- Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2
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A series of twenty-nine new quinazoline-2,4-dione compounds were synthesized and their IC50 values for binding toward sphingosine-1-phosphate receptor 2 (S1PR2) were determined using a [32P]S1P binding assay. Seven compounds 2a, 2g, 2h, 2i, 2j, 2k, and 5h exhibit high S1PR2 binding potencies (IC50 values 98%), and high molar activity (153-222 GBq μmol-1, at the end of bombardment). [11C]2a and [11C]2i were further evaluated by the ex vivo biodistribution study. The results showed that both tracers have low brain uptake, preventing their potential for neuroimaging application. Further explorations of this class of S1PR2 PET tracers in peripheral tissue diseases are underway. This journal is
- Gropler, Robert J.,Klein, Robyn S.,Liu, Hui,Luo, Zonghua,Tu, Zhude,Yu, Yanbo
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supporting information
p. 202 - 207
(2022/03/30)
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- Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides
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DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.
- Waszkowycz, Bohdan,Smith, Kate M.,McGonagle, Alison E.,Jordan, Allan M.,Acton, Ben,Fairweather, Emma E.,Griffiths, Louise A.,Hamilton, Niall M.,Hamilton, Nicola S.,Hitchin, James R.,Hutton, Colin P.,James, Dominic I.,Jones, Clifford D.,Jones, Stuart,Mould, Daniel P.,Small, Helen F.,Stowell, Alexandra I. J.,Tucker, Julie A.,Waddell, Ian D.,Ogilvie, Donald J.
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p. 10767 - 10792
(2019/01/04)
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- Synthesis of methyl [3-alkyl-2-(2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl)-acetamido] alkanoate
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A series of methyl [3-alkyl-2-(2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl)-acetamido] alkanoate 10-13a-f has been developed on the basis of the N-chemoselective reaction of 3-substituted quinazoline-2,4-diones 3a-d with ethyl chloroacetate and azide coupling method with amino acid ester hydrochloride. The precursor quinazoline diones 3a-d chemoselective reactions were studied using DFT(B3LYP)/6-311G level of theory and were prepared by a new rearrangement method from the corresponding 2-(3-methyl-4-oxo-3,4- dihydroquinazolin-2-ylthio) acetohydrazide 6. {figure presented}.
- Ismail, El Fekki,Ali, Ibrahim A.I.,Fathalla, Walid,Alsheikh, Amer A.,Tamney, El Said El
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p. 104 - 120
(2017/06/19)
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- 2,4-DIOXO-QUINAZOLINE-6-SULFONAMIDE DERIVATIVES AS INHIBITORS OF PARG
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The present invention relates to compounds of formula I that function as inhibitors of PARG (Poly ADP-ribose glycohydrolase) enzyme activity wherein R1a, R1b, R1c, R1d, R1e, W, X1, X2, X3, X4, X5, X6, X7, c are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which PARG activity is implicated.
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Paragraph 00197; 00198
(2016/07/05)
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- Synthesis of 3-methylquinazolin-4(3H)-one derivatives
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Oxidation of 3-methyl-2-sulfanylquinazolin-4(3H)-one with chlorine dioxide under different conditions gave 2,2'-disulfanediylbis[3-methylquinazolin-4(3H)- one], 3-methyl-4-oxo-3,4-dihydroquinazoline-2-sulfonic acid, 3-methylquinazoline-2,4(1H,3H)-dione, 6
- Lezina,Rubtsova,Polukeev,Kutchin
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p. 1222 - 1225
(2013/01/15)
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- Synthesis of novel quinazoline-4-one derivatives and their acyclonucleoside analogs
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A number of quinazolin-4-one derivatives were synthesized. Reaction of the 2-hydrazonoquinazoline-4-one derivatives with aldoses afforded the corresponding sugar hydrazones which on treatment with ferric chloride to afford the corresponding acyclic nucleoside analogues.
- Zahran, Magdy A.-H.,Ali, Omar M.,Zeid, Ibrahim F.,Rageb, Elham
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experimental part
p. 2121 - 2124
(2012/08/28)
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- Metal and phosgene-free synthesis of 1H-quinazoline-2,4-diones by selenium-catalyzed carbonylation of o-nitrobenzamides
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1H-Quinazoline-2,4-diones were efficiently synthesized by selenium-catalyzed carbonylation of o-nitrobenzamides under relatively mild conditions. In situ-generated carbonyl selenide (SeCO) is proposed to initiate the catalytic carbonylation. Thus, a concise transition metal and phosgene-free synthetic route to potentially bioactive-substituted 1H-quinazoline-2,4-dione derivatives has been developed.
- Wu, Xiaowei,Yu, Zhengkun
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experimental part
p. 1500 - 1503
(2010/04/29)
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- Room-temperature palladium-catalyzed C-H activation: Ortho-carbonylation of aniline derivatives
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Pd and CO - ureally got me! The title reaction proceeds efficiently at 18°C under CO (1 atm) with 5 % [Pd(OTs)2 (MeCN)2] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ=benzoquinone, Ts=4-toluenesulfonyl).
- Houlden, Chris E.,Hutchby, Marc,Bailey, Chris D.,Ford, J.Gair,Tyler, Simon N. G.,Gagne, Michel R.,Lloyd-Jones, Guy C.,Booker-Milburn, Kevin I.
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supporting information; experimental part
p. 1830 - 1833
(2009/08/07)
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- Copper-mediated N-arylation of quinazolinediones
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A mild, ligand-free method of arylating 2,4-quinazolinediones using arylboronates in the presence of copper salts is described. The reaction is tolerant of a variety of functional groups and works for arylboronic acid, arylboronic ester, and aryltrifluoro
- Guy, Collette S.,Jones, Teyrnon C.
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body text
p. 2253 - 2256
(2009/12/24)
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- Traceless synthesis of quinazoline-2,4-diones by curtius rearrangement reaction using poly(ethylene glycol) as soluble polymeric support
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(Chemical Equation Presented) We have developed an efficient method to synthesize various quinazoline-2,4-diones using polyethylene glycol) as soluble polymeric support. The procedure of this reaction included: formation of acyl azide, efficient Curtius rearrangement, nucleophlic addition with amines to produce ureas, cyclization and concurrent cleavage of the resulted six-membered heterocycle from PEG-support in excellent yields. This method is mild and manipulation is easy.
- Huang, Yanling,Lu, Cuifen,Chen, Zuxing,Yang, Guichun
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p. 1421 - 1424
(2008/09/19)
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- Tandem palladium-catalyzed urea arylation-intramolecular ester amidation: Regioselective synthesis of 3-alkylated 2,4-quinazolinediones
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(Chemical Equation Presented) o-Halo benzoates can be combined with monoalkyl ureas in a tandem palladium-catalyzed arylation-ester amidation sequence to deliver quinazolinedione products. The reactions are regioselective for formation of the 3-N-alkyl isomers. Significant variation of both coupling partners is possible, allowing the synthesis of a diverse array of substituted quinazolinediones, exemplified by the preparation of a simple unsymmetric-dialkylated natural product.
- Willis, Michael C.,Snell, Robert H.,Fletcher, Anthony J.,Woodward, Robert L.
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p. 5089 - 5091
(2007/10/03)
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- An efficient one-pot procedure for preparation of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolinone derivatives under microwave irradiation
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An efficient one-pot synthesis of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolinone derivatives are given by the condensation of isatoic anhydride, primary amine and urea or thiourea in the absence of organic or inorganic reagents under microwave irr
- Azizian, Javad,Mohammadi, Ali A.,Karimi, Ali R.
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p. 415 - 420
(2007/10/03)
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- A Facile Synthesis of 3-Substituted 2-Cyanoqmnazolin-4(3H)-ones and 3-Alkyl-2-cyanothieno[3,2-d]pyrimidin-4(3H)-ones via 1,2,3-Dithiazoles
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The reaction of methyl anthranilate with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel's salt) in the presence of pyridine (2 equivalents) in dichloromethane at room temperature gave methyl N-(4-chloro-5H-l,2,3-dithiazol-5-ylidene)anthranilate (3a) (50% yield), which reacted with sterically less hindered primary alkylamines to give directly 3-alkyl-2-cyanoquinazolin-4(3H)-ones 5 in moderate to good yields. With tertbutylamine, N-(2-methoxycarbonylphenyl)iminocyanomethyl N-(tert-butyl) disulfide 7 and methyl 2-(N-cyanothioformamido)anthranilate (8) were isolated in 33% and 59% yields, respectively. The cyano group of quinazoline 5a (R = CH3) is readily displaced by various nucleophiles to give 2-substituted quinazolinones 11-19, which indicates that compounds 5 can be utilized as starting materials for the synthesis of new 2-substituted quinazolines. Similarly 3-alkyl-2-cyanothieno[3,2,-d]pyrimidin-4(3H)-ones 22 were prepared from methyl 3-[N-(4-chloro-5H-l,2,3-dithiazol-5-ylidene)]-2-thiophencarboxylate (21) in moderate to good yields.
- Lee, Hyi-Seung,Chang, Yong-Goo,Kim, Kyongtae
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p. 659 - 668
(2007/10/03)
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- Quantum chemical investigation of the effect of cation size on the course of the methylation of 2,4-dioxoquinazoline salts
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The effect of cation size on the dual reactivity of the lithium, sodium, and potassium salts of 2,4-dioxoquinazolines in liquid and solid phase methylation reactions has been studied. The results obtained were confirmed by data of quantum chemical calculations and IR spectroscopy. 1997 Plenum Publishing Corporation.
- Ashirmatov,Urakov,Shakhidoyatov
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p. 708 - 711
(2007/10/03)
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- NEW METHODOLOGY FOR THE PREPARATIONOF QUINAZOLINE DERIVATIVES VIA TANDEM AZA-WITTIG/HETEROCUMULENE-MEDIATED ANNULATION. SYNTHESIS OF 4(3H)QUINAZOLINONES, BENZIMIDAZOQUINAZOLINES, QUINAZOLINOQUINAZOLINES AND BENZOTHIAZOLOQUINAZOLINES.
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The aza-Wittig reaction of iminophosphoranes derived from N-substituted o-azidobenzamides, 2-(o-azidophenyl)-benzimidazole, -benzothiazole or -3,1-benzoxazin-4-one with heterocumulenes leads to functionalized quinazolines.Iminophosphoranes 9, derived from N-substituted o-azidobenzamides, react under mild conditions with isocyanates to form 4H-3,1-benzoxazine-4-imines 11 which are converted into 2-substituted-4(3H)-quinazolinones 12.Iminophosphoranes 9 also react with carbon disulfide and carbon dioxide to give the quinazolinones 13 and 14 respectively.Iminophosphorane 26, derived from 2-(o-azidophenyl)benzimidazole, reacts with isocyanates, carbon disulfide and carbon dioxide to form 6-substituted benzimidazoquinazolines 27, 28, and 29 respectively.In benzene at room temperature, iminophosphorane 31, reacts with isocyanates yielding quinazolinoquinazolines 34.Compounds 34 can also be prepared from iminophosphorane 36 and isocyanates.Iminophosphorane 40 derived from 2-(o-azidophenyl)benzothiazole reacts with aliphatic and aromatic isocyanates or isothiocyanates to give 7H-benzothiazoloquinazoline-7-imines 42.Iminophosphorane 40 also reacts with carbon dioxide or carbon disulfide to afford the corresponding isocyanate 43 or isothiocyanate 44, The molecular structures of 11d and 42a have been determined by X-ray diffraction methods.
- Molina, Pedro,Alajarin, Mateo,Vidal, Angel
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p. 4263 - 4286
(2007/10/02)
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- HETEROCYCLIC SYNTHESIS VIA A TANDEM AZA-WITTIG REACTION/ HETEROCUMULENE-MEDIATED ANNULATION REACTION.NEW METHODOLOGY FOR THE PREPARATION OF QUINAZOLINE DERIVATIVES.
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The aza-Wittig reaction of iminophosphoranes derived from N-substituted o-azidobenzamides or 2-(o-azido)phenyl benzimidazole with isocyanates, carbon dioxide or carbon disulphide, lead to functionalized 4(3H)-quinazolinones and benzimidazoquinazolines respectively.
- Molina, Pedro,Alajarin, Mateo,Vidal, Angel
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p. 3849 - 3852
(2007/10/02)
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- INTRAMOLECULAR NUCLEOPHILIC ATTACK ON CARBOXYLATE BY UREIDE ANION. GENERAL ACID-BASE CATALYSIS OF THE ALKALINE CYCLISATION OF 2,2,3,5-TETRAMETHYLHYDANTOIC ACID
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The cyclisation of the title compound to the corresponding hydantoin is a model for the carboxylation of biotin by hydrogen carbonate.The reaction is rapid over the whole pH range, and is catalysed by both general acids and general bases.Above ph 9.2 the reaction is first order in hydroxide, which is shown to act as a general base.The prefered mechanism is specific base-general acid catalysis, involving nucleophilic attack by the ureide anion on the ionised carboxy group, assisted by proton transfer from the general acid.This defines also the mechanism of the reverse reaction, and clarifies for the first time the role of the second hydroxide ion in the ->2 term for the hydrolysis of amides with good leaving groups.
- Blagoeva, Iva B.,Pojarlieff, Ivan G.
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p. 745 - 752
(2007/10/02)
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- Azaisatoic anhydrides
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A method for producing heterocyclic acid anhydrides and pyrimidinediones from the corresponding acids, dicarboxamides, 2,3-and 3,4-pyridinedicarboxamides, and N-monosubstituted 2,3-and 3,4-pyridinedicarboxamides, in which the aforesaid compounds are reacted with lead tetra-acetate in the presence of a suitable anhydrous inert solvent.
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