Controlling the transmembrane transport of nucleosides

Abstract

Nucleoside analogues are used as drugs. Due to their hydrophilicity, nucleosides are poorly permeable to membranes and transporter proteins are required for efficient uptake. One approach towards improving membrane permeability of nucleosides is to use synthetic transporters. We describe ways to control transport of nucleosides across a liquid membrane. Hexanoylguanosine 1 selectively extracts and transports cytidines across a CHCl 3 membrane. Transport catalysed by G 1 was influenced by the nucleoside's sugar, with a selectivity of dC 4 . rC 3 . araC 5. Selective transport could be modulated by adding compounds to the aqueous source phase or to the organic phase. Addition of K þ 2,6-DNP -8 to CHCl 3 containing G 1 switched off transport of rC 3 and dC 4 due to formation of a G-quartet assembly. A lipophilic G 1·C 2 base pair could not transport dC 4, but did catalyse transport of dG 7 across the CHCl 3 barrier. We propose that transport occurs because of formation of a base triple G 1·C 2·dG 7. Addition of Na 2 B 4 O 7 9 to a source phase containing rC 3, dC 4 and araC 5 shuts down transport of rC 3 by G 1, due to formation of borate esters. These results indicate that one can control the selective transport of nucleosides.

Self-Assembly of Metallo-Nucleoside Hydrogels for Injectable Materials That Promote Wound Closure

“…As shown in the top trace in Figure b, 11 B NMR of a 50 mM solution of C containing 0.5 equiv of boric acid gave a strong signal at δ 11.8 ppm for the cytidine borate (CB) diester (C–B–C) and a signal at δ 8.0 ppm for a CB monoester. These 11 B chemical shifts matched values we have previously reported for cytidine’s borate esters . Solution-state 11 B NMR of a hydrogel made from 50 mM C with 0.5 equiv of both KB­(OH) 4 and AgNO 3 (lower trace in Figure b) showed severely broadened 11 B NMR signals in the δ 8–12 ppm range.…”

“…The 1 H NMR spectra of C (50 mM) in the presence of varying amounts of KB­(OH) 4 are clearly different (Figure c, traces on left). Chemical shifts for the C ribose H1′ are diagnostic for borate ester formation, as the addition of increasing amounts of KB­(OH) 4 gave new signals at δ 5.84 (d, J = 3.1 Hz) for the borate monoester CB and two doublets, in a 1:1 ratio, between δ 5.7–5.9 (d, J = 2.9 Hz) for the 2 diastereomeric C–B–C borate diesters . As depicted in Figure c (upper trace on right), samples that formed hydrogels in the NMR tube (50 mM C with 0.5 equiv of KB­(OH) 4 and AgNO 3 ) showed significantly broadened and decreased intensity NMR signals for both the C–B–C borate diesters and the CB monoester, again indicating that the C borate-ester species are now major components of the gel network and can no longer be observed via solution-state NMR …”

“…These 11 B chemical shifts matched values we have previously reported for cytidine's borate esters. 45 Solution-state 11 B NMR of a hydrogel made from 50 mM C with 0.5 equiv of both KB(OH) 4 and AgNO 3 (lower trace in Figure 2b) showed severely broadened 11 B NMR signals in the δ 8−12 ppm range. This indicates that the addition of Ag + caused the C−B−C diesters and CB monoester in the solution to become part of the gel, forming high-molecular-weight species that are no longer detectable by solution 11 B NMR.…”

“…Chemical shifts for the C ribose H1′ are diagnostic for borate ester formation, as the addition of increasing amounts of KB(OH) 4 gave new signals at δ 5.84 (d, J = 3.1 Hz) for the borate monoester CB and two doublets, in a 1:1 ratio, between δ 5.7−5.9 (d, J = 2.9 Hz) for the 2 diastereomeric C−B−C borate diesters. 45 As depicted in Figure 2c (upper trace on right), samples that formed hydrogels in the NMR tube (50 mM C with 0.5 equiv of KB(OH) 4 and AgNO 3 ) showed significantly broadened and decreased intensity NMR signals for both the C−B−C borate diesters and the CB monoester, again indicating that the C borate-ester species are now major components of the gel network and can no longer be observed via solution-state NMR. 27 To gain more evidence that the C•Ag + •C H-bond motif was necessary for hydrogelation, we explored the metal cation's influence on gelation by adding 0.5 equiv of various cations (Ag + , K + , Cu 2+ , Hg 2+ , Zn 2+ , and Mg 2+ ) to a solution containing 1 equiv of C and 0.5 equiv of B(OH) 3 .…”

Magic-angle spinning NMR spectroscopy provides insight into the impact of small molecule uptake by G-quartet hydrogels

“…It has been reported that added sugars including ribose 65 and especially galactose and lactose 66 can enhance the solubility of adenine in water by using CH-p interactions 67 that disrupt the base stacking processes that lead to adenine aggregation. 68,69 In addition, supramolecular chemistry approaches, 70 including using Rebek/Kemp triacid receptors, 71 cyclodextrins 72,73 and biodegradable polymers 74 have been exploited to increase the water solubility of adenine and enhance its transport across biological membranes.…”