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1.
6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance 下载免费PDF全文
Dr. Baomin Liu Qianqian Qiu Tianxiao Zhao Lei Jiao Prof. Yunman Li Prof. Wenlong Huang Prof. Hai Qian 《ChemMedChem》2015,10(2):336-344
P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC50=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development. 相似文献
2.
Bastian Tewes Dr. Bastian Frehland Dirk Schepmann Dr. Kai‐Uwe Schmidtke Thomas Winckler Prof. Dr. Bernhard Wünsch Prof. Dr. 《ChemMedChem》2010,5(5):687-695
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ol ( 12 ), which was synthesized in six steps starting from 2‐phenylethylamine 3 , represents the central building block for the introduction of several N‐linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4‐phenylbutyl derivative 13 (WMS‐1405, Ki=5.4 nM ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 (Ki=10 nM ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ1 (Ki=33 nM ) and σ2 receptors (Ki=82 nM ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC50 value of 360 nM , indicating that 13 is an NMDA antagonist. 相似文献
3.
Toward the Development of Dual‐Targeted Glyceraldehyde‐3‐phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi 下载免费PDF全文
Prof. Dr. Federica Belluti Elisa Uliassi Giacomo Veronesi Dr. Christian Bergamini Dr. Marcel Kaiser Prof. Dr. Reto Brun Angelo Viola Prof. Dr. Romana Fato Prof. Dr. Paul A. M. Michels Prof. Dr. R. Luise Krauth‐Siegel Prof. Dr. Andrea Cavalli Prof. Dr. Maria Laura Bolognesi 《ChemMedChem》2014,9(2):371-382
A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox–eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone–coumarin hybrids against glyceraldehyde‐3‐phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi, and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual‐target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2‐{[3‐(3‐dimethylaminopropoxy)‐2‐oxo‐2H‐chromen‐7‐yl]oxy}anthracene‐1,4‐dione ( 10 ) showed an IC50 value of 5.4 μM against TbGAPDH and a concomitant Ki value of 2.32 μM against TcTR. Notably, 2‐{4‐[6‐(2‐dimethylaminoethoxy)‐2‐oxo‐2H‐chromen‐3‐yl]phenoxy}anthracene‐1,4‐dione (compound 6 ) displayed a remarkable EC50 value for T. brucei parasites (0.026 μM ) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μM ). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase. 相似文献
4.
5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site 下载免费PDF全文
Dr. Jacob Krall Dr. Kenneth T. Kongstad Birgitte Nielsen Troels E. Sørensen Dr. Thomas Balle Dr. Anders A. Jensen Dr. Bente Frølund 《ChemMedChem》2014,9(11):2475-2485
A series of bioisosteric N1‐ and N2‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABAAR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC50~300 μM ) is a weak antagonist at the α1β2γ2 GABAAR, whereas substituting the N1‐ or N2‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABAARs. Docking studies using a α1β2γ2 GABAAR homology model along with the obtained SAR indicate that the N1‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold. 相似文献
5.
Rubn S. Ramn Christophe Pottier Adrin Gmez‐Surez Steven P. Nolan 《Advanced Synthesis \u0026amp; Catalysis》2011,353(9):1575-1583
The formation of 4‐alkoxy‐2(5H)‐furanones was achieved via tandem alkoxylation/lactonization of γ‐hydroxy‐α,β‐acetylenic esters catalyzed by 2 mol% of [2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine]gold bis(trifluoromethanesulfonyl)imidate [Au(IPr)(NTf2)]. The economic and simple procedure was applied to a series of various secondary propargylic alcohols allowing for yields of desired product of up to 95%. In addition, tertiary propargylic alcohols bearing mostly cyclic substituents were converted into the corresponding spiro derivatives. Both primary and secondary alcohols reacted with propargylic alcohols at moderate temperatures (65–80 °C) in either neat reactions or using 1,2‐dichloroethane as a reaction medium allowing for yields of 23–95%. In contrast to [Au(IPr)(NTf2)], reactions with cationic complexes such as [2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine](acetonitrile)gold tetrafluoroborate [Au(IPr)(CH3CN)][BF4] or (μ‐hydroxy)bis{[2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine]gold} tetrafluoroborate or bis(trifluoromethanesulfonyl)imidate – [{Au(IPr)}2(μ‐OH)][X] (X=BF4, NTf2) – mostly stop after the alkoxylation. Analysis of the intermediate proved the exclusive formation of the E‐isomer which allows for the subsequent lactonization. 相似文献
6.
Dr. Giulio Ferino Prof. Enzo Cadoni Dr. Maria João Matos Dr. Elias Quezada Prof. Eugenio Uriarte Prof. Lourdes Santana Dr. Santiago Vilar Dr. Nicholas P. Tatonetti Matilde Yáñez Dolores Viña Dr. Carmen Picciau Dr. Silvia Serra Prof. Giovanna Delogu 《ChemMedChem》2013,8(6):956-966
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds. 相似文献
7.
Huiling Geng Xiaowei Zhang Mingxin Chang Le Zhou Wenjun Wu Xumu Zhang 《Advanced Synthesis \u0026amp; Catalysis》2011,353(16):3039-3043
A highly efficient and enantioselective hydrogenation of unprotected β‐ketoenamines catalyzed with ruthenium(II) dichloro{(S)‐(−)‐2,2′‐bis[di(3,5‐xylyl)phosphino]‐1,1′‐binaphthyl}[(2S)‐(+)‐1,1‐bis(4‐methoxyphenyl)‐3‐methyl‐1,2‐butanediamine] {Ru[(S)‐xylbinap][(S)‐daipen]Cl2} has been successfully developed. This methodology provides a straightforward access to free γ‐secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases. 相似文献
8.
Comparison of in Silico,Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ1 Receptor Ligands Designed for Positron Emission Tomography 下载免费PDF全文
Dr. Christian Wiese Dr. Eva Große Maestrup Dr. Fabian Galla Dr. Dirk Schepmann Dr. Achim Hiller Dr. Steffen Fischer Dr. Friedrich‐Alexander Ludwig Dr. Winnie Deuther‐Conrad Dr. Cornelius K. Donat Prof. Dr. Peter Brust Dr. Lars Büter Prof. Dr. Uwe Karst Prof. Dr. Bernhard Wünsch 《ChemMedChem》2016,11(21):2445-2458
The imaging of σ1 receptors in the brain by fluorinated radiotracers will be used for the validation of σ1 receptors as drug targets as well as for differential diagnosis of diseases in the central nervous system. The biotransformation of four homologous fluorinated PET tracers 1′‐benzyl‐3‐(ω‐fluoromethyl to ω‐fluorobutyl)‐3H‐spiro[2]benzofuran‐1,4′‐piperidine] ([18F] 1 – 4 ) was investigated. In silico studies using fast metabolizer (FAME) software, electrochemical oxidations, in vitro studies with rat liver microsomes, and in vivo metabolism studies after application of the PET tracers [18F] 1 – 4 to mice were performed. Combined liquid chromatography and mass spectrometry (HPLC–MS) analysis allowed structural identification of non‐radioactive metabolites. Radio‐HPLC and radio‐TLC provided information about the presence of unchanged parent radiotracers and their radiometabolites. Radiometabolites were not found in the brain after application of [18F] 2 – 4 , but liver, plasma, and urine samples contained several radiometabolites. Less than 2 % of the injected dose of [18F] 4 reached the brain, rendering [18F] 4 less appropriate as a PET tracer than [18F] 2 and [18F] 3 . Compounds [18F] 2 and [18F] 3 possess the most promising properties for imaging of σ1 receptors in the brain. High σ1 affinity (Ki=0.59 nm ), low lipophilicity (logD7.4=2.57), high brain penetration (4.6 % of injected dose after 30 min), and the absence of radiometabolites in the brain favor the fluoroethyl derivative [18F] 2 slightly over the fluoropropyl derivative [18F] 3 for human use. 相似文献
9.
Paul M. Wood Dr. L. W. Lawrence Woo Dr. Jean‐Robert Labrosse Dr. Mark P. Thomas Dr. Mary F. Mahon Dr. Surinder K. Chander Dr. Atul Purohit Dr. Michael J. Reed Prof. Barry V. L. Potter Prof. 《ChemMedChem》2010,5(9):1577-1593
The design and synthesis of a series of bicyclic ring containing dual aromatase–sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4‐[(4‐bromobenzyl)(4H‐1,2,4‐triazol‐4‐yl)amino]benzonitrile are reported. Biological evaluation with JEG‐3 cells revealed structure–activity relationships. The X‐ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate‐containing series, compounds containing a naphthalene ring are both the most potent AI ( 39 , IC50 AROM=0.25 nM ) and the best STS inhibitor ( 31 , IC50 STS=26 nM ). The most promising DASI is 39 (IC50 AROM=0.25 nM , IC50 STS=205 nM ), and this was evaluated orally in vivo at 10 mg kg?1, showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone‐dependent breast cancer. 相似文献
10.
KonstantinV. Luzyanin Vadim Yu. Kukushkin Maximilian N. Kopylovich Alexey A. Nazarov Markus Galanski Armando J.L. Pombeiro 《Advanced Synthesis \u0026amp; Catalysis》2008,350(1):135-142
Refluxing a mixture of phthalonitrile C6R1R2R3R4(CN)2 1 (R1–R4=H), or its substituted derivatives 2 (R1, R3, R4=H, R2=Me), or 3 (R1, R4=H, R2, R3=Cl) (1 equiv.) and N,N‐diethylhydroxylamine, Et2NOH, (4 equivs.) in methanol for 4 h results ( Route A ) in precipitation of the symmetrical ( 6 and 8 ) and an isomeric mixture of unsymmetrical ( 7 ) phthalocyanines, isolated in good (55–65 %) yields. The reaction of phthalonitriles 1 , 2 , or 4 (R1, R3, R4=H, R2=NO2) (4 equivs.) with Et2NOH (8 equivs.) in the presence of a metal salt MCl2 (M=Zn, Cd, Co, Ni) (1 equiv.) in n‐BuOH or without solvent results in the formation of metallated phthalocyanine species ( 9 – 17 ). Upon refluxing in freshly distilled dry chloroform, phthalonitrile 1 or its substituted analogues 2 , 3 or 5 (R1–R4=F) (1 equiv.) react with N,N‐diethylhydroxylamine (2 equivs.) affording 3‐iminoisoindolin‐1‐ones 18 – 21 ( Route B ) isolated in good yields (55–80 %). All the prepared compounds were characterized with C, H, and N elemental analyses, ESI‐MS, IR, and compounds 18 – 21 also by 1D (1H, 13C{1H}), and 2D (1H,15N‐HMBC and 1H,13C‐HMQC, 1H,13C‐HMBC) NMR spectroscopy. 相似文献
11.
Jeeyeon Kim Youngjae Kim Prof. Jinsung Tae Miyoung Yeom Prof. Bongjin Moon Dr. Xi‐Ping Huang Prof. Bryan L. Roth Kangho Lee Dr. Hyewhon Rhim Prof. Il Han Choo Prof. Youhoon Chong Dr. Gyochang Keum Dr. Ghilsoo Nam Prof. Hyunah Choo 《ChemMedChem》2013,8(11):1855-1864
The 5‐HT7 receptor (5‐HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT7R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT7R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT7R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT7R. Among the synthesized compounds, 1‐([2′‐methoxy‐(1,1′‐biphenyl)‐3‐yl]methyl)‐4‐(2‐methoxyphenyl)piperazine ( 28 ) was the best binder to the 5‐HT7R (pKi=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT7R over other serotonin receptor subtypes, such as 5‐HT1R, 5‐HT2R, 5‐HT3R, and 5‐HT6R. In a molecular modeling study, the 2‐methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. 相似文献
12.
Jingtang Chen Karlheinz Sünkel Wolfgang Beck 《Advanced Synthesis \u0026amp; Catalysis》1999,341(8):792-796
The reaction of the Cu(II) bis N,O‐chelate‐complexes of L‐2,4‐diaminobutyric acid, L‐ornithine and L‐lysine {Cu[H2N–CH(COO)(CH2)nNH3]2}2+(Cl–)2 (n = 2–4) with terephthaloyl dichloride or isophthaloyl dichloride gives the polymeric complexes {‐OC–C6H4–CO–NH–(CH2)n–CH(nh2)(COO)Cu(OOC)(NH2)CH–CH2)n–NH‐}x 1 – 5 . From these the metal can be removed by precipitation of Cu(II) with H2S. The liberated ω,ω′‐N,N′‐diterephthaloyl (or iso‐phthaloyl)‐diaminoacids 6 – 10 react with [Ru(cymene)Cl2]2, [Ru(C6Me6)Cl2]2, [Cp*RhCl2]2 or [Cp*IrCl2]2 to the ligand bridged bis‐amino acidate complexes [Ln(Cl)M–(OOC)(NH2)CH–(CH2)nNH–CO]2–C6H4 11 – 14 . 相似文献
13.
Steven Hostyn Gitte VanBaelen Guy L.F. Lemire Bert U.W. Maes 《Advanced Synthesis \u0026amp; Catalysis》2008,350(16):2653-2660
9H‐α‐Carbolines have been prepared via consecutive intermolecular Buchwald–Hartwig reaction and Pd‐catalyzed intramolecular direct arylation from commercially available 2,3‐dichloropyridines and substituted anilines. The combination of a high reaction temperature (180 °C) and the use of DBU were found to be crucial for the intramolecular direct arylation reactions of the 3‐chloro‐N‐phenylpyridin‐2‐amines as no reaction was observed at 120 °C and 180 °C using different inorganic and other organic bases. On the other hand, nitrogen‐methylated pyridine analogues of these substrates {N‐[3‐chloro‐1‐methylpyridin‐2(1H)‐ylidene]anilines} do undergo ring closure at 120 °C, with K3PO4 as base, affording the respective 1‐methyl‐1H‐α‐carbolines in good yields. 相似文献
14.
Stephen Patterson Dr. Deuan C. Jones Dr. Emma J. Shanks Dr. Julie A. Frearson Prof. Ian H. Gilbert Prof. Paul G. Wyatt Prof. Alan H. Fairlamb Prof. 《ChemMedChem》2009,4(8):1341-1353
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μM ) and biologically active against bloodstream T. brucei (EC50=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC50=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed. 相似文献
15.
In this work, we report a lead‐free piezoelectric ceramic of (0.9‐x)NaNbO3‐0.1BaTiO3‐xBaZrO3, and the effects of BaZrO3 on the phase structure, microstructure, electrical properties and temperature stability are investigated. A morphotropic phase boundary‐like region consisting of rhombohedral (R) and tetragonal (T) phases is constructed in the compositions with x = 0.035‐0.04. More importantly, in situ temperature independence of the piezoelectric effect {piezoelectric constant (d33) and strain} can be achieved below the Curie temperature (Tc). Intriguingly, the electric field‐induced strain is still observed at T ≥ Tc due to the combined actions of the electrostrictive effect and the electric field‐induced phase transition. We believe that NaNbO3‐based ceramics of this type have potential for applications in actuators and sensors. 相似文献
16.
In this study, we synthesized 1,2,4‐triarylpyrroles as ligands for the estrogen receptor (ER). Two pyrrole series were prepared with either C3‐alkyl or C3/C5‐dialkyl residues. Compounds from both series were susceptible to oxidative degradation—dialkylated compounds (t1/2=33–66 h) to a higher extent than their monoalkylated congeners (t1/2=140–211 h). Nevertheless, stability was sufficient for determination of in vitro ER binding affinity. The most active agonist in hormone‐dependent, ERα‐positive MCF‐7/2a and U2‐OS/α cells was 1,2,4‐tris(4‐hydroxyphenyl)‐3‐propyl‐1H‐pyrrole ( 6 d ) (MCF‐7/2a: EC50=70 nM ; U2‐OS/α: EC50=1.6 nM ). A corresponding inactivity in U2‐OS/β cells demonstrated the high ERα selectivity. This trend was confirmed in a competition experiment using estradiol (E2) and purified hERα and hERβ proteins (relative binding affinity (RBA) calculated for 6 d : RBA(ERα)=1.85 %; RBA(ERβ) <0.01 %). Generally, C3/C5‐dialkyl substitution led to reduction of activity, possibly due to lower stability. 相似文献
17.
Anticancer Potential of (Pentamethylcyclopentadienyl)chloridoiridium(III) Complexes Bearing κP and κP,κS‐Coordinated Ph2PCH2CH2CH2S(O)xPh (x=0–2) Ligands 下载免费PDF全文
Gerd Ludwig Ivan Ranđelović Dr. Danijela Maksimović‐Ivanić Dr. Sanja Mijatović Mirna Z. Bulatović Dr. Djordje Miljković Prof. Marcus Korb Prof. Dr. Heinrich Lang Prof. Dr. Dirk Steinborn Prof. Dr. Goran N. Kaluđerović 《ChemMedChem》2014,9(7):1586-1593
Iridium(III) complexes of the type [Ir(η5‐C5Me5)Cl2{Ph2PCH2CH2CH2S(O)xPh‐κP}] (x=0–2; 1 – 3 ) and [Ir(η5‐C5Me5)Cl{Ph2PCH2CH2CH2S(O)xPh‐κP,κS}][PF6] (x=0–1; 4 and 5 ) with 3‐(diphenylphosphino)propyl phenyl sulfide, sulfoxide, and sulfone ligands Ph2PCH2CH2CH2S(O)xPh were designed, synthesized, and characterized fully, including X‐ray diffraction analyses for complexes 3 and 4 . In vitro studies against human thyroid carcinoma (8505C), submandibular carcinoma (A253), breast adenocarcinoma (MCF‐7), colon adenocarcinoma (SW480), and melanoma (518A2) cell lines provided evidence for the high biological potential of the neutral and cationic iridium(III) complexes. Neutral iridium(III) complex 5 proved to be the most active, with IC50 values up to about 0.1 μM , representing activities of up to one order of magnitude higher than cisplatin. Using 8505C cells, apoptosis was shown to be the main mechanism through which complex 5 exerts its tumoricidal action. The described iridium(III) complexes represent potential leads in the search for novel metal‐based anticancer agents. 相似文献
18.
L. W. Lawrence Woo Paul M. Wood Christian Bubert Mark P. Thomas Atul Purohit Barry V. L. Potter 《ChemMedChem》2013,8(5):779-799
4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate and its ortho‐halogenated (F, Cl, Br) derivatives are first‐generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para‐cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG‐3 cell preparation of 0.2 and 2.5 nM , respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay. 相似文献
19.
Evaluation of a 7‐Methoxycoumarin‐3‐carboxylic Acid Ester Derivative as a Fluorescent,Cell‐Cleavable,Phosphonate Protecting Group 下载免费PDF全文
Prof. Andrew J. Wiemer Rebekah R. Shippy Ashley M. Kilcollins Jin Li Dr. Chia‐Hung Christine Hsiao Prof. Rocky J. Barney Prof. M. Lei Geng Prof. David F. Wiemer 《Chembiochem : a European journal of chemical biology》2016,17(1):52-55
Cell‐cleavable protecting groups often enhance cellular delivery of species that are charged at physiological pH. Although several phosphonate protecting groups have achieved clinical success, it remains difficult to use these prodrugs in live cells to clarify biological mechanisms. Here, we present a strategy that uses a 7‐methoxycoumarin‐3‐carboxylic acid ester as a fluorescent protecting group. This strategy was applied to synthesis of an (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl diphosphate (HMBPP) analogue to assess cellular uptake and human Vγ9Vδ2 T cell activation. The fluorescent ester displayed low cellular toxicity (IC50>100 μm ) and strong T cell activation (EC50=0.018 μm ) relative to the unprotected anion (EC50=23 μm ). The coumarin‐derived analogue allowed no‐wash analysis of biological deprotection, which revealed rapid internalization of the prodrug. These results demonstrate that fluorescent groups can be applied both as functional drug delivery tools and useful biological probes of drug uptake. 相似文献
20.
Dr. Yi‐Yu Ke Dr. Hui‐Yi Shiao Dr. Yung Chang Hsu Dr. Chang‐Ying Chu Dr. Wen‐Chieh Wang Yen‐Chun Lee Dr. Wen‐Hsing Lin Chun‐Hwa Chen Dr. John T. A. Hsu Chun‐Wei Chang Dr. Cheng‐Wei Lin Dr. Teng‐Kuang Yeh Dr. Yu‐Sheng Chao Dr. Mohane Selvaraj Coumar Dr. Hsing‐Pang Hsieh 《ChemMedChem》2013,8(1):136-148
We describe the 3D‐QSAR‐assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D‐QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nM to 10.5 μM . The best 3D‐QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r2CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R2pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent‐exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC50=43 nM ; HCT‐116 IC50=400 nM ) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC50=25 nM ; HCT‐116 IC50=23 nM ). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24 , and holds potential for further development. 相似文献