Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

Milling-induced disorder of pharmaceuticals: one-phase or two-phase system?

During milling, components are subjected to shear and tensile stresses, which can result in physical phase transformations. The purpose of the work described in this report is to understand the pathway by which two test compounds, d-salicin and γ-indomethacin, undergo a crystalline to amorphous transformation during cryomilling. The results show that the transformation cannot be described by a standard one-phase or two-phase disordering mechanism. In the one-phase model, a continuous set of states exist, linking perfect crystalline with completely amorphous material, whereas the two-phase model of disorder depicts the material as a binary mixture of crystalline and amorphous fractions. Instead, a model is proposed where two one-phase regions, defected crystalline and amorphous regions, are separated by a distinct transition.

Apoptotic and chemotherapeutic properties of iron (III)-salophene in an ovarian cancer animal model.

The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC(50) at ~1 muM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC(50) at 60 muM) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30-60 muM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 muM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in the induction of cell death by Fe-SP occurred after 3 hrs as indicated by the mitochondrial transmembrane potential (DeltaPsim) and was mainly linked to apoptotic, not necrotic events. To evaluate the toxicity of Fe-SP in vivo we conducted an acute toxicity study in rats. The LD(50) of Fe-SP is >2000 mg/kg orally and >5.5 mg/kg body weight by intraperitoneal injection. An ovarian cancer animal model showed that the chemotherapeutic relevant dose of Fe-SP in rats is 0.5-1 mg/kg body weight. The present report suggests that Fe-SP is a potential therapeutic drug to treat ovarian cancer.

Employment of 2,6-diacetylpyridine dioxime as a new route to high nuclearity metal clusters: Mn6 and Mn8 complexes.

The employment of the anion of 2,6-diacetylpyridine dioxime (dapdoH2) as a pentadentate chelate in transition metal cluster chemistry is reported. The syntheses, crystal structures, and magnetochemical characterization are described for [Mn6O2(OMe)2(dapdo)2(dapdoH)4](ClO4)2 (1), [Mn6O2(OMe)2(dapdo)2(dapdoH)4][Ca(NO3)4] (2), and [Mn8O4(OH)4(OMe)2(N3)2(dapdo)2(dapdoH)2(H2O)2] (3). The reaction of [Mn3O(O2CMe)6(py)3](ClO4) with 3 equiv of dapdoH2 (with or without 2 equiv of NEt3) in MeOH gave 1. The same cation, but with a [Ca(NO3)4]2- anion, was found in complex 2, which was obtained from the reaction in MeOH between Mn(NO3)2, Ca(NO3)2, and dapdoH2 in the presence of NEt3. In contrast, addition of NaN3 to several reactions comprising MnCl2, dapdoH2, and NEt3 in MeOH gave the octanuclear complex 3. Complexes 1-3 all possess rare topologies and are mixed-valence: 2MnII, 4MnIII for 1 and 2, and 2MnII, 6MnIII for 3. The core of the cation of 1 and 2 consists of two edge-sharing Mn4 tetrahedra at the center of each of which is a micro4-O2- ion. Peripheral ligation is provided by two micro-OMe-, four micro-dapdoH-, and two micro3-dapdo2- groups. The core of 3 consists of two [MnIIMnIII3(micro3-O)2]7+ "butterfly" units linked together by one of the micro3-O2- ions, which thus becomes micro4. Peripheral ligation is provided by four micro-OMe-, two micro-OH-, two micro-dapdoH-, and two micro4-dapdo2- groups. Variable-temperature, solid-state dc and ac magnetization studies were carried out on complexes 1-3 in the 5.0-300 K range; the data for 1 and 2 are identical. Fitting of the obtained magnetization versus field (H) and temperature (T) data by matrix diagonalization and including only axial anisotropy (zero-field splitting, D) established that 1 possesses an S=5 ground state with D=-0.24 cm(-1). For 3, low-lying excited states precluded obtaining a good fit from the magnetization data, and the ground state was instead determined from the ac data, which indicated an S=1 ground state for 3. The combined work demonstrates the ligating flexibility of pyridyl-dioxime chelates and their usefulness in the synthesis of new polynuclear Mnx clusters without requiring the co-presence of carboxylate ligands.

Coordination polymer gels: synthesis, structure and mechanical properties of amorphous coordination polymers.

The synthesis and mechanical properties of a new class of coordination polymer based materials, amorphous coordination polymer sol-gels and xerogels, is presented.