5213-08-1Relevant academic research and scientific papers
Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
, p. 5403 - 5413 (2011/10/02)
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase
Liu, Yaya,Donner, Pamela L.,Pratt, John K.,Jiang, Wen W.,Ng, Teresa,Gracias, Vijaya,Baumeister, Steve,Wiedeman, Paul E.,Traphagen, Linda,Warrior, Usha,Maring, Clarence,Kati, Warren M.,Djuric, Stevan W.,Molla, Akhteruzzaman
scheme or table, p. 3173 - 3177 (2009/04/11)
Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.
Synthesis and anti-staphylococcal activity of new halogenated pyrroles related to pyrrolomycins F
Raimondi, Maria Valeria,Schillaci, Domenico,Petruso, Salvatore
, p. 1407 - 1411 (2008/09/19)
(Chemical Equation Presented) The chemical synthesis of new halogenated pyrroles related to pyrrolomycins F is described and the anti-staphylococcal activity compared. The replacement of 4′-bromo atom of parent compounds with two chloro atoms at 3′ and 5′
Synthesis of bis(arylcarbonylamino-1H-benzimidazol-5-yl) ethers
Pilyugin,Sapozhnikov,Chikisheva,Kiseleva,Vorob'eva,Klimakova,Sapozhnikova,Kuznetsova
, p. 1327 - 1330 (2008/02/04)
A procedure has been developed for the synthesis of bis(arylcarbonylamino- 1H-benzimidazol-5-yl) ethers by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide, followed by treatment of the resulting N-cyanobenzamide with 4-(3,4-diaminophenoxy)benzene-1,2-diamine in acid medium. Nauka/Interperiodica 2006.
Acyl derivatives of 2-aminobenzimidazole and their fungicide activity
Pilyugin,Sapozhnikov,Sapozhnikova
, p. 738 - 743 (2007/10/03)
Procedures have been developed for the preparation of methyl 2-benzimidazolylcarbamate, 2-acetylaminobenzimidazole, 2- benzoylaminobenzimidazole, 2-(3,5-dibromo-2-hydroxybenzoylamino)benzimidazole, 1-(3,6-dichloro-2-methoxybenzoyl)-2-aminobenzimidazole, 2-(3,5-dichloro-2- hydroxybenzoylamino)benzimidazole, 2-(3,5-dichloro-2-methoxybenzoylamino) benzimidazole, and 1-(3,5,6-trichloro-2-methoxybenzoyl)-2-aminobenzimidazole. The synthesized compounds have been tested for fungicide activity.
A Complex Induced Proximity Effect in the Anionic Fries Rearrangement of o-Iodophenyl Benzoates: Synthesis of Dihydro-O-methylsterigmatocystin and Other Xanthones
Horne, Stephen,Rodrigo, Russell
, p. 4520 - 4522 (2007/10/02)
The success of an anionic Fries rearrangement, used to synthesise dihydro-O-methylsterigmatocystin and other xanthones, is dependent on the presence of a remote methoxyl substituent.
Marine Bacteria, I. - Synthesis of Pentabromopseudiline, a Cytotoxic Phenylpyrrole from Alteromonas luteo-violaceus
Laatsch, Hartmut,Pudleiner, Heinz
, p. 863 - 882 (2007/10/02)
A new synthesis of 2,3,4-tribromo-5-(3,5-dibromo-2-hydroxyphenyl)pyrrole (1a, pentabromopseudiline), an antibiotic, enzymeinhibitory and cytotoxic active constituent of the marine bacterium Alteromonas luteo-violaceus, is described.For investigation of structure-activity relationships further 2-phenylpyrroles are investigated.Key step in their synthesis is the Grignard reaction of 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (9d) with benzoyl chlorides yielding γ-phenyl-γ-ketoaldehydes 24, and the Paal-Knorr cyclisation of the latter. - Key Words: Alteromonas luteo-violaceus / Bromopyrrole / Marine bacteria / Pentabromopseudiline
