- Discovery of potent small molecule PROTACs targeting mutant EGFR
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Epidermal growth factor receptor (EGFR) is an important therapeutic target for the treatment of non-small cell lung cancer. A number of efficacious EGFR tyrosine kinase inhibitors have been developed. However, acquired drug resistance largely encumbered their clinical practicability. Therefore, there is an urgent need to develop new therapeutic regime. Herein, we designed and synthesized a set of EGFR-targeting small molecule PROTACs which showed promising efficacy. In particular, VHL-recruiting compound P3 showed potent anti-proliferative activity against HCC827 and H1975 cell lines with IC50 values of 0.83 and 203.01 nM, respectively. Furthermore, both EGFRdel19 and EGFRL858R/T790M could be significantly induced to be degraded under treatment of P3 with DC50 values of 0.51 and 126.2 nM, respectively. Compound P3 was able to dramatically suppress EGFR pathway signal transduction. Moreover, compound P3 could significantly induce cell apoptosis, arrest cell cycle and suppress cell colony formation. In addition, we identified that ubiquitination was indispensable in the degradation process, and found that the degradation was related to autophagy. Our work would provide an alternative approach for development of potentially effective EGFR degraders and give a new clue for investigation of PROTAC-induced protein degradation.
- Zhao, Hong-Yi,Yang, Xue-Yan,Lei, Hao,Xi, Xiao-Xiao,Lu, She-Min,Zhang, Jun-Jie,Xin, Minhang,Zhang, San-Qi
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- Trimethyl-substituted carbamate as a versatile self-immolative linker for fluorescence detection of enzyme reactions
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Self-immolative linker is a useful building block of molecular probes, with broad applications in the fields of enzyme activity analysis, stimuli-responsive material science, and drug delivery. This manuscript presents N-methyl dimethyl methyl (i.e., trimethyl) carbamate as a new class of self-immolative linker for the fluorescence detection of enzyme reactions. The trimethyl carbamate was shown to spontaneously undergo intramolecular cyclization upon formation of a carboxylate group, to liberate a fluorophore with the second time rapid reaction kinetics. Interestingly, the auto-cleavage reaction of trimethyl carbamate was also induced by the formation of hydroxyl and amino groups. Fluorescent probes with a trimethyl carbamate could be applicable for fluorescence monitoring of the enzyme reactions catalyzed by esterase, ketoreductase, and aminotransferase, and for fluorescence imaging of intracellular esterase activity in living cells, hence demonstrating the utility of this new class of self-immolative linker.
- Inoue, Kazuya,Nakamura, Noriaki,Ojida, Akio,Uchinomiya, Shohei
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supporting information
(2020/05/25)
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- Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
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Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.
- Büttner, Dominik,Kramer, Jan S.,Klingler, Franca-M.,Wittmann, Sandra K.,Hartmann, Markus R.,Kurz, Christian G.,Kohnh?user, Daniel,Weizel, Lilia,Brüggerhoff, Astrid,Frank, Denia,Steinhilber, Dieter,Wichelhaus, Thomas A.,Pogoryelov, Denys,Proschak, Ewgenij
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p. 360 - 372
(2017/12/18)
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- Rearrangement of oxazolo[3,2-a]pyridines as an approach of synthesizing aza[3.3.2]cyclazines
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[MediaObject not available: see fulltext.]5-Methyloxazolo[3,2-a]pyridinium salts were shown to react with (methylamino)acetaldehyde dimethyl acetal leading to the formation of functionalized 5-aminoindolizines, which in turn are capable of closing the pyr
- Babaev, Eugene V.,Nevskaya, Aleksandra A.,Dlynnikh, Ilya V.
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p. 269 - 274
(2016/01/12)
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- Method of use of pharmaceutical formulations for the treatment of apicomplexan diseases in animals
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The present invention is directed to the method of use of effective pharmaceutical formulations for the treatment of diseases caused by apicomplexan parasites, said formulation comprised of a salicylanilide or salicylanilide derivative, disclosed herein,
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Paragraph 0095
(2014/01/07)
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- SWITCHABLE POLYMERS AND SURFACES WITH REVERSIBLY SWITCHABLE PROPERTIES
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Reversibly switchable polymers, surfaces that include the polymers, and methods for making and using the polymers and surfaces. The switchable polymers are non-fouling in their zwitterionic form and are antimicrobial in their cationic form.
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- Manipulating sticky and non-sticky properties in a single material
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Sticky and non-sticky, together? A newly developed zwitterionic material (CB-OH; blue structure in scheme) has an equilibrium counterpart (CB-Ring; red). This interchangeable material allows control over two distinct properties: "non-sticky" CB-OH (biomolecular resistance) and "sticky" CB-Ring (binding by covalent bonds). Copyright
- Cao, Zhiqiang,Brault, Norman,Xue, Hong,Keefe, Andrew,Jiang, Shaoyi
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supporting information; experimental part
p. 6102 - 6104
(2011/09/12)
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- Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations
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We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.
- Pospí?il, Ji?í,Potá?ek, Milan
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p. 337 - 346
(2007/10/03)
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- Synthesis and nucleic acid binding studies of novel pyrrolidinyl PNA carrying an N-amino-N-methylglycine spacer
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Two novel pyrrolidinyl peptide nucleic acids comprising alternating sequences of thymine-modified D- or L-proline and an N-amino-N-methylglycine spacer were synthesized using solid-phase methodology. UV and CD titrations together with a gel-binding shift assay revealed that neither of the homothymine PNA decamers bind to their complementary DNA or RNA. This was considered to be due to an unfavorable secondary structure which could not be alleviated by the presence of the positively charged protonated amine in the PNA backbone.
- Vilaivan, Tirayut,Suparpprom, Chaturong,Duanglaor, Preeyanut,Harnyuttanakorn, Pongchai,Lowe, Gordon
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p. 1663 - 1666
(2007/10/03)
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- Highly efficient synthesis of sterically hindered peptides containing N-methylated amino acid residues using a novel 1H-benzimidazolium salt
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Novel 1H-benzimidazolium type peptide coupling reagent, CMBI, was designed, synthesized, and shown to be efficient in the promotion of the formation of sterically hindered amide and ester bonds. Its high efficiency was proved by model reaction tests and the successful synthesis of various hindered oligopeptides and peptide segments containing N-methyl amino acid residues with fast reaction speeds, low racemization and excellent yields. A mechanism for amide bond formation mediated by the reagent was proposed. (C) 2000 Elsevier Science Ltd.
- Li, Peng,Xu, Jie Cheng
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p. 9949 - 9955
(2007/10/03)
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- New prototypical O-linked-glycopeptidomimetics corresponding to the linkage region of proteoglycans
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A new class of glycopeptidomimetic composed of N-substituted oligoglycine (peptoid) mimicking the β-D-Xy1-(1 → 3)-O-L-Ser linkage region of proteoglycans was synthesized using a convergent approach. Reiterative N-alkylation-N-bromoacetylation reactions we
- Kim, Jin Mi,Roy, Rene
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p. 173 - 179
(2007/10/03)
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- Folate-based inhibitors of thymidylate synthase: Synthesis and antitumor activity of γ-linked sterically hindered dipeptide analogues of 2-desamino- 2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)
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In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of γ-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was pre
- Bavetsias, Vassilios,Jackman, Ann L.,Marriott, Jonathan H.,Kimbell, Rosemary,Gibson, William,Boyle, F. Thomas,Bisset, Graham M. F.
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p. 1495 - 1510
(2007/10/03)
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- First Synthesis of N-Linked-Glycopeptoid as New Glycopeptidomimetics
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The first N-linked glycopeptoid containing N-acetylglucosaminide (D-GlcNAc) was synthesized using the oligo(N-substituted glycines) (NSGs) approach.The strategy presented herein offers the advantage of a convergent synthesis.
- Saha, Uttam K.,Roy, Rene
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p. 3635 - 3638
(2007/10/02)
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- Toward the design of an RNA:DNA hybrid binding agent
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One characteristic function of the retroviruses, which is generally not found in normal eukaryotic cells, is production of a long RNA:DNA hybrid in the viral replication phase. If agents are designed which bind only to the RNA:DNA hybrid, but neither to DNA nor to RNA, such agents will be able to inhibit specifically the RNase H activity of retroviral reverse transcriptase, and therefore will suppress viral replication. Actinomycin D binds to double-stranded DNA, but not to RNA, because steric hindrance between the 2-amino group of the phenoxazinone ring and the 2'-hydroxyl group of RNA prevents intercalation of the antibiotic. However, if the C8-H in the phenoxazinone ring is replaced by an aromatic nitrogen N8, a strong hydrogen bond acceptor, this analog (N8-actinomycin D) might be able to bind intercalatively to an RNA:DNA hybrid by forming an additional hydrogen bond between N8 and the 2'-hydroxyl group of guanosine ribose. This hypothesis has been tested by a molecular mechanics calculation using a model structure of the complex between N8-actinomycin D and a small RNA:DNA hybrid, r(GC):d(GC). The results of the molecular mechanics calculation suggest that N8-actinomycin D can intercalatively bind to the RNA:DNA hybrid by making an additional intracomplex hydrogen bond. This hydrogen bonding capability of N8 has been confirmed in the crystal structure of the chromophore of N8-actinomycin D. Thus, N8-actinomycin D has been synthesized by coupling the pyridine and benzene fragments obtained independently. A binding study indicates that both actinomycin D and N8-actinomycin D bind intercalatively not only to DNA:DNA double strands but also to RNA:DNA hybrids. Although the overall binding capacity of N8-actinomycin D is reduced substantially in comparison with that of actinomycin D itself, N8-actinomycin D tends to bind relatively more favorably than actinomycin D to the RNA:DNA hybrids. Thus, this initial attempt at designing an RNA:DNA hybrid binding agent appears to be successful. However, it is necessary to modify the agent further to increase its RNA:DNA hybrid binding character and to decrease the DNA:DNA binding character, in order to make a useful RNA:DNA hybrid binding agent.
- Chu, Wenhua,Kamitori, Shigehiro,Shinomiya, Miho,Carlson, Robert G.,Takusagawa, Fusao
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p. 2243 - 2253
(2007/10/02)
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- Role of D-valine residues in the antitumor drug actinomycin D: Replacement of D-valines with other D-amino acids changes the DNA binding characteristics and transcription inhibitory activities
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D-valine analogues of the antitumor drug actinomycin D, in which D-valine residues were replaced with D-threonine, D-tyrosine, D-phenylalanine, and D-O-methyltyrosine residues, have been totally synthesized. The crystal structure of the D-O-methyltyrosine analogue has been determined (a = b = 21.352(6), c = 44.525(9) ?; space group P41212; R = 0.19 for 803 out of 1114 reflections at 1.8 ? resolution data). Replacements of D-valines did not change the overall conformation of the molecule, and the substituted groups were located on the side opposite to the DNA binding site, suggesting that the analogues can bind intercalatively at 5'-GC-3' sequences of DNA like actinomycin D does. In the crystals, the analogue molecules constitute a tight dimer, and a pair of stacked chromophores of the dimer was further sandwiched by two methoxyphenyl groups of neighboring molecules. These strong aromatic aromatic stacking forces among the molecules appear to reduce very much the water solubility of the aromatic analogues. The characteristics of binding of the analogues to various DNA's including d(GAAGCTTC)2, d(GTTGCAAC)2, poly(dA-dT), poly(dG-dC), and calf thymus DNA have been examined by using the visible spectrum methods. Difference spectra of actinomycin D and the analogues with oligonucleotides indicated that the analogues bind intercalatively to the DNA, as actinomycin D does, but the association constants were reduced to approximately one-half that of actinomycin D. The spectra of the aromatic analogues titrated with calf thymus DNA indicated that the aromatic analogues bound somehow differently to the longer DNA's. A simple profile analysis of the spectra suggested that the aromatic analogues bound to calf thymus DNA not only with intercalation, as actinomycin D does, but also with side binding. Nevertheless, the association constants of the aromatic analogues to calf thymus DNA with the intercalation mode were found to be quite similar to those of the short oligonucleotides. This conclusion has been supported by the melting behaviors of the DNA with the aromatic analogues, in which the melting curves of the analogues were superimposable on the melting curve of DNA with actinomycin D, suggesting that the aromatic analogue molecules were intercalated into the DNA. The inhibitory activities of actinomycin D and analogues on RNA polymerase in vitro were examined using calf thymus DNA and E. coli RNA polymerase. All actinomycin D analogues severely inhibited RNA synthesis at relatively low drug concentrations. In general, inhibitory activities of the analogues on the RNA synthesis were found to be correlated with those of DNA binding characteristics. However, the analogue in which D-phenylalanine replaced D-valines inhibited RNA synthesis more strongly than actinomycin D itself, but this analogue bound to the DNA's much more weakly than actinomycin D. In this study, the D-valine residues in the cyclic depsipeptides of actinomycin D were found not to be directly involved in DNA binding, but this amino acid residue was found to be an important biological medulator of the antibiotic. Although the D-valine is a hydrophobic amino acid residue, this amino acid residue appears to play an important role in increasing the water solubility of the antibiotic. Replacements of D-valine residues reduced drastically the water solubility of the analogues, and consequently, this physical character of the analogues reduced their capacities for binding to DNA. As a result, the biological activities of the analogues were generally decreased.
- Chu, Wenhua,Shinomiya, Miho,Kamitori, Kazuyo Y.,Kamitori, Shigehiro,Carlson, Robert G.,Weaver, Robert F.,Takusagawa, Fusao
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p. 7971 - 7982
(2007/10/02)
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- SUBSTITUTED PROLINE COMPOUNDS, COMPOSITION AND METHOD OF USE
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Compounds of the formula STR1 are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.
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- HYDROXY SUBSTITUTED UREIDO AMINO AND IMINO ACIDS
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Compounds of the formula STR1 are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase
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