Live cell cytoplasm staining and selective labeling of intracellular proteins by non-toxic cell-permeant thiophene fluorophores.

A structurally correlated series of cell-permeant thiophene fluorophores, characterized by intense green or red fluorescence inside live mouse embryonic fibroblasts, was developed. The fluorophores displayed rapid internalization, excellent retention inside the cells, and high optical stability in the cytosolic environment and did not alter cell viability and reproducibility. Depending on the molecular structure, they experienced distinct fate inside the cells: from bright and lasting staining of the cytoplasm to selective tagging of a small set of globular proteins.

Solution-phase microwave-assisted synthesis of unsubstituted and modified alpha-quinque- and sexithiophenes.

The facile synthesis of poorly soluble unsubstituted and modified alpha-quinque- and sexithiophenes under microwave irradiation in the liquid phase is described. The use of microwave irradiation allowed these compounds to be prepared in a few minutes and at high yields by means of the Suzuki cross-coupling reaction. Unsubstituted sexithiophene was obtained in 10 min via the one-pot borylation/Suzuki reaction, purified according to a very simple procedure, and isolated in 84% yield. The efficient synthesis of two new methylated quinque- and sexithiophenes displaying liquid crystalline properties is reported. A new microwave-assisted methodology for the conversion of aldehyde-terminated quinque- and sexithiophenes into the corresponding cyano derivatives is also described. The use of microwaves was extended to the Sonogashira coupling reaction and found to be very effective in the preparation of a quinquethiophene containing acetylenic spacers. The electronic and optical characterization of this compound is reported and discussed in relation to that of unsubstituted quinquethiophene.

Ribavirin conjugated with lactosaminated poly-L-lysine: selective delivery to the liver and increased antiviral activity in mice with viral hepatitis.

Ribavirin (RIBV) is a useful drug in the treatment of chronic type C hepatitis but displays a toxicity for red blood cells (RBC), which limits its dosage and necessitates withdrawal in some patients. Selective concentration of RIBV in liver should improve therapeutic results. Liver targeting can be achieved by coupling the drug to galactosyl-terminating peptides, which specifically enter hepatocytes. In the present work, we conjugated RIBV to lactosaminated poly-L-lysine (L-Poly(Lys)), a hepatotropic carrier enabling intramuscular (IM) administration of conjugates. The L-Poly(Lys)-RIBV conjugate had a heavy drug load (312-327 microg of RIBV in 1 mg of conjugate) and was very soluble in 0.9% NaCl (200 mg/mL). The conjugate was devoid of acute toxicity in mouse. When incubated with human or mouse blood, it did not release the drug. After IM administration to mice, the conjugate was selectively taken up by the liver, where the drug was released in a pharmacologically active form. This was demonstrated using mice infected with a strain of murine hepatitis virus (MHV) sensitive to RIBV. Coupled RIBV, IM injected, inhibited MHV replication in liver at a daily dose two to three times lower than that of the free drug. In mice IM injected with a conjugate tritiated in the RIBV moiety, the ratios between the levels of radioactivity in liver and RBC were two times higher than in animals injected with free tritiated RIBV. In conclusion, the present results support the possibility that the chemotherapeutic index of RIBV in chronic type C hepatitis can be increased by conjugation with L-Poly(Lys).

Polyhydroxyoligothiophenes. 2. Hydrogen-Bonding-Oriented Solid State Conformation of 3,3'-Bis(2-hydroxyethyl)-2,2'-bithiophene and Regioselective Synthesis of the Corresponding Head-to-Head/Tail-to-Tail Quater- and Sexithiophene.

This paper reports the X-ray structure of 3,3'-bis(2-hydroxyethyl)-2,2'-bithiophene (1), which is the building block for the synthesis of head-to-head/tail-to-tail 2-hydroxyethyl-substituted oligothiophenes. Contrary to all the bithiophenes reported so far, 1 exhibits a noncoplanar anti conformation and an inter-ring twist angle (67.5 degrees ) which is the largest ever measured for adjacent rings of alpha-conjugated oligothiophenes. This unusual conformation appears to be dictated by intermolecular hydrogen-bonding interactions involving the OH groups, which bind the molecule in close packed layers. The paper also describes the regioselective synthesis of the dimer and the trimer of 1, namely of 3,3',4",3"'-tetrakis(2-hydroxyethyl)-2,2':5',2":5",2"'-quaterthiophene (3c) and of 3,3',4",3"',4"",3""'-hexakis(2-hydroxyethyl)-2,2':5',2":5",2"':5"',2"":5"",2""'-sexithiophene (4b). 3c And 4b were obtained through palladium(0)-catalyzed coupling of the mono- and distannanes of the tetrahydropyranyl derivative of 1 with the appropriate monobromo compound (Stille's reaction). Finally, the paper reports force-field calculations which suggest that the low lambda(max) values measured for 1, 3c, and 4b are also the result of intramolecular hydrogen-bonding interactions which favor highly twisted conformations in solution.

[Exercise tolerance in angina patients 3 and 24 hours after administration of a new delayed-action preparation of metoprolol]. / Tolleranza allo sforzo fisico, in anginosi, a 3 e 24 ore dalla somministrazione di una nuova formulazione "retard" di metoprololo.

To assess the duration of improved exercise tolerance by metoprolol given in a new sustained-release formulation, 40 in-patients affected by stable exercise-induced angina pectoris received single-blind placebo in day 1 and thereafter, in double-blind cross-over once daily administration, metoprolol RETARD 100 mg and 200 mg in days 3 and 5. Symptom-limited cycloergometric exercise tests were performed at 3 and 24 hours after placebo and after each of the two doses of metoprolol RETARD. Duration of exercise, maximal workload and total work performed did significantly increase at 3 and 24 hours after metoprolol RETARD 100 mg (P less than 0.01) and 200 mg (P less than 0.01), without any significant difference between the two doses. Peak systolic arterial pressure and heart rate were lowered by metoprolol RETARD 200 mg at 3 (P less than 0.01) and 24 (P less than 0.01) hours, whereas only the peak heart rate at 3 hours was lowered (P less than 0.05) by the 100 mg dose. It is concluded that in patients with stable exercise-induced angina pectoris, metoprolol RETARD 200 mg appears to be able to increase exercise tolerance and to reduce exercise-induced myocardial oxygen consumption throughout 24 hours period. This may justify a once daily dosing schedule of the 200 mg dose, aimed at improving patient compliance.