Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold.


:In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025 μM and 0.49 μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50 = 1.7 nM) and EGFRL858R/T790M (IC50 = 23.3 nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50 mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.


Bioorg Med Chem


Zhang H,Wang J,Zhao HY,Yang XY,Lei H,Xin M,Cao YX,Zhang SQ




Has Abstract


2018-07-23 00:00:00














  • Retinoic acid signaling pathways in development and diseases.

    abstract::Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retino...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Das BC,Thapa P,Karki R,Das S,Mahapatra S,Liu TC,Torregroza I,Wallace DP,Kambhampati S,Van Veldhuizen P,Verma A,Ray SK,Evans T

    更新日期:2014-01-15 00:00:00

  • A prenylbisabolane with NF-kappaB inhibiting properties from Cascarilla (Croton eluteria).

    abstract::Investigation of the bark of Croton eluteria Bennett for biologically active compounds has led to the isolation of the new prenylbisabolane 3, whose structure was assessed by spectroscopic methods. The corresponding known enone 4 and the eudesmane sesquiterpene 2 were also obtained. Compound 3 proved active in selecti...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Campagnuolo C,Fattorusso E,Petrucci F,Taglialatela-Scafati O,Appendino G,Marquez N,Muñoz E

    更新日期:2005-07-01 00:00:00

  • Interactions between 1-benzoyl-4-p-chlorophenyl thiosemicarbazide and serum albumin: investigation by fluorescence spectroscopy.

    abstract::The interactions between 1-benzoyl-4-p-chlorphenyl thiosemicarbazide (BCPT) and bovine serum albumin (BSA) or human serum albumin (HSA) have been studied by fluorescence spectroscopy. By the analysis of fluorescence spectrum and fluorescence intensity, it was showed that BCPT has a strong ability to quench the intrins...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cui FL,Fan J,Li JP,Hu ZD

    更新日期:2004-01-02 00:00:00

  • A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies.

    abstract::A series of new Luotonin A derivatives with substituents at rings A and E was synthesized, together with some E-ring-unsubstituted derivatives. Subsequently, the compound library was examined in silico for their binding into a previously proposed site in the DNA/topoisomerase I binary complex. Whereas no convincing co...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ibric A,Battisti V,Deckardt S,Haller AV,Lee C,Prötsch C,Langer T,Heffeter P,Schueffl HH,Marian B,Haider N

    更新日期:2020-05-01 00:00:00

  • 1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

    abstract::Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the termi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Mokrosz MJ,Bojarski AJ,Duszyńska B,Tatarczyńska E,Kłodzińska A,Dereń-Wesołek A,Charakchieva-Minol S,Chojnacka-Wójcik E

    更新日期:1999-02-01 00:00:00

  • 3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents.

    abstract::The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 b...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shaw AY,Liau HH,Lu PJ,Yang CN,Lee CH,Chen JY,Xu Z,Flynn G

    更新日期:2010-05-01 00:00:00

  • Synthesis, structure, molecular docking, and structure-activity relationship analysis of enamines: 3-aryl-4-alkylaminofuran-2(5H)-ones as potential antibacterials.

    abstract::Thirty-one 3-aryl-4-alkylaminofuran-2(5H)-ones were designed, prepared and tested for their antibacterial activity. Some of them showed significant antibacterial activity against Gram-positive organisms, especially against Staphylococcus aureus ATCC 25923, but all were inactive against Gram-negative organisms. Out of ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Xiao ZP,He XB,Peng ZY,Xiong TJ,Peng J,Chen LH,Zhu HL

    更新日期:2011-03-01 00:00:00

  • Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.

    abstract::DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on compu...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li D,Yuan Z,Chen S,Zhang C,Song L,Gao C,Chen Y,Tan C,Jiang Y

    更新日期:2017-07-01 00:00:00

  • Synthesis of amino acid derived seven-membered lactams by RCM and their evaluation against HIV protease.

    abstract::A versatile synthesis of hydroxylated and epoxy 1-azepin 2-ones substituted at N1, C-3 and C-4 or C-7 has been developed. The sequence involves ring-closing metathesis of an amino acid derived diene amide, followed by either epoxidation or dihydroxylation, of the resulting alkene. Assay of the product epoxides (10, 18...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zaman S,Campaner P,Abell AD

    更新日期:2006-12-15 00:00:00

  • Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives.

    abstract::The inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with some novel glycine and phenylalanine sulfonamide derivatives were investigated. Newly synthesized compounds G1-4 and P1-4 showed effective inhibition profiles with KI values in the range of 14.66-315μM for hCA I and of 18.31-143.8μM again...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fidan İ,Salmas RE,Arslan M,Şentürk M,Durdagi S,Ekinci D,Şentürk E,Coşgun S,Supuran CT

    更新日期:2015-12-01 00:00:00

  • Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses.

    abstract::Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of pol...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Carney DW,Nelson CD,Ferris BD,Stevens JP,Lipovsky A,Kazakov T,DiMaio D,Atwood WJ,Sello JK

    更新日期:2014-09-01 00:00:00

  • Synthesis and anticonvulsant activity of new N-Mannich bases derived from 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones. Part II.

    abstract::Synthesis and anticonvulsant activity of new N-Mannich bases of 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones have been described. Initial anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetr...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Obniska J,Rzepka S,Kamiński K

    更新日期:2012-08-01 00:00:00

  • Click synthesis of estradiol-cyclodextrin conjugates as cell compartment selective estrogens.

    abstract::Cyclodextrin (CD) is a well known drug carrier and excipient for enhancing aqueous solubility. CDs themselves are anticipated to have low membrane permeability because of relatively high hydrophilicity and molecular weight. CD derivatization with 17-beta estradiol (E(2)) was explored extensively using a number of diff...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kim HY,Sohn J,Wijewickrama GT,Edirisinghe P,Gherezghiher T,Hemachandra M,Lu PY,Chandrasena RE,Molloy ME,Tonetti DA,Thatcher GR

    更新日期:2010-01-15 00:00:00

  • Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity.

    abstract::1α,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compound...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Anami Y,Sakamaki Y,Itoh T,Inaba Y,Nakabayashi M,Ikura T,Ito N,Yamamoto K

    更新日期:2015-11-15 00:00:00

  • Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors.

    abstract::The ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) receptor has been successfully substituted with a rigid methanocarba ring system, leading to the conclusion that the North (N) ring conformation is preferred in receptor binding. Similarly, at P2Y(2) and P2Y(4) receptors, nucleotides ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ohno M,Costanzi S,Kim HS,Kempeneers V,Vastmans K,Herdewijn P,Maddileti S,Gao ZG,Harden TK,Jacobson KA

    更新日期:2004-11-01 00:00:00

  • Structural advantage of dendritic poly(L-lysine) for gene delivery into cells.

    abstract::This study aimed to investigate the relationships between structures of gene carrier molecules and their activities for gene delivery into cells. We compared 2 types of poly(L-lysine) as carriers, that is, dendritic poly(L-lysine) (KG6) and linear poly(L-lysine) (PLL). KG6 formed a neutral DNA complex, and its DNA com...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yamagata M,Kawano T,Shiba K,Mori T,Katayama Y,Niidome T

    更新日期:2007-01-01 00:00:00

  • Use of a deoxynojirimycin-fluorophore conjugate as a cell-specific imaging probe targeting α-glucosidase on cell membranes.

    abstract::Molecules designed for cell-specific imaging were studied, taking advantage of an enzyme-inhibitor interaction. 1-Deoxynojirimycin (DNJ) can be actively captured by cells which express the surface membrane protein α-glucosidase. New probes composed of DNJ for recognition linked to a fluorophore signal portion were pre...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hatano A,Kanno Y,Kondo Y,Sunaga Y,Umezawa H,Fukui K

    更新日期:2019-03-01 00:00:00

  • Synthesis and binding mode of heterocyclic analogues of suramin inhibiting the human basic fibroblast growth factor.

    abstract::The design, synthesis, and biological evaluation of a series of pyrrole and pyrazole congeners 2 of suramin, directed toward the development and identification of new ligands that complex the human fibroblast growth factor (bFGF), thereby inhibiting tumor-promoted angiogenesis, is reported. Compounds 2 were evaluated ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Manetti F,Cappello V,Botta M,Corelli F,Mongelli N,Biasoli G,Borgia AL,Ciomei M

    更新日期:1998-07-01 00:00:00

  • Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold.

    abstract::As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius sp...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Choomuenwai V,Andrews KT,Davis RA

    更新日期:2012-12-15 00:00:00

  • The structural basis for kainoid selectivity at AMPA receptors revealed by low-mode docking calculations.

    abstract::The kainoids are a class of excitatory and excitotoxic pyrrolidine dicarboxylates that act at ionotropic glutamate receptors. The kainoids bind kainate receptors with high affinity and, while binding affinity is lower at AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, they are active in func...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Carcache LM,Rodriguez J,Rein KS

    更新日期:2003-02-20 00:00:00

  • Synthesis and properties of triplex-forming oligonucleotides containing 2'-O-(2-methoxyethyl)-5-(3-aminoprop-1-ynyl)-uridine.

    abstract::2'-O-(2-Methoxyethyl)-5-(3-aminoprop-1-ynyl)-uridine phosphoramidite (MEPU) has been synthesized from d-ribose and 5-iodouracil and incorporated into triplex-forming oligonucleotides (TFOs) by automated solid-phase oligonucleotide synthesis. The TFOs gave very high triplex stability with their target duplexes as measu...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lou C,Xiao Q,Brennan L,Light ME,Vergara-Irigaray N,Atkinson EM,Holden-Dye LM,Fox KR,Brown T

    更新日期:2010-09-01 00:00:00

  • Synthesis and initial PET imaging of new potential dopamine D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides.

    abstract::D3 receptor radioligands (E)-4,3,2-[11C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-[11C]MMC, [11C]1a; 3-[11C]MMC, [11C]1b; and 2-[11C]MMC, [11C]1c) were synthesized for evaluation as novel potential positron emission tomography (PET) imaging agents for brain D3 receptors. The new tracers 4...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gao M,Mock BH,Hutchins GD,Zheng QH

    更新日期:2005-11-15 00:00:00

  • Design and synthesis of labeled analogs of PhTX-56, a potent and selective AMPA receptor antagonist.

    abstract::Polyamines and polyamine toxins are biologically important molecules, having modulatory effects on nucleotides and proteins. The wasp toxin, philanthotoxin-433 (PhTX-433), is a non-selective and uncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine recepto...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Andersen TF,Vogensen SB,Jensen LS,Knapp KM,Strømgaard K

    更新日期:2005-09-01 00:00:00

  • Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy.

    abstract::Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gao Z,Hurst WJ,Hall D,Hartung R,Reynolds W,Kang J,Nagorny R,Hendrix JA,George PG

    更新日期:2015-02-01 00:00:00

  • Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity.

    abstract::Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 c...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tripathi A,Fornabaio M,Kellogg GE,Gupton JT,Gewirtz DA,Yeudall WA,Vega NE,Mooberry SL

    更新日期:2008-03-01 00:00:00

  • Cell surface biotinylation by azaelectrocyclization: easy-handling and versatile approach for living cell labeling.

    abstract::Versatile method for living cell labeling has been established. Cell surfaces are initially biotinylated by azaelectrocyclization, and then treated with the fluorescence-labeled avidin or the anti-biotin antibody. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tanaka K,Yokoi S,Morimoto K,Iwata T,Nakamoto Y,Nakayama K,Koyama K,Fujiwara T,Fukase K

    更新日期:2012-03-15 00:00:00

  • Bacterial biofilm formation inhibitory activity revealed for plant derived natural compounds.

    abstract::Use of herbal plant remedies to treat infectious diseases is a common practice in many countries in traditional and alternative medicine. However to date there are only few antimicrobial agents derived from botanics. Based on microbiological screening tests of crude plant extracts we identified four compounds derived ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Artini M,Papa R,Barbato G,Scoarughi GL,Cellini A,Morazzoni P,Bombardelli E,Selan L

    更新日期:2012-01-15 00:00:00

  • A novel library of saccharin and acesulfame derivatives as potent and selective inhibitors of carbonic anhydrase IX and XII isoforms.

    abstract::Small libraries of N-substituted saccharin and N-/O-substituted acesulfame derivatives were synthesized and tested as atypical and selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC Most of them inhibited hCA XII in the low nanomolar range, hCA IX with KIs ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Carradori S,Secci D,De Monte C,Mollica A,Ceruso M,Akdemir A,Sobolev AP,Codispoti R,De Cosmi F,Guglielmi P,Supuran CT

    更新日期:2016-03-01 00:00:00

  • 3-(1-piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels.

    abstract::3-(4-Piperidinyl)-5-arylpyrazoles, such as 1, were selective for the cloned human dopamine D4 receptor (hD4), but also showed affinity at voltage sensitive calcium, sodium and potassium ion channels. A combination of substituent changes to reduce the basicity of the piperidine nitrogen and conformational restriction t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Collins I,Rowley M,Davey WB,Emms F,Marwood R,Patel S,Patel S,Fletcher A,Ragan IC,Leeson PD,Scott AL,Broten T

    更新日期:1998-06-01 00:00:00

  • Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[e][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation.

    abstract::A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-positio...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Saifuzzaman M,Morrison R,Zheng Z,Orive S,Hamilton J,Thompson PE,Al-Rawi JMA

    更新日期:2017-10-15 00:00:00