Preparation and Antiviral Activity of Several Deoxygenated Ribavirin and Tiazofurin Derivatives

Abstract

Ribavirin and tiazofurin, two nucleosides of known antiviral activity, have been transformed by previously reported methods to yield several deoxy,epoxy, or dideoxy analogues. The deoxygenated derivatives were evaluated for antiviral activity against a host of DNA and RNA viruses; however, no significant in vitro activity was detected.     

Note: NAMD–LP: Filtering and Translating NAMD-generated Files

Abstract

We have empirically tested limits of the magnitude of multiple time steps in molecular dynamics simulations of aqueous systems, and the extent to which these offer a means to shorten computation time. Three different steps were employed, δ₀t for calculation of “bonded” forces, δ₁t for calculations of short-range (< 6 Å) non-bonded forces, and δ₂t for long-range (< 10 Å) non-bonded forces. Each longer step was a multiple of the shortest one. The leap-frog integration algorithm was used with SHAKE for restraint of all bond lengths and water molecules. For a system of SPC water molecules, calculation of short-range non-bonded forces could be done with a time step δ₁t = 10 fs, without appreciable change of the average temperature and energy, radial distribution function or diffusion coefficient. These properties were found to be insensitive to the inclusion of long-range non-bonded forces. A multiple-step protocol with δ₀t = 2, δ₁t = 4 and δ₂t = 16 fs has been compared with a single-step procedure with δt 2 fs for small polypeptides in water. The exploration of conformation space, with crossing of low energy barriers, was tested with the glycine dipeptide and was found to proceed at similar rates. Mean, hysteresis and statistical error of the free energy for changing alanine to α-amino butyric acid in the dipeptide, calculated by the slow-growth method, proved independent of the cutoff distance or exact protocol, within 1 kJ/mol. In conclusion, we recommend, instead of use of a single time step of 2 fs at a 10 Å cutoff, use of a time step δ_t = 4 fs for short-range nonbonded forces and a time step δ₂t = 16 fs for long-range nonbonded forces for a 60% reduction of computation time.     

The Paleobiosphere: a novel device for the in vivo testing of hydrocarbon producing-utilizing microorganisms

The construction and testing of a unique instrument, the Paleobiosphere, which mimics some of the conditions of the ancient earth, is described. The instrument provides an experimental testing system for determining if certain microbes, when provided an adequate environment, can degrade biological materials to produce fuel-like hydrocarbons in a relatively short time frame that become trapped by the shale. The conditions selected for testing included a particulate Montana shale (serving as the “Trap Shale”), plant materials (leaves and stems of three extant species whose origins are in the late Cretaceous), a water-circulating system, sterile air, and a specially designed Carbotrap through which all air was passed as exhaust and volatile were hydrocarbons trapped. The fungus for initial testing was Annulohypoxylon sp., isolated as an endophyte of Citrus aurantifolia. It produces, in solid and liquid media, a series of hydrocarbon-like molecules. Some of these including 1,8-cineole, 2-butanone, propanoic acid, 2-methyl-, methyl ester, benzene (1-methylethyl)-, phenylethyl alcohol, benzophenone and azulene, 1,2,3,5,6,7,8,8a-octahydro-1,4-dimethyl-7-(1-methylethenyl), [1S-(1α,7α,8aβ)]. These were the key signature compounds used in an initial Paleobiosphere test. After 3 weeks, incubation, the volatiles associated with the harvested “Trap Shale” included each of the signature substances as well as other fungal-associated products: some indanes, benzene derivatives, some cyclohexanes, 3-octanone, naphthalenes and others. The fungus thus produced a series of “Trap Shale” products that were representative of each of the major classes of hydrocarbons in diesel fuel (Mycodiesel). Initial tests with the Paleobiosphere offer some evidence for a possible origin of hydrocarbons trapped in bentonite shale. Thus, with modifications, numerous other tests can also be designed for utilization in the Paleobiosphere.     

Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists

Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT₄ receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT_4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT₄ receptor antagonists may be beneficial for treating these conditions. The 5-HT₄ receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT₄ receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT₄ receptor antagonist with moderate affinity for the AT₁ receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a–f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT₄ receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT₄ receptors in both CNS and peripheral organs.     

Stereoselective Synthesis of 1- and 2-O-α-d-Cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols Related to Rhynchosporoside

The stereoselective synthesis of 1- and 2-O-α-d-cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols, which determined the structure of rhynchosporoside produced by Rhynchosporium secalis, and their phytotoxicity toward the host plant (Hordeum vulgare) are described in detail.