当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

Abstract：

:PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Yan G,Pu C,Lan S,Zhong X,Zhou M,Hou X,Yang J,Shan H,Zhao L,Li R

doi

10.1016/j.ejmech.2019.06.021

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

667-686

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30546-X

journal_volume

178

pub_type

杂志文章

相关文献

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.

    abstract：:The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.01.024

    authors： Patel KN,Telvekar VN

    更新日期：2014-03-21 00:00:00

  • Synthesis, antibacterial evaluation and QSAR studies of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone derivatives.

    abstract：:A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolones (I-XXI) were synthesized using an appropriate synthetic route and characterized by elemental and spectral analysis. The antibacterial activities of all the synthesized compounds were evaluated against identifiable bacterial strains. Compounds III, ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2011.04.035

    authors： Kumar R,Kumar A,Jain S,Kaushik D

    更新日期：2011-09-01 00:00:00

  • The photodynamic activities of dimethyl 131-[2-(guanidinyl)ethylamino] chlorin e6 photosensitizers in A549 tumor.

    abstract：:Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their effi...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.05.050

    authors： Gao YH,Lovreković V,Kussayeva A,Chen DY,Margetić D,Chen ZL

    更新日期：2019-09-01 00:00:00

  • Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin.

    abstract：:In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.07.027

    authors： Zuma NH,Smit FJ,de Kock C,Combrinck J,Smith PJ,N'Da DD

    更新日期：2016-10-21 00:00:00

  • Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.

    abstract：:We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitutio...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.11.001

    authors： Ouach A,Pin F,Bertrand E,Vercouillie J,Gulhan Z,Mothes C,Deloye JB,Guilloteau D,Suzenet F,Chalon S,Routier S

    更新日期：2016-01-01 00:00:00

  • Synthesis and biochemical evaluation of guanidino-alkyl-ribitol derivatives as nucleoside hydrolase inhibitors.

    abstract：:Nucleoside hydrolase (NH) is a key enzyme in the purine salvage pathway. The purine specificity of the IAG-NH from Trypanosoma vivax is at least in part due to cation-pi-stacking interactions. Guanidinium ions can be involved in cation-pi-stacking interactions, therefore a series of guanidino-alkyl-ribitol derivatives...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2007.03.027

    authors： Goeminne A,McNaughton M,Bal G,Surpateanu G,Van Der Veken P,De Prol S,Versées W,Steyaert J,Haemers A,Augustyns K

    更新日期：2008-02-01 00:00:00

  • Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor.

    abstract：:While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0223-5234(02)01335-1

    authors： He Y,Yin D,Perera M,Kirkovsky L,Stourman N,Li W,Dalton JT,Miller DD

    更新日期：2002-08-01 00:00:00

  • Synthesis and preliminary in vitro biological evaluation of 7α-testosterone-chlorambucil hybrid designed for the treatment of prostate cancer.

    abstract：:The synthesis of 7α-testosterone-chlorambucil hybrid is reported. This compound is made from testosterone in a 6 step reaction sequence and with 23% overall yield. An alternative convergent reaction sequence yielded the same hybrid through a Grubbs metathesis reaction between chlorambucil allyl ester and 7α-allyltesto...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.04.027

    authors： Bastien D,Hanna R,Leblanc V,Asselin É,Bérubé G

    更新日期：2013-06-01 00:00:00

  • 1,2,3-Triazolyl ester of Ketorolac: A "Click Chemistry"-based highly potent PAK1-blocking cancer-killer.

    abstract：:An old anti-inflammatory/analgesic drug called Toradol is a racemic form of Ketorolac (50% R-form and 50% S-form) that blocks the oncogenic RAC-PAK1-COX-2 (cyclooxygenase-2) signaling, through the direct inhibition of RAC by the R-form and of COX-2 by the S-form, eventually down-regulating the production of prostaglan...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.11.038

    authors： Nguyen BCQ,Takahashi H,Uto Y,Shahinozzaman MD,Tawata S,Maruta H

    更新日期：2017-01-27 00:00:00

  • Heterodimeric Rifampicin-Tobramycin conjugates break intrinsic resistance of Pseudomonas aeruginosa to doxycycline and chloramphenicol in vitro and in a Galleria mellonella in vivo model.

    abstract：:Intrinsic resistance in Pseudomonas aeruginosa, defined by chromosomally encoded low outer membrane permeability and constitutively over-expressed efflux pumps, is a major reason why the pathogen is refractory to many antibiotics. Herein, we report that heterodimeric rifampicin-tobramycin conjugates break this intrins...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.04.034

    authors： Idowu T,Arthur G,Zhanel GG,Schweizer F

    更新日期：2019-07-15 00:00:00

  • Synthesis and evaluation of fatty acyl ester derivatives of cytarabine as anti-leukemia agents.

    abstract：:Cytarabine is a chemotherapeutic agent predominately used for the treatment of acute myeloid leukemia and lymphoblastic leukemia. Cytarabine is a polar nucleoside, has a short plasma half-life, and its use is associated with severe side effects. Fatty acyl derivatives of cytarabine were synthesized with the expectatio...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2010.07.024

    authors： Chhikara BS,Mandal D,Parang K

    更新日期：2010-10-01 00:00:00

  • In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors.

    abstract：:Inhibition data on rat monoamine oxidase B isoform of a large number of 7-metahalobenzyloxy-2H-chromen-2-one derivatives (67 compounds) carrying at position 4 a variety of substituents differing in steric, electrostatic, lipophilic and H-bonding properties, were modeled by Gaussian field-based 3D-QSAR and docking simu...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.10.029

    authors： Pisani L,Farina R,Nicolotti O,Gadaleta D,Soto-Otero R,Catto M,Di Braccio M,Mendez-Alvarez E,Carotti A

    更新日期：2015-01-07 00:00:00

  • Antiproliferative effect of novel platinum(II) and palladium(II) complexes on hepatic tumor stem cells in vitro.

    abstract：:Novel platinum and palladium complexes with (2-isopropoxyphenyl)dicyclohexylarsine and (2-methoxyphenyl)dicyclohexylarsine ligands were synthesized and tested on different tumor cells. Adducts with general formula MX(2)L(2) (M = Pt(II), Pd(II); X = Cl or I; L = organoarsenic ligand) were fully characterized. According...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2011.12.001

    authors： Miklášová N,Fischer-Fodor E,Lönnecke P,Tomuleasa CI,Virag P,Schrepler MP,Mikláš R,Dumitrescu LS,Hey-Hawkins E

    更新日期：2012-03-01 00:00:00

  • Post-docking virtual screening of diverse binding pockets: comparative study using DOCK, AMMOS, X-Score and FRED scoring functions.

    abstract：:Most of the benchmark studies on docking-scoring methods reported in the last decade conclude that no single scoring function performs well across different protein targets. In this study a comparison of thirteen commonly used force field and empirical scoring functions as implemented in DOCK, AMMOS, X-Score and FRED ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2009.12.025

    authors： Pencheva T,Soumana OS,Pajeva I,Miteva MA

    更新日期：2010-06-01 00:00:00

  • Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death.

    abstract：:Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high t...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2017.02.026

    authors： da Silva EB,Oliveira E Silva DA,Oliveira AR,da Silva Mendes CH,Dos Santos TA,da Silva AC,de Castro MC,Ferreira RS,Moreira DR,Cardoso MV,de Simone CA,Pereira VR,Leite AC

    更新日期：2017-04-21 00:00:00

  • Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation.

    abstract：:Tumor immunotherapy has made great progress in recent years. In the tumor microenvironment, the binding of PD-1 and its ligand PD-L1 can promote tumor immune escape and tumor survival. Clinical studies have indicated that antibodies blocking PD-1 and PD-L1 have reliable effects on many advanced malignant tumors. Howev...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2021.113170

    authors： Pan C,Yang H,Lu Y,Hu S,Wu Y,He Q,Dong X

    更新日期：2021-01-09 00:00:00

  • Synthesis and pharmacological evaluation of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazole derivatives as anti-inflammatory and analgesic agents.

    abstract：:A series of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazole derivatives have been synthesized. The structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass spectral data and elemental analyses. Compounds were evaluated for their anti-inflammatory and analgesic activity as well as gastri...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2010.01.067

    authors： Gaba M,Singh D,Singh S,Sharma V,Gaba P

    更新日期：2010-06-01 00:00:00

  • ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.

    abstract：:Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-β (Aβ). Therefore, an alternative strategy in AD drug design is ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2020.112997

    authors： Liu Z,Zhang B,Xia S,Fang L,Gou S

    更新日期：2020-11-06 00:00:00

  • Model for high-throughput screening of drug immunotoxicity--study of the anti-microbial G1 over peritoneal macrophages using flow cytometry.

    abstract：:Quantitative Structure-Activity (mt-QSAR) techniques may become an important tool for prediction of cytotoxicity and High-throughput Screening (HTS) of drugs to rationalize drug discovery process. In this work, we train and validate by the first time mt-QSAR model using TOPS-MODE approach to calculate drug molecular d...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.08.035

    authors： Tenorio-Borroto E,Peñuelas-Rivas CG,Vásquez-Chagoyán JC,Castañedo N,Prado-Prado FJ,García-Mera X,González-Díaz H

    更新日期：2014-01-24 00:00:00

  • Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives.

    abstract：:Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined thro...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.07.016

    authors： An L,Han LL,Zheng YG,Peng XN,Xue YS,Gu XK,Sun J,Yan CG

    更新日期：2016-11-10 00:00:00

  • Concise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative activity against HCT-116 and HL-60 cells.

    abstract：:We report a convenient synthesis of carbazole-1,4-quinone alkaloid koeniginequinones A and B using a tandem ring-closing metathesis with the dehydrogenation reaction sequence under an O2 atmosphere as an important step. Using this method, carbazole-1,4-quinones substituted at the 5-, 6-, 7-, and/or 8-positions have be...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.05.065

    authors： Nishiyama T,Hatae N,Yoshimura T,Takaki S,Abe T,Ishikura M,Hibino S,Choshi T

    更新日期：2016-10-04 00:00:00

  • Synthesis and biological evaluation of novel C-indolylxylosides as sodium-dependent glucose co-transporter 2 inhibitors.

    abstract：:Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure-activity relationship studies revealed that substituents at the...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2012.06.053

    authors： Yao CH,Song JS,Chen CT,Yeh TK,Hsieh TC,Wu SH,Huang CY,Huang YL,Wang MH,Liu YW,Tsai CH,Kumar CR,Lee JC

    更新日期：2012-09-01 00:00:00

  • New diarylamides and diarylureas possessing 8-amino(acetamido)quinoline scaffold: synthesis, antiproliferative activities against melanoma cell lines, kinase inhibition, and in silico studies.

    abstract：:Synthesis of a new series of diarylureas and diarylamides possessing 4-aryl-8-amino(acetamido)quinoline scaffold is described. Their in vitro antiproliferative activities against ten melanoma cell lines were tested. Compounds 1l, 2l, 3c, and 4c showed the highest potency against A375P cell line with IC50 values in sub...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.06.060

    authors： Koh EJ,El-Gamal MI,Oh CH,Lee SH,Sim T,Kim G,Choi HS,Hong JH,Lee SG,Yoo KH

    更新日期：2013-01-01 00:00:00

  • Synthesis and in vitro and in vivo biological evaluation of novel derivatives of flexicaulin A as antiproliferative agents.

    abstract：:As our research focuses on anticancer drugs, a series of novel derivatives of flexicaulin A (FA), an ent-kaurene diterpene, condensed with an aromatic ring were synthesized, and their antiproliferative activities against four human cancer cell lines (TE-1, EC109, MCF-7, and MGC-803) were evaluated. The activities of m...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2020.112789

    authors： Huo JF,Hu TX,Dong YL,Zhao JZ,Liu XJ,Li LL,Zhang XY,Li YF,Liu HM,Ke Y,Wang C

    更新日期：2020-12-15 00:00:00

  • Pharmacological activity and hydrolysis behavior of novel ibuprofen glucopyranoside conjugates.

    abstract：:Novel ester prodrugs (II, III and IV) of ibuprofen (I) were synthesized using alpha-methyl, ethyl and propyl glucopyranoside as promoieties and tested for their anti-inflammatory, analgesic and ulcerogenic activities. Study of their chemical hydrolysis in aqueous buffer (pH 3.0-10.0) showed that these compounds acted ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2006.05.014

    authors： Zhao X,Tao X,Wei D,Song Q

    更新日期：2006-11-01 00:00:00

  • Platanic acid: A new scaffold for the synthesis of cytotoxic agents.

    abstract：:Thirty-seven different derivatives (2-38) have been prepared from platanic acid, a natural occurring triterpenoid. Main emphasis was the introduction of several N-containing functional groups such as amines, amides and oximes and their screening for cytotoxic activity employing several human tumor cell lines using SRB...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2017.11.046

    authors： Kahnt M,Heller L,Grabandt P,Al-Harrasi A,Csuk R

    更新日期：2018-01-01 00:00:00

  • Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity.

    abstract：:Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2010.10.032

    authors： Maggio B,Raimondi MV,Raffa D,Plescia F,Cascioferro S,Plescia S,Tolomeo M,Di Cristina A,Pipitone RM,Grimaudo S,Daidone G

    更新日期：2011-01-01 00:00:00

  • Synthesis and in vitro antitumor activity of new series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives.

    abstract：:New series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives were synthesized and characterized by analytical and spectrometrical methods (IR, HRMS, (1)H and (13)C NMR). Nineteen of the synthesized compounds were selected by the National Cancer Institute (NCI), USA, to be screened for their antitumor activ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.07.097

    authors： Gabr MT,El-Gohary NS,El-Bendary ER,El-Kerdawy MM

    更新日期：2014-10-06 00:00:00

  • Synthesis and antibacterial study of unsaturated Mannich ketones.

    abstract：:Several Mannich ketones of 2-arylmethylenecycloalkanones were synthesised using the classical acid-catalysed Mannich reaction. Antibacterial activity of these new water-soluble compounds was reported against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus saprophyticus, Micrococcus lute...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0223-5234(01)01264-8

    authors： Lóránd T,Kocsis B,Sohár P,Nagy G,Kispál G,Krane HG,Schmitt H,Weckert E

    更新日期：2001-09-01 00:00:00

  • Synthesis of polyfluoroalkyl sp2-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies.

    abstract：:Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine sto...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.111604

    authors： Sánchez-Fernández EM,García-Moreno MI,Arroba AI,Aguilar-Diosdado M,Padrón JM,García-Hernández R,Gamarro F,Fustero S,Sánchez-Aparicio JE,Masgrau L,García Fernández JM,Ortiz Mellet C

    更新日期：2019-11-15 00:00:00