- Synthesis of theophylline-based iridium(I) N-heterocyclic carbene complexes including fluorinated-thiophenolate ligands. Preliminary evaluation of their in vitro anticancer activity
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A series of theophylline-based Ir(I) N-heterocyclic carbene complexes including fluorinated-thiolate ligands have been prepared and fully characterized. The molecular structures of the complexes [(NHC)Ir(SC6F5)(COD)] (3a) and [(NHC)I
- Eslava-Gonzalez, Itzel,Valdés, Hugo,Teresa Ramírez-Apan, María,Hernandez-Ortega, Simón,Rosario Zerme?o-Ortega, Miriam,Avila-Sorrosa, Alcives,Morales-Morales, David
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- Chitosan–silica sulfate nanohybrid: a highly efficient and green heterogeneous nanocatalyst for the regioselective synthesis of N-alkyl purine, pyrimidine and related N-heterocycles via presilylated method
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Abstract: The presilylation of purine and pyrimidine nucleobases as well as other related N-heterocycles with HMDS utilizing chitosan–silica sulfate nanohybrid (CSSNH) is described. CSSNH is proved to be a useful, highly efficient and eco-friendly heterogeneous nanohybrid catalyst for silylation of nucleobases. The presilylated nucleobases then underwent the reaction with different sources of carbon electrophiles to afford the desired N-alkyl-substituted derivatives in good-to-excellent yields. CSSNH exhibits several advantageous involving ease of handling and preparation, low cost, reusability and environmental benignity. These unique properties render the CSSNH to be an ideal candidate for use in green industrial processes. Graphic abstract: [Figure not available: see fulltext.].
- Behrouz, Somayeh,Soltani Rad, Mohammad Navid,Piltan, Mohammad Amin
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p. 113 - 124
(2019/07/30)
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- Synthesis of new allyl palladium complexes bearing purine-based NHC ligands with antiproliferative and proapoptotic activities on human ovarian cancer cell lines
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A series of new palladium allyl complexes bearing purine-based carbenes derived from caffeine, theophylline and theobromine have been prepared and characterized by NMR spectroscopy, and elemental analysis and in two cases by single crystal X-ray diffraction. The cytotoxic and proapoptotic activities of compounds have been determined in vitro on human ovarian cancer A2780 and SKOV-3 cell lines. These experiments have shown that the palladium-allyl fragment induces a general cytotoxicity, but the choice of the supporting ligands is of paramount importance for achieving the best results. In particular complexes 4c, 4d and 5d exhibit a higher antiproliferative effect (IC50: 0.09, 0.81 and 0.85 μM respectively) than cisplatin (IC50: 1.5 μM) on A2780 cells, and 4d (IC50: 1.7 μM vs. 5.94 μM) on SKOV-3 cell line. Moreover in many cases it has been proved that the cytotoxicity of our complexes is associated with the induction of apoptosis.
- Scattolin, Thomas,Caligiuri, Isabella,Canovese, Luciano,Demitri, Nicola,Gambari, Roberto,Lampronti, Ilaria,Rizzolio, Flavio,Santo, Claudio,Visentin, Fabiano
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p. 13616 - 13630
(2018/10/15)
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- Novel caffeine derivatives with antiproliferative activity
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Caffeine is probably the best known and most widely used psychoactive substance in the world. Beside its psychoactive effects, caffeine has been found to affect the cell cycle and DNA repair, as a consequence of the inhibition of ATM and ATR kinases. Thes
- Andrs, Martin,Muthna, Darina,Rezacova, Martina,Seifrtova, Martina,Siman, Pavel,Korabecny, Jan,Benek, Ondrej,Dolezal, Rafael,Soukup, Ondrej,Jun, Daniel,Kuca, Kamil
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p. 32534 - 32539
(2016/05/09)
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- Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors
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Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38–90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5–125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.
- Shelke, Rupesh U.,Degani, Mariam S.,Raju, Archana,Ray, Mukti Kanta,Rajan, Mysore G. R.
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p. 602 - 613
(2016/08/28)
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- Caffeine-based gold(I) N-heterocyclic carbenes as possible anticancer agents: Synthesis and biological properties
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A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.
- Bertrand, Benoiit,Stefan, Loic,Pirrotta, Marc,Monchaud, David,Bodio, Ewen,Richard, Philippe,Le Gendre, Pierre,Warmerdam, Elena,De Jager, Marina H.,Groothuis, Geny M.M.,Picquet, Michel,Casini, Angela
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supporting information
p. 2296 - 2303
(2014/03/21)
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- N 7-Tosyltheophylline (TsTh): A highly efficient reagent for the one-pot synthesis of n 7-alkyltheophyllines from alcohols
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A convenient and highly efficient one-pot N-alkylation of theophylline from alcohols via N 7-tosyltheophylline (TsTh) is described. In this protocol, the treatment of primary and/or secondary alcohols with a mixture of TsTh and 1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing acetonitrile affords the corresponding N 7-alkyltheophylline in good to excellent yields; the reaction was optimized for solvent and base. This methodology is highly efficient for various structurally diverse primary and secondary alcohols. A plausible mechanism for the one-pot N-alkylation of theophylline with alcohols via TsTh has been suggested. Georg Thieme Verlag Stuttgart New York.
- Soltani Rad, Mohammad Navid,Behrouz, Somayeh,Najafi, Hosnieh
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p. 1380 - 1388
(2014/06/09)
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- Double C-H activation: The palladium-catalyzed direct C-arylation of xanthines with arenes
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The novel Pd-catalyzed C(sp2)-H/C(sp2)-H cross-coupling of unactivated xanthines with unactivated arenes utilizing a combination of Ag(I) and O2 as oxidants exclusively yields C-8 arylated xanthines in a single synthetic o
- Malakar, Chandi C.,Schmidt, Dietmar,Conrad, Juergen,Beifuss, Uwe
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supporting information; experimental part
p. 1378 - 1381
(2011/05/03)
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- 3-Substituted xanthines as promising candidates for quadruplex formation: Computational, synthetic and analytical studies
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Our computational studies suggest that 3-substituted xanthines are good candidates for tetrad and quadruplex structures. 3-Methylxanthine (3MX) has been synthesized from 7-benzylxanthine, and the existence of tetrameric and octameric aggregates of 3MX with NH4+, Na+ and K+ ions in the gas phase (MS) and in DMSO-d6 solution (NMR) has been observed. The "internal" H-bonds (N1H...O6) are stronger than the "external" ones (N7H...O2) in these clusters (NMR).
- Szolomajer, Janos,Paragi, Gabor,Batta, Gyula,Guerra, Celia Fonseca,Bickelhaupt, F. Matthias,Kele, Zoltan,Padar, Petra,Kupihar, Zoltan,Kovacs, Lajos
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experimental part
p. 476 - 482
(2011/04/22)
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- Purines. XLIX. Synthesis and proton nuclear magnetic resonance study of 3,7-dialkylxanthines and 1,3,7-trialkylxanthines
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A general synthetic route to 3,7-dialkylxanthines (type 9) from 3,7-dialkyladenines (6) [hence from 3- or 7-alkyladenines (11 or 10)] has been established. The route started with ethoxycarbonylation of 1-alkyl-4-(alkylamino)1H-imidazole-5-carboxamides (7), readily obtainable from 6 by alkaline hydrolysis, and proceeded through cyclization of the resulting carbamates (8) under alkaline conditions. Alkylation of 9 with alkyl halide in N,N-dimethylformamide in the presence of anhydrous K2CO3 extended the above synthetic route to the 1,3,7-trialkylxanthine level (type 14). Hydrogenolytic deb nzylation of 3-benzyl-1,7-dimethylxanthine (16), prepared by following this general synthetic route, furnished paraxanthine (26) in fair yield. Conversion of 26 into 3-(4-hydroxy-3-nitrobenzyl)-1,7-dimethylxanthine (24), isomeric with the bryozoan purine phidolopin (2), was effected through aralkylation with 4-(methoxymethoxy)-3-nitrobenzyl bromide (28) followed by O-deprotection. On the basis of proton nuclear magnetic resonance data for the 3,7-dialkylxanthines (3 and 9b-i) and 1,3,7-trialkylxanthines (5 and 14-22) thus prepared, reliable criteria for distinguishing signals of N-alkyl substituents at various positions are put forward.
- Fujii,Saito,Tamura
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p. 2855 - 2862
(2007/10/02)
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- Analogue of Coffeine and Theophylline: Effect of Structural Alterations on Affinity at Adenosine Receptors
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A variety of analogues of caffeine and theophylline in which the 1-, 3-, and 7-methyl substituents have been replaced with n-propyl, allyl, propargyl, and isobutyl and, in few cases with chloroethyl, hydroxyethyl, or benzyl were assessed for potency and s
- Daly, J. W.,Padgett, W. L.,Shamim, M. T.
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p. 1305 - 1308
(2007/10/02)
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- ISOMERIZATION AND DEALKYLATION OF METHYLATED XANTHINIUM DERIVATIVES
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The isomerization or dealkylation of methylated xanthinium derivatives takes place with the participation of nucleophiles and is facilitated in the presence of a sterically hindered configuration.When heated, 7,9-dimethyl- and 1,7,9-trimethylxanthinium salts isomerize to theobromine and caffeine respectively.Under these conditions 3,7,9-trimethyl- and 1,3,7,9-tetramethylxanthinium salts are dealkylated.The 1,7,9- and 3,7,9-trimethylxanthinium betaines are isomerized quantitatively to caffeine.The role of the nucleophile under these conditions is played by the negatively charged fragment in the pyridine part of molecule.An intermolecular mechanism of rearrangement of the 3,7,9-trimethylxanthinium betaine is demonstrated.The sterically overloaded 1,3,8,9-tetramethylxanthine and 1,3,9-trimethyl-8-azaxanthine and not the charged compounds undergo rearrangement.In these cases the nucleophilic center is the doubly bonded N7 atom in the five-membered ring.
- Muravich-Aleksandr, Kh. L.,Kolesova, M. B.,Pernikova, V. G.,Smirnova, N. V.
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p. 562 - 567
(2007/10/02)
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- Les systemes biphasiques. 3. Alkylation des purines en catalyse par transfert de phase (1a)
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The phase transfer catalysed methylation of adenine gave selectively 9-methyladenine (98percent), while benzylation yields 9-benzyladenine as the major product accompanied by very small amounts of the 3-isomer.Alkylation of xanthine, theobromine and theophylline by the same technique gave also the corresponding N.alkyl derivatives in high yields, with no other O-alkylated regioisomer.These alkylation procedures, owing to their simplicity and selectivity, constitute a considerable improvement upon classical techniques.
- Hedayatullah, Mir
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p. 249 - 251
(2007/10/02)
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