36438-66-1Relevant articles and documents
Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2
Nguyen, Lien,Lee, Ju Yeon,Wong, Chun-Ho,Zimmerman, Steven C.
, p. 2455 - 2462 (2014)
Myotonic dystrophy type 2 (DM2) is caused by an expansion of CCTG repeats in the zinc-finger protein gene (ZNF9). Transcribed CCUG repeats sequester muscleblind-like protein 1 (MBNL1), an important alternative splicing regulator, preventing its normal function, leading to the disease phenotype. We describe a series of ligands that disrupt the MBNL1-r(CCUG)n interaction as potential lead agents for developing DM2 therapeutics. A previously reported triaminopyrimidine-acridine conjugate was a moderate inhibitor in vitro, however it proved to be poorly water-soluble and not cell-permeable. To improve its therapeutic potential, the new set of ligands maintained the key triaminopyrimidine recognition unit but replaced the acridine intercalator with a bisamidinium groove binder. The optimized ligands exhibit low micromolar inhibition potency to MBNL1-r(CCUG)8. Importantly, the ligands are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cytotoxicity. Targeting toxic RNA: A series of optimized ligands with two triaminopyrimidine recognition units linked to a bisamidinium groove binder is described. They exhibit low-micromolar inhibition potency to the MBNL1-r(CCUG)8 interaction and are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cytotoxicity.
Direct platination as a route to conformationally restricted enantiopure C2-symmetric bisoxazoline pincer complexes
Fossey, John S.,Jones, Geraint,Motevalli, Majid,Nguyen, Huy V.,Richards, Christopher J.,Stark, Mark A.,Taylor, Helen V.
, p. 2067 - 2073 (2007/10/03)
(S)-3-Amino-4-cyclohexyl-2-methylbutan-2-ol 10 was synthesised in four-steps from (S)-2-amino-3-cyclohexanepropanoic acid (47% overall yield). Reaction of 10 with 1,3-bis(ethyl carboximidate)benzene gave (S,S)-1,3-bis(4′-cyclohexylmethyl-5
Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles)
Fairley,Tidwell,Donkor,Naiman,Ohemeng,Lombardy,Bentley,Cory
, p. 1746 - 1753 (2007/10/02)
A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA)·poly(dT), poly(dA-dT)·poly-(dA-dT), and poly(dG-dC)·poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (ΔT(m)) and viscosity. The compounds show a greater affinity for poly(dA)·poly(dT) and poly(dA-dT)·poly(dA-dT) than for poly(dG-dC)·poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.
