Spectroscopic Evaluation of Novel Adenine/Thymine-Conjugated Naphthalenediimides: Preference of Adenine-Adenine over Thymine-Thymine Intermolecular Hydrogen Bonding in Adenine- and Thymine-Functionalized Naphthalenediimides.

The synthesis and spectroscopic characterization of novel nucleobase (adenine/thymine)-conjugated naphthalenediimides (NDIs), namely, NDI-AA, NDI-TT, and NDI-AT have been successfully achieved. NDI-AA, NDI-TT and NDI-AT have similar absorption in the 300-400 nm region. The effect of solvent on the absorption spectrum indicates aggregation, either through intermolecular π-σ interaction among the main chromophore or through intermolecular hydrogen bonding between adenine and adenine group. Addition of water does not assist hydrogen bond formation between thymine-thymine, rather increasing the polarity of the solvent encourages π-σ interaction among NDI-TTs. No spectral change for NDI-TT with increasing temperature confirms hydrogen bonding is not playing a crucial role in NDI-TT. A fluorescence study on NDI-AA also establishes excimer formation along with ground state aggregation. As the water content in the solvent mixture increases, aggregation of NDI-AA is discouraged due to adenine-adenine hydrogen bonding in accordance with earlier results. At the same time, the NDI-TT emission spectrum does not shift to the blue region and the intensity of the peak around 535 nm increases at the expense of fluorescence in 411 nm. Thus, increasing water content in the solvent mixture facilitates aggregation through π-σ interaction in NDI-TT as thymine-thymine hydrogen bonding is less pronounced.

Synthesis and polymerization of 1-(2-diallylaminoethyl)pyrimidines.

We report the preparation and characterization of three pyrimidine-based monomers, specifically: 1-(2-diallylaminoethyl)uracil, 1-(2-diallylaminoethyl)thymine and 1-(2-diallylaminoethyl)cytosine. Monomer synthesis was initiated by reaction of the pyrimidine with ethylene carbonate to form the hydroxyethyl adduct which was subsequently chlorinated to afford the chloroethyl intermediate. Reaction of the chloroethyl derivatives with diallylamine resulted in the desired monomers. We demonstrated a two-fold increase in the overall yield of the three monomers in comparison to reported procedures. The cyclopolymerization and cyclo-copolymerization of 1-(2-diallylaminoethyl)pyrimidine trifluoroacetate salts in water resulted in low-yield homopolymers. In contrast, the neutral 1-(2-diallylaminoethyl)pyrimidines cyclo-copolymerized with sulfur dioxide and V-50 initiator to yield the corresponding copolymers in higher yields ranging from 30 to 60%.

Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu. II. Acylhydrazone-functionalized pyrimidines.

We report herein the synthesis of a novel series of carbocyclic acylhydrazone derivatives of uracil, thymine and cytosine from the corresponding nucleic bases and their biological activity to treat diabetic nephropathy. Intriguingly, five derivatives significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. The anti-oxidative effects displayed by these molecules suggest that their activity might involve a ROS-dependent mechanism.

Turning the heat on conjugated polyelectrolytes: an off-on ratiometric nanothermometer.

We report a self-referenced ratiometric nanothermometer based on short conjugated polyelectrolytes. An amphiphilic macromolecule destabilizes the polymer π-π stacking and makes it possible to shift the equilibrium between the less emissive aggregated state (520 nm) and the brighter individual chain (450 nm) within 20.0 °C and 70.0 °C.

Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu.

The synthesis of a series of novel 3,4-cis- and 3,4-trans-substituted carbocyclic nucleoside analogs from protected uracil and thymine is described. The key reaction in the followed synthetic protocols utilized the Mitsunobu reaction to couple 3,4-substituted cyclopentanols to (3)N-benzoyl uracil or (3)N-benzoyl thymine. These molecules were evaluated with regard to their ability to treat diabetic nephropathy. Our results show that two analogs significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro and, more interestingly, exhibited an anti-oxidative effect suggesting that the activity may be mediated through ROS-dependent mechanism.

Potent and fully noncompetitive peptidomimetic inhibitor of multidrug resistance P-glycoprotein.

N(α)-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-proline (4(R)Hyp) gave compounds 11 and 15 characterized by half-maximal inhibitory concentrations (IC(50)) of 0.6 and 0.2 µM, which are 2- and 7-fold lower than that of the parent molecule. The difference in IC(50) between 11 and 15 rests on the carbonyl group of the peptidyl bond, reduced in 15. Those compounds are rather specific of P-gp, having no or limited activity on MRP1 and BCRP. 15 displayed no marked cytotoxicity up to 10-fold its IC(50). Importantly, 15 equally inhibited the Hoechst 33342 and daunorubicin effluxes through a typical noncompetitive inhibition mechanism, suggesting its binding to a site different from the H and R drug-transport sites.

Inhibition of P-glycoprotein-mediated multidrug efflux by aminomethylene and ketomethylene analogs of reversins.

Several aminomethylene analogs and a ketomethylene analog of reversins were synthesized in order to evaluate their ability to inhibit P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein. These analogs retained good activity compared to cyclosporin A and the original reversins.