129487-99-6Relevant articles and documents
Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
Prasad, Bagineni,Jamroskovic, Jan,Bhowmik, Sudipta,Kumar, Rajendra,Romell, Tajanena,Sabouri, Nasim,Chorell, Erik
, p. 7926 - 7938 (2018)
Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.
Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain
Kort, Michael E.,Drizin, Irene,Gregg, Robert J.,Scanio, Marc J. C.,Shi, Lei,Gross, Michael F.,Atkinson, Robert N.,Johnson, Matthew S.,Pacofsky, Gregory J.,Thomas, James B.,Carroll, William A.,Krambis, Michael J.,Liu, Dong,Shieh, Char-Chang,Zhang, XuFeng,Hernandez, Gricelda,Mikusa, Joseph P.,Zhong, Chengmin,Joshi, Shailen,Honore, Prisca,Roeloffs, Rosemarie,Marsh, Kennan C.,Murray, Bernard P.,Liu, Jinrong,Werness, Stephen,Faltynek, Connie R.,Krafte, Douglas S.,Jarvis, Michael F.,Chapman, Mark L.,Marron, Brian E.
, p. 407 - 416 (2008/09/18)
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an NavL8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 v1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed > 100-fold selectivity versus human sodium (Na v1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
QUINAZOLINE DERIVATIVES
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Page/Page column 107, (2008/06/13)
The invention concerns quinazoline derivatives of Formula (I) or a pharmaceutically-acceptable salt thereof, wherein each of X1, p, R1, q, R2, R3, R4, R5, Ring A, r and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.
