- Development of a series of bis-triazoles as G-quadruplex ligands
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Maintenance of telomeres-specialized complexes that protect the ends of chromosomes-is provided by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types. Telomeric ends of chromosomes consist of noncoding repeat sequences of guanine-rich DNA. These G-rich ends can fold into structures called G-quadruplexes. Stabilization of G-quadruplexes by small binding molecules called G4 ligands can prevent telomerase enzyme from maintaining telomere integrity in cancer cells. G-quadruplexes can exist in other parts of the genome too, especially within promoter sequences of oncogenes, and also be interesting drug targets. Here, we describe the development of a new series of novel bis-triazoles, designed to stabilize G-quadruplex structures selectively as G4 ligands. FRET assays showed two compounds to be moderately effective G4 binders, with particular affinity for the quadruplex formed by the Hsp90a promoter sequence, and good selectivity for G-quadruplex DNA vs. duplex DNA. However, CD spectroscopy failed to provide any information about the folding topology of the human telomeric G-quadruplex resulting from its interaction with one of the ligands. All the new ligands showed potent cell growth inhibitory properties against human colon and pancreatic cancer cell lines, as evidenced by the MTT assay; notably, they were more potent against cancer cells than in fetal lung fibroblasts. Docking studies were performed to rationalize the affinity of these ligands for binding to the telomeric parallel G-quadruplex DNA.
- Saleh, Maysaa M.,Laughton, Charles A.,Bradshaw, Tracey D.,Moody, Christopher J.
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p. 47297 - 47308
(2017/10/19)
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- PYRIDOIMIDAZOLE DERIVATIVES
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The present invention relates to pyridoimidazole derivatives that act as cannabinoid receptor ligands, e.g., CB2 ligands. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment
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Page/Page column 15
(2008/06/13)
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- Quinazoline derivatives as VEGF inhibitors
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The invention relates to quinazoline derivatives of formula (I) STR1wherein: Z represents --O--, --NH-- or --S--; m is an integer from 1 to 5; R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluorometlyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or NR 5 R 6 (wherein R 5 and R 6, which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino, or nitro; R 3 represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X 1 represents --O--, --CH 2 --, --S--, --SO--, SO 2 --, --NR 6 --, NR 8 CO--, --CONR 9 --SO 2 NR 10 -- or --NR 11 SO 2 --, (wherein R 7, R 8, R 9, R 10 and R 11 each represents C 1-3 alkyl, C 1-3 alkoxyC 2-3 alkyl); R 4 represents a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted 5 or 6 membered saturated carbocylic or heterocyclic group; and salts thereof, processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient the compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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- Fast ester cleavage of sterically hindered α- and β-aminoesters under non-aqueous conditions. Application to the kinetic resolution of aziridine esters
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Various protected α- and β-aminoesters undergo fast ester cleavage by treatment with t-BuOK in THF. The accelerating effect of a neighboring chelating group was used for the efficient kinetic resolution of non-racemic aziridine esters. (C) 2000 elsevier Science Ltd.
- Alezra, Valérie,Bouchet, Céline,Micouin, Laurent,Bonin, Martine,Husson, Henri-Philippe
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p. 655 - 658
(2007/10/03)
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- New N-substituted 1-hydroxy-3-aminopropylidenediphosphonic acids
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N-Substituted 1-hydroxy-3-aminopropylidenediphosphonic acids were synthesized. Their acid-base and complexation properties toward a wide series of metal cations in water were investigated.
- Shcherbakov,Bel'skii,Gukasova,Polikarpov,Kabachnik
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p. 1732 - 1735
(2007/10/03)
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- Symmetry-Based Inhibitors of HIV Protease. Structure-Activity Studies of Acylated 2,4-Diamino-1,5-diphenyl-3-hydroxypentane and 2,5-Diamino-1,6-diphenylhexane-3,4-diol
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The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described.Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed.Aqueous solubility was enhanced >1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro.Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors.The oral bioavailability of inhibitor 19 in rats was 19percent; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro.Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
- Kempf, Dale J.,Codacovi, Lynnmarie,Wang, Xiu Chun,Kohlbrenner, William E.,Wideburg, Norman E.,et al.
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p. 320 - 330
(2007/10/02)
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- Chartreusin derivatives and salts thereof
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This invention relates to a novel chartreusin derivative of the general formula (I): STR1 and a salt thereof. This chartreusin derivative and a salt thereof have an excellent antitumor activity, which is exhibited even when the site of cancer inoculation
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- Ester Saponification in Dipolar Aprotic Solvents: Role of Solvent-Solute Ground State Interactions
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The rates of hydrolysis of the aryl esters of 3-aminopropionates and phenyl 3-morpholinopropionate have been measured in aqueous ethanol and aqueous DMSO solvent media.The magnitude of rate acceleration in aq.DMSO as compared to aq. ethanolis much lower for above esters than that observed for aryl benzoates.The reduced rate acceleration in aq.DMSO is due to the solvation of the ground state of the ester by DMSO by interaction of the lone pair on the nitrogen of the ester with the DMSO dipole.
- Chandrasekar, R.,Venkoba Rao, G.,Venkatasubramanian, N.
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p. 515 - 516
(2007/10/02)
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