Uracyl derivatives functionalized with N-, S-, O-heterocycles

Abstract

Reactions of 1,3-bis(bromopentyl)-5(6)-substituted uracyls with a series of fi ve-membered heterocycles containing in the ring N, S, or O atoms and a mercapto group as a substituent at the carbon atom of the ring afforded uracyl derivatives of acyclic and macrocyclic structure with 2-thiobenzoxazole, 2-thio-5-methyl-1,3,4-thiadiazole, 2-thiobenzimidazole, and 2,5-dithio-1,3,4-thiadiazole fragments. N atoms of benzoxazole and imidazole fragments of compounds obtained undergo alkylation and quaternization with alkyl iodides and alkyl tosylates.Heterocyclic systems, in particular, fi ve-membered systems containing in the ring N, S, O atoms, exhibit a wide range of biological action. Versatile derivatives of fi ve-membered N-, S-, O-heterocycles containing diverse substituents were synthesized and their biological activity was investigated [1-6]. Compounds of three-dimensional architecture of acyclic or macrocyclic structure containing various number of heterocycles connected by some bridges are far less understood. For instance, the derivatives of nucleotide bases, in particular, of uracyls, connected with hydrocarbon bridges with N-, S-, O-heterocycles are very important. It is presumed that uracyl derivatives due to stronger binding with the biotarget may enhance the physiologic effect or even modify the biological activity of a specifi c pharmacophore connected to uracyl, in our case fi ve-membered N-, S-, O-heterocycles [7-9].This report described the synthesis of compounds consisting of 5-or 6-substituted uracyls connected by methylene chains to versatile fi ve-membered heterocycles. To obtain a uniform reaction course we used heterocycles with a mercapto group attached to a carbon atom of the ring.The choice of initial compounds included the possibility to vary the heteroatoms in the heterocycle composition (N, O, S), to have in the heterocycle composition alongside the mercapto group also another reaction center, in particular, an imide function, and to vary the number of mercapto groups in the heterocyclic fragment. As a result the following heterocycles were used: 2-mercaptobenzoxazole (I), 2-mercapto-5-methyl-1,3,4-thiadiazole (II), 2-mercaptobenzimidazole (III), and 2,5-dimercapto-1,3,4-thiadiazole (IV). The following uracyl derivatives were applied containing haloalkyl substituents: 1,3-bis(bromopentyl)-6-methyluracyl (V) and 1,3-bis(bromopentyl)-5-bromouracyl (VI). The bromine atom was inserted into the uracyl fragment aiming further to replace it by another substituent, e.g., by amino group.The use of DMF as the solvent and sodium hydride as the salt-forming reagent in the reaction of replacing bromine in the 1,3-bis(bromoalkyl)uracyls with heterocyclic fragment was an approach which had been suffi ciently successful in introducing purine derivatives into the alkylsubstituted uracyls [10].In the reaction of dibromide V with heterocycles I and II at room temperature in DMF in the presence of NaH products of substitution of both Br atoms, compounds VII and VIII, were obtained in 66 and 70% yield respecti...

Influence of lipid bilayer properties on nanodisc formation mediated by styrene/maleic acid copolymers

“…Population of a significant pool of free SMA(3 : 1) in the aqueous solution would manifest in a nonzero ordinate intercept in the phase diagrams, as observed for detergents with high critical micellar concentrations. 37,44,45 Note, however, that this does not formally rule out the existence of free polymer chains at polymer/lipid ratios higher than R m,SOL S or in proteincontaining samples, as it is conceivable that membrane proteins retain lipid molecules in bilayer patches and, thus, render them unavailable for interaction with the polymer. 46 Then, addition of "excess" polymer could, in principle, result in the build-up of a pool of free polymer that coexists with polymerbounded, protein-containing nanodiscs.…”