- Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups
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A synthesis of new 2,6-disubstituted and 2,6,8-trisubstituted 7-methylpurines as well as 8-substituted 3,7-dimethylxanthines containing a triple bond chain have been worked out. Purinethiones and xanthinethiones were converted into propynylthio derivatives, which were then further transformed via a Mannich reaction into aminobutynylthio derivatives (amine = pyrrolidine, piperidine, morpholine, and diethylamine). The products thus obtained represent various types of the purine and xanthine structure: 8-mono-, 2,6- and 6,8-dipropynylthio, 6- and 8-monoaminobutynylthio, 2,6- and 6,8-diaminobutynylthio derivatives. All of these compounds were tested for their anticancer activity against human glioblastoma SNB-19, human adenocarcinoma MDA-MB-231, and melanoma C-32 cell lines. The anticancer activity depends on the nature of the substituent and its localization in the purine and xanthine framework. Generally, compounds possessing two alkynylthio groups (propynylthio or aminobutynylthio) were more active than those possessing only one group. Some compounds exhibited stronger or similar anticancer activity to cisplatin. All compounds were also tested for their cytotoxic activity against normal human fibroblasts (HFF-1). The most promising anticancer compounds were found to be 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N-morpholinylbutynylthio)-7-methylpurine 15c acting selectively on glioblastoma SNB-19, melanoma C-32, and adenocarcinoma MDA-MB-231 with the IC50 = 0.07–4.08 μg/mL.
- Kowalska, Alicja,Pluta, Krystian,Latocha, Ma?gorzata
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- Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
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Fibroblast activation protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
- Jansen, Koen,De Winter, Hans,Heirbaut, Leen,Cheng, Jonathan D.,Joossens, Jurgen,Lambeir, Anne-Marie,De Meester, Ingrid,Augustyns, Koen,Van Der Veken, Pieter
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supporting information
p. 1700 - 1707
(2014/12/12)
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- Microwave-assisted synthesis of 8-mercapto-3-methyl-7-alkyl xanthines - An improved method
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A microwave-assisted synthetic method to prepare novel 8-mercapto-3-methyl- 7-alkyl xanthine compounds is reported. Compared to conventional synthetic route, the new method significantly shortened synthetic steps and reaction time.
- Zhang, Lei,Zhang, Y. John
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p. 775 - 778
(2007/10/03)
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- Therapeutic compounds for inhibiting interleukin-12 signals and method for using same
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- THERAPEUTIC COMPOUNDS FOR INHIBITING INTERLEUKIN-12 SIGNALING AND METHODS FOR USING SAME
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- Compounds for ceramide-mediated signal transduction
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Novel isoquinoloine compounds inhibit inflammatory responses associated with TNF-α and fibroblast proliferation in vivo and in vitro. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Preferred compounds of the invention are esters. Methods for the use of the novel compounds to inhibit ceramide-mediated intracellular responses to stimuli in vivo (particularly TNF-α) are also described. The methods are expected to be of use in reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression.
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- Substituted xanthines, pteridinediones, and related compounds as potential antiinflammatory agents. Synthesis and biological evaluation of inhibitors of tumor necrosis factor α
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A series of analogues of pentoxifylline metabolites were prepared in the purine, pteridine, [1,2,5]-thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and evaluated for their ability to inhibit the production of tumor necrosis factor-α (TNFα) in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human neutrophils in order to help determine their mechanism of action. Selected compounds which showed good activity in the in vitro TNFα assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compounds in the TNFα assay, 6, 31, and 58, inhibited TNFα production at an IC50 of approximately 5 μM for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leukopenia induced by TNFα in mice, providing more than 60% protection at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNFα production but are devoid of PDE IV inhibitory properties, may have potential as new antiinflammatory agents.
- Cottam, Howard B.,Shih, Hsiencheng,Tehrani, Lida R.,Wasson, D. Bruce,Carson, Dennis A.
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- Novel Syntheses of Theobromine Mercurials Followed by Their Iodo- and Bromo-Demercuration Reactions
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On a prolonged heating the mixture of theobromine (I) with an excess of molten Hg(OCOCF3)2 (obtained in situ), some strongly contaminated melt (II) was furnished containing, however, a considerable amount of a permercurated I.This, on boiling with a large excess of glacial CH3COOH gave the supposed-to-be 1,8-bis(acetoxydimercuri)theobromine (III) in ca 28percent yield.Several attempts to symetrize III by hot aq. solutions of KI or Na2S2O3 failed, a better result was obtained with a hot aq. solution of (NH4)SCN.New 8,8'-mercuribis(threobromine) (IV) was preferably obtained, in 88percent yield, by heating III with an ethanolic solution of hydrazine.Iodo-demercuration of II or III as well as bromo-demercuration of III gave either 8-iodo- (V) or 8-bromo-theobromine (VI), respectively.The structures of III-VI were supported by their reactions, elemental analyses as well as by their 1H-NMR and IR spectra.
- Baranowski, Andrzej,Skulski, Lech
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- ELECTROPHILIC AND NUCLEOPFILIC SUBSTITUTION REACTION IN THE SERIES OF 3-METHYLXANTHINE AND ITS DERIVATIVES
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The reactions of nitration and bromination of 3-methylxanthine were studied.Heating 3-methyl-8-nitroxanthine with con.HCl and HBr leads to a replacement of the nitro group by a halogen atom.The alkylation of 8-haloxanthines by alkyl halides were studied.It was shown that boiling 7-substituted 3-methyl-8-bromoxanthine derivatilves with POCl3 and PCl5 leads to the formation of 2,6,8-trichloro-7-alkylpurines.The structure of synthetized compounds was confirmed by counter synthesis, the data of elementary analysis, and mass spectrometry.
- Priimenko, B.A.,Romanenko, N.I.,Klyuev, N.A.,Fedulova, I.V.,Gnatov, N.I.,Garmash, S.N.
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p. 924 - 927
(2007/10/02)
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- BROMO- AND IODODEMERCURATION OF 8-TRIFLUOROACETOXYMERCURI DERIVATIVES OF THEOPHYLLINE AND THEOBROMINE
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Direct C-mercuration in the 8 position of N-acyl derivatives of theophylline and theobromine with mercury(II) trifluoroacetate in a mixture of anhydrous trifluoroacetic acid and trifluoroacetic anhydride is described. 8-Bromo and, respectively, 8-iodo derivatives of both dimethylxanthines were obtained in high yields from 8-trifluoroacetoxymercuri derivatives by the action of an aqueous solution of potassium tribromide or a solution of iodine in acetonitrile.
- Skulski, L.,Wroczynski, P.
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p. 447 - 450
(2007/10/02)
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