共查询到20条相似文献,搜索用时 31 毫秒
1.
Shingo Dan Mutsumi Okamura Takao Yamori 《Biochemical and biophysical research communications》2009,379(1):104-1599
Phosphoinositide 3-kinase (PI3K) is a potential target in cancer therapy. Inhibition of PI3K is believed to induce apoptosis. We recently developed a novel PI3K inhibitor ZSTK474 with antitumor efficacy. In this study, we have examined the underlying mode of action by which ZSTK474 exerts its antitumor efficacy. In vivo, ZSTK474 effectively inhibited the growth of human cancer xenografts. In parallel, ZSTK474 treatment suppressed the expression of phospho-Akt, suggesting effective PI3K inhibition, and also suppressed the expression of nuclear cyclin D1 and Ki67, both of which are hallmarks of proliferation. However, ZSTK474 treatment did not increase TUNEL-positive apoptotic cells. In vitro, ZSTK474 induced marked G0/G1 arrest, but did not increase the subdiploid cells or activate caspase, both of which are hallmarks of apoptosis. These results clearly indicated that inhibition of PI3K by ZSTK474 did not induce apoptosis but rather induced strong G0/G1 arrest, which might cause its efficacy in tumor cells. 相似文献
2.
Anna C. Giddens Swarna A. Gamage Jackie D. Kendall Woo-Jeong Lee Bruce C. Baguley Christina M. Buchanan Stephen M.F. Jamieson James M.J. Dickson Peter R. Shepherd William A. Denny Gordon W. Rewcastle 《Bioorganic & medicinal chemistry》2019,27(8):1529-1545
Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation. 相似文献
3.
Upul Bandarage Brian Hare Jonathan Parsons Ly Pham Craig Marhefka Guy Bemis Qing Tang Cameron Stuver Moody Steve Rodems Sundeep Shah Chris Adams Jose Bravo Emmanuelle Charonnet Vladimir Savic Jon H. Come Jeremy Green 《Bioorganic & medicinal chemistry letters》2009,19(17):5191-5194
We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki <1 nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3. 相似文献
4.
Estrada-Soto S Villalobos-Molina R Aguirre-Crespo F Vergara-Galicia J Moreno-Díaz H Torres-Piedra M Navarrete-Vázquez G 《Life sciences》2006,79(5):430-435
The relaxant activity of 2-(o, p-substituted phenyl)-1H-benzimidazole derivatives with various 5- and 6-position substituents (-H, -CH3, -NO2, -CF3), namely 1-7, was recorded using the in vitro rat aorta ring test. Compounds 3 and 6 [2-(5-nitro-1H-benzimidazol-2-yl)phenol and 2-(4-methoxyphenyl)-5-nitro-1H-benzimidazole] were prepared using a short route, and were the most potent compounds of the series, showing IC50 value of 0.95 and 1.41 (with endothelium) and 2.01 and 3.61 microM (without endothelium), respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these benzimidazole derivatives should provide novel vasorelaxant leads and possibly against hypertensive diseases. 相似文献
5.
Joel T. Arcari Jean S. Beebe Martin A. Berliner Vincent Bernardo Merin Boehm Gary V. Borzillo Tracey Clark Bruce D. Cohen Richard D. Connell Heather N. Frost Deborah A. Gordon William M. Hungerford Shefali M. Kakar Aaron Kanter Nandell F. Keene Elizabeth A. Knauth Susan D. LaGreca Yong Lu Jinshan M. Chen 《Bioorganic & medicinal chemistry letters》2013,23(10):3059-3063
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models. 相似文献
6.
Pao-Chiung Hong Li-Jung Chen Tzu-Yun Lai Huei-Yu Yang Shih-Jan Chiang Yann-Yu Lu Ping-Kuei Tsai Hung-Yi Hsu Win-Yin Wei Chu-Bin Liao 《Bioorganic & medicinal chemistry letters》2010,20(17):5065-5068
A series of selenophene derivatives 3 were synthesized as potential CHK1 inhibitors. The effects of substitution on the 4′- or 5′-position of selenophene moiety and shifting the hydroxyl group position on C6- phenolic ring of oxindole were explored. This study led to the discovery of the most potent CHK1 inhibitors 29–33 and 39–43, which had IC50 values in the subnanomolar range. 相似文献
7.
ABSTRACT: BACKGROUND: Using novel small-molecular inhibitors, we explored the feasibility of the class I PI3K/Akt/mTORC1 signaling pathway as a therapeutic target in canine oncology either by using pathway inhibitors alone, in combination or combined with conventional chemotherapeutic drugs in vitro. RESULTS: We demonstrate that growth and survival of the cell lines tested are predominantly dependent on class I PI3K/Akt signaling rather than mTORC1 signaling. In addition, the newly developed inhibitors ZSTK474 and KP372-1 which selectively target pan-class I PI3K and Akt, respectively, and Rapamycin which has been well-established as highly specific mTOR inhibitor, decrease viability of canine cancer cell lines. All inhibitors demonstrated inhibition of phosphorylation of pathway members. Annexin V staining demonstrated that KP372-1 is a potent inducer of apoptosis whereas ZSTK474 and Rapamycin are weaker inducers of apoptosis. Simultaneous inhibition of class I PI3K and mTORC1 by ZSTK474 combined with Rapamycin additively or synergistically reduced cell viability whereas responses to the PI3K pathway inhibitors in combination with conventional drug Doxorubicin were cell linedependent. CONCLUSION: This study highlighted the importance of class I PI3K/Akt axis signaling in canine tumour cells and identifies it as a promising therapeutic target. 相似文献
8.
Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells
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Loris Bertazza Susi Barollo Claudia Maria Radu Elisabetta Cavedon Paolo Simioni Diego Faggian Mario Plebani Maria Rosa Pelizzo Beatrice Rubin Marco Boscaro Raffaele Pezzani Caterina Mian 《Journal of cellular and molecular medicine》2015,19(9):2244-2252
Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer‐related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto‐oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3‐kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine‐protein kinase B‐Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET‐mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen‐activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC. 相似文献
9.
Satoshi Endo Dawei Hu Miho Suyama Toshiyuki Matsunaga Kenji Sugimoto Yuji Matsuya Ossama El-Kabbani Kazuo Kuwata Akira Hara Yukio Kitade Naoki Toyooka 《Bioorganic & medicinal chemistry》2013,21(21):6378-6384
Inhibitors of a human member (AKR1B10) of the aldo–keto reductase superfamily are regarded as promising therapeutics for the treatment of cancer. Recently, we have discovered (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) as the potent competitive inhibitor using the virtual screening approach, and proposed its 4-methoxy group on the 2-phenylimino moiety as an essential structural prerequisite for the inhibition. In this study, 18 derivatives of 1 were synthesized and their inhibitory potency against AKR1B10 evaluated. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (5n) was the most potent inhibitor showing a Ki value of 1.3 nM. The structure–activity relationship of the derivatives indicated that the 7-hydroxyl group on the chromene ring, but not the 4-methoxy group, was absolutely required for inhibitory activity, The molecular docking of 5n in AKR1B10 and site-directed mutagenesis of the enzyme residues suggested that the hydrogen-bond interactions between the 7-hydroxyl group of 5n and the catalytic residues (Tyr49 and His111) of the enzyme, together with a π-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition. 相似文献
10.
Xudong Gong Guan Wang Jing Ren Zheng Liu Zhen Wang Tiantian Chen Xiaojun Yang Xiangrui Jiang Jingshan Shen Hualiang Jiang Haji Akber Aisa Yechun Xu Jianfeng Li 《Bioorganic & medicinal chemistry letters》2013,23(17):4944-4947
The substituents both at the 6-position of the 5-bromopyrimidinone ring and at the 5′-position of the phenyl ring of 5-bromopyrimidin-4(3H)-ones were explored. 5-Bromo-6-isopropyl-2-(2-propoxy-phenyl)pyrimidin-4(3H)-one was identified as a new scaffold for potent PDE5 inhibitors. The crystal structures of PDE5/2e and PDE5/10a complexes provided a structural basis for the inhibition of 5-bromopyrimidinones to PDE5. In addition, it was also found that there is a great tolerance for the substitution at the 5′-position of the phenyl ring of 5-bormopyrimidinones and the resulted compound 13a has the highest inhibition activity to PDE5 (IC50, 1.7 nM). 相似文献
11.
William Kemnitzer Jared Kuemmerle Songchun Jiang Nilantha Sirisoma Shailaja Kasibhatla Candace Crogan-Grundy Ben Tseng John Drewe Sui Xiong Cai 《Bioorganic & medicinal chemistry letters》2009,19(13):3481-3484
As a continuation of our efforts to discover and develop the apoptosis inducing 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as potential anticancer agents, we explored substitutions at the 4-, 5-, 6-, 7- and 8-positions of pyrrolo[1,2-a]quinoline. SAR studies showed that substitution at the 6-position by a small group such as Cl resulted in potent compounds. Substitutions at the 5- and 8-positions were tolerated while substitutions at the 4- and 7-position led to inactive compounds. Several compounds, including 2c, 3a, 3b and 3f, were found to be highly active against human breast cancer cells T47D with EC50 values of 0.053–0.080 μM, but much less active against human colon cancer cells HCT116 and hepatocellular carcinoma cancer cells SNU398 in the caspase activation assay. Compound 3f also was found to be highly active with a GI50 value of 0.018 μM against T47D cells in a growth inhibition assay. 相似文献
12.
Hidekazu Tokuhara Yasuhiro Imaeda Yoshiyuki Fukase Koichi Iwanaga Naohiro Taya Koji Watanabe Ray Kanagawa Keisuke Matsuda Yumiko Kajimoto Keiji Kusumoto Mitsuyo Kondo Gyorgy Snell Craig A. Behnke Takanobu Kuroita 《Bioorganic & medicinal chemistry》2018,26(12):3261-3286
We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio. 相似文献
13.
《Bioorganic & medicinal chemistry》2016,24(9):2072-2096
In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified. 相似文献
14.
Wataru Hamaguchi Naoyuki Masuda Mai Isomura Satoshi Miyamoto Shigetoshi Kikuchi Yasushi Amano Kazuya Honbou Takuma Mihara Toshihiro Watanabe 《Bioorganic & medicinal chemistry》2013,21(24):7612-7623
A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1. 相似文献
15.
《Bioorganic & medicinal chemistry》2016,24(2):179-190
In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors. 相似文献
16.
The effect of substituents on the 1,4-benzoquinone ring of ubiquinone on its electron-transfer activity in the bovine heart mitochondrial succinate-cytochrome c reductase region is studied by using synthetic ubiquinone derivatives that have a decyl (or geranyl) side-chain at the 6-position and various arrangements of methyl, methoxy and hydrogen in the 2, 3 and 5 positions of the benzoquinone ring. The reduction of quinone derivatives by succinate is measured with succinate-ubiquinone reductase and with succinate-cytochrome c reductase. Oxidation of quinol derivatives is measured with ubiquinol-cytochrome c reductase. The electron-transfer efficacy of quinone derivatives is compared to that of 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone. When quinone derivatives are used as the electron acceptor for succinate-ubiquinone reductase, the methyl group at the 5-position is less important than are the methoxy groups at the 2- and 3-positions. Replacing the 5-methyl group with hydrogen causes a slight increase in activity. However, replacing one or both of 2- and 3-methoxy groups with a methyl completely abolishes electron-acceptor activity. Replacing the 3-methoxy group with hydrogen results in a complete loss of electron-acceptor activity, while replacing the 2-methoxy with hydrogen results in an activity decrease by 70%, suggesting that the methoxy group at the 3-position is more specific than that at the 2-position. The structural requirements for quinol derivatives to be oxidized by ubiquinol-cytochrome c reductase are less strict. All 1,4-benzoquinol derivatives examined show partial activity when used as electron donors for ubiquinol-cytochrome c reductase. Derivatives that possess one unsubstituted position at 2, 3 or 5, with a decyl group at the 6-position, show substrate inhibition at high concentrations. Such substrate inhibition is not observed when fully substituted derivatives are used. The structural requirements for quinone derivatives to be reduced by succinate-cytochrome c reductase are less specific than those for succinate-ubiquinone reductase. Replacing one or both of the 2- and 3-methoxy groups with a methyl and keeping the 5-position unsubstituted (plastoquinone derivatives) yields derivatives with no acceptor activity for succinate-Q reductase. However, these derivatives are reducible by succinate in the presence of succinate-cytochrome c reductase. This reduction is antimycin-sensitive and requires endogenous ubiquinone, suggesting that these (plastoquinone) derivatives can only accept electrons from the ubisemiquinone radical at the Qi site of ubiquinol-cytochrome c reductase, and cannot accept electrons from the QPs of succinate-ubiquinone reductase. 相似文献
17.
The synthesis and structure-activity relationships of N-phenyl-N'-[3-(4-phenylnaphthylidinoyl)]urea derivatives 3 as a novel structural class of potent ACAT inhibitors is described. A 3-methoxy group substituted on the naphthylidinone 4-phenyl ring, together with a 1-N-(n)butyl substitution, SM-32504 (3m), gave a potent ACAT inhibitor, in vitro, respectively. The most potent compound, SM-32504 (3m), decreased the serum cholesterol level significantly in a high fat and high cholesterol-fed mouse model. 相似文献
18.
《Bioorganic & medicinal chemistry》2016,24(10):2307-2317
New phenothiazine derivatives 6–20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6–8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies. 相似文献
19.
Maria Joao Matos Dolores Viña Carmen Picciau Francisco Orallo Lourdes Santana Eugenio Uriarte 《Bioorganic & medicinal chemistry letters》2009,19(17):5053-5055
A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC50 values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC50 against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(?)-deprenyl (reference compound). 相似文献
20.
Matthias Goebel Gerhard Wolber Patrick Markt Bart Staels Thomas Unger Ulrich Kintscher Ronald Gust 《Bioorganic & medicinal chemistry》2010,18(16):5885-5895
In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARγ activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b–5/6, 3c), phenylcarbonyl (3d–5/6), hydroxy(phenyl)methyl (3g–5/6), hydroxymethyl (3h–5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a–3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARγDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARγ activation. An enhanced effect on PPARγ activation could be observed if lipophilic moieties are introduced in these positions. 4′-[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC50 of 0.26 μM and the profile of a full agonist.Together with compounds of the former structure–activity relationship study (position 2-substituted benzimidazole derivatives 4a–4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments. 相似文献