performed to position Erlotinib and the target compounds into the active site of the epidermal growth factor receptor(EGFR) to determine the probable binding model, a novel series of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as the novel potential EGFR kinase inhibitors was designed and synthesized. The antitumor activity of all the target compounds against human pulmonary carcinoma cell line A549 has been screened. Of all the target compounds, 4-[2-(1-piperidyl)carbonylmethoxyl- phenthio]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine(7j) demonstrated the most potent antitumor activity. Several of the target compounds exhibited moderate antitumor activity. The preliminary structure-activity relationships of some target compounds were summarized.     

The Synthesis and Biological Evaluation of Aloe-Emodin-Coumarin Hybrids as Potential Antitumor Agents

A series of novel aloe-emodin–coumarin hybrids were designed and synthesized. The antitumor activity of these derivatives was evaluated against five human tumor cell lines (A549, SGC-7901, HepG2, MCF-7 and HCT-8). Some of the synthesized compounds exhibited moderate to good activity against one or more cell lines. Particularly, compound 5d exhibited more potent antiproliferative activity than the reference drug etoposide against all tested tumor cell lines, indicating that it had a broad spectrum of antitumor activity and that it may provide a promising lead compound for further development as an antitumor agent by structural modification. Furthermore, the structure–activity relationship study of the synthesized compounds was also performed.     

Synthesis and antitumor activity evaluation of some 1, 2, 4-triazine and fused triazine derivatives

Reactions of 3-hyrazino-5,6-diphenyl-1,2,4-triazine with various carbonyl compounds such as ethyl acetoacetate, acetylacetone, benzoin, isatin, phthalic anhydride, phenyl isocyanate and acetic anhydride were discussed. Its reactions with α, β unsaturated compounds such as arylidinemalononitrile, diethyl acetylenedicarboxylate, dibenzylidine hydrazine were studied. These reactions led to the formation of various triazine and fused-triazine derivatives. The antitumor activity of the synthesized compounds was tested against HePG2 and MCF-7 cell lines. Some of the tested compounds were most active, whereas other compounds exhibited little or no activity.     

Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.     

Synthesis,polarography and herbicidal activity of quaternary salts of 2-(4-pyridyl)-1,3,5-triazines, 5-(4-pyridyl)pyrimidine, 2-(4-pyridyl)pyrimidine and related compounds

2-(4-Pyridyl)-1,3,5-triazine, 2-(4-pyridyl)-4-methyl-1,3,5-triazine, 2-(4-pyridyl)-4,6-dimethyl-1,3,5-triazine and 2-(4-pyridyl)pyrimidine have been prepared by modification of established triazine and pyrimidine syntheses. These compounds and some of their relatives have been converted to quaternary pyridinium salts. The polarographic reduction potentials of the salts in aqueous solution are pH dependent. The activity of the salts as post-emergent herbicides is reported.     

Synthesis and antitumor activity of duocarmycin derivatives: a-ring pyrrole compounds bearing 5-membered heteroarylacryloyl groups.

A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10(2)- to 10(3)-fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC50 < 0.3 nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl] derivatives of 4'-methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'-pyrrolecarboxamide unit.     

Synthesis and antitumor evaluation of symmetrical 1,5-diamidoanthraquinone derivatives as compared to their disubstituted homologues

A series of symmetrical 1,5-diamidoanthraquinone derivatives with potentially bioreducible groups has been synthesized and their cytostatic activity against the panel of various cancer cell lines in vitro has been studied. Preliminary structure-activity relationships were established. The results indicated that compounds 5 and 18 exhibited significant potent cytotoxicity at 1.24-1.75 microM for Hepa G2 cell line; compounds 5, 16, and 18 exhibited cytotoxicity at 0.14-1.82 microM for 2.2.15 cell line as determined by XTT colorimetric assay. Two structurally related compounds, mitoxantrone and adriamycin, were tested in parallel as positive controls. In addition, it was found that compounds 5 and 18 were a more potent and specific human hepatoma cell line than mitoxantrone and showed comparable activity to adriamycin. Among them, compound 18 was the most potent for 2.2.15 cells. We have demonstrated that the anthraquinone moiety is essential for activity and that less sterically hindered substituents contribute to enhanced in vitro efficacy. Implications for amidoanthraquinone cytotoxicity as potential anticancer agents are discussed. We further delineate the nature of the pharmacophore for this class of compounds, which provides a rational basis for the structure-activity relationships.     

均三氮苯类除草剂结构与活性的理论研究

利用Gaussian03程序包中的B3LYP方法,选择6-31G基组对均三氮苯类除草剂及类似衍生物2-(4-溴苄氨基)-4-甲基-6-三氟甲基-1,3,5-三氮苯进行了量子化学计算,从理论上讨论了它们的空间结构、电子结构特征与活性的关系.计算结果表明:三氮苯环与N(7)和N(8)原子形成了共轭结构,分子活性大小与LUMO轨道的得电子能力以及在LUMO轨道中占主要成分的原子有重要关系.N(7)和N(8)连接单个具有推电子能力的基团,有利于生物活性的提高.对于2-(4-溴苄氨基)-4-甲基-6-三氟甲基-1,3,5-三氮苯中,N(8)和C(9)是重要的活性部位,和传统的均三氮苯类除草剂分子相比,与D1蛋白上不同的氨基酸残基发生了键合作用.     

Design, synthesis and antitumor activity of 6,7-disubstituted-4-(heteroarylamino)quinoline-3-carbonitrile derivatives

<正>A series of new 6,7-disubstituted-4-(benzothiazol-6-ylamino)quinoline-3-carbonitrile derivatives(12a-l) were synthesized.The cytotoxicity of 12 new compounds was evaluated in AGS,HepG2 and HT-29 cell lines.The results showed that compounds 12g, 12h,12i,12k and 12l displayed more potent cytotoxic activities than Bosutinib,compound 12l exhibited the most potent antitumor activity among the tested compounds.     

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.