Single-Crystal X-ray Diffraction Studies of Solvated Crystals of C60 Reveal the Intermolecular Interactions between the Component Molecules.

The solid-state structures of seven solvates of C60 (C60·4tetrachloroethylene, C60·2tetrachloroethylene, C60·3benzene, C60· n-pentane, C60·diethyl ether, C60·chlorobenzene, and C60·benzene·dichloromethane) were determined by single-crystal X-ray diffraction at low temperature. At 90 K, the fullerene and solvate components are generally well-ordered and do not show the orientational disorder that plagues similar structures determined at room temperature. Interactions between the solvate molecules and the fullerene and between adjacent C60 molecules were examined and analyzed. Van der Waals and weak charge-transfer interactions are important to help to organize the individual components in these structures. The weak Lewis acid behavior of C60, such as when it cocrystallizes with diethyl ether or chlorinated solvents, is apparent. In addition, π-stacking interactions are prevalent. The solvates of C60 reported here were frequently obtained from attempts to cocrystallize C60 with another chemical compound. Although the desired cocrystals were never formed, the unincorporated molecules influenced solvate formation.

2-Aminoethanol Extraction as a Method for Purifying Sc3N@C80 and for Differentiating Classes of Endohedral Fullerenes on the Basis of Reactivity.

Extraction with 2-aminoethanol is an inexpensive method for removing empty cage fullerenes from the soluble extract from electric-arc-generated fullerene soot that contains endohedral metallofullerenes of the type Sc3N@C2n (n = 34, 39, 40). Our method of separation exploits the fact that C60, C70, and other larger, empty cage fullerenes are more susceptible to nucleophilic attack than endohedral fullerenes and that these adducts can be readily extracted into 2-aminoethanol. This methodology has also been employed to examine the reactivity of the mixture of soluble endohedral fullerenes that result from doping graphite rods used in the Krätschmer-Huffman electric-arc generator with the oxides of Y, Lu, Dy, Tb, and Gd. For example, with Y2O3, we were able to detect by mass spectrometry several new families of endohedral fullerenes, namely Y3C108 to Y3C126, Y3C107 to Y3C125, Y4C128 to Y4C146, that resisted reactivity with 2-aminoethanol more than the empty cage fullerenes and the mono- and dimetallo fullerenes. The discovery of the family Y3C107 to Y3C125 with odd numbers of carbon atoms is remarkable, since fullerene cages must involve even numbers of carbon atoms. The newly discovered families of endohedral fullerenes with the composition M4C2n (M = Y, Lu, Dy, Tb, and Gd) are unusually resistant to reaction with 2-aminoethanol. Additionally, the individual endohedrals, Y3C112 and M3C102 (M = Lu, Dy, Tb and Gd), were remarkably less reactive toward 2-aminoethanol.

Zafirlukast inhibits complexation of Lsr2 with DNA and growth of Mycobacterium tuberculosis.

The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a global repressor of gene transcription. Here we describe experiments demonstrating that zafirlukast inhibits the complexation between Lsr2 and DNA in vitro. Zafirlukast is shown to inhibit growth in two different species of mycobacteria tested but exhibits no growth inhibition of Escherichia coli. The Lsr2 inhibitory activity is reflected in vivo as determined by monitoring of transcription levels in Mycobacterium tuberculosis. These data suggest that zafirlukast inhibits Lsr2 function in vivo, promoting dysregulation of the expression of an array of genes typically bound by Lsr2 and hindering growth. Since zafirlukast likely operates by a mechanism distinct from current M. tuberculosis drugs and is currently used as a prophylactic treatment for asthma, it offers an intriguing lead for development of new treatments for tuberculosis.

Kinase Inhibitor Library Screening Identifies the Cancer Therapeutic Sorafenib and Structurally Similar Compounds as Strong Inhibitors of the Fungal Pathogen Histoplasma capsulatum.

Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the midwestern and southern United States. It causes mycoses ranging from subclinical respiratory infections to severe systemic disease, and is of particular concern for immunocompromised patients in endemic areas. Clinical management of histoplasmosis relies on protracted regimens of antifungal drugs whose effectiveness can be limited by toxicity. In this study, we hypothesize that conserved biochemical signaling pathways in the eukaryotic domain can be leveraged to repurpose kinase inhibitors as antifungal compounds. We conducted a screen of two kinase inhibitor libraries to identify compounds inhibiting the growth of Histoplasma capsulatum in the pathogenic yeast form. Our approach identified seven compounds with an elongated hydrophobic polyaromatic structure, five of which share a molecular motif including a urea unit linking a halogenated benzene ring and a para-substituted polyaromatic group. The top hits include the cancer therapeutic Sorafenib, which inhibits growth of Histoplasma in vitro and in a macrophage infection model with low host cell cytotoxicity. Our results reveal the possibility of repurposing Sorafenib or derivatives thereof as therapy for histoplasmosis, and suggest that repurposing of libraries developed for human cellular targets may be a fruitful source of antifungal discovery.

New tetraazaannulene hosts for fullerenes.

Two modifications to the doubly concaved host molecules based on well-known nickel tetraazaannulene complexes have resulted in the preparation of the compounds Ni(NapTMTAA).2benzene, 1,6,8,15,17-tetramethyldinapthalene-5,9,14,18-tetraazacyclotetradecinatonickel(II), and Ni(Cl(4)TMTAA).CH(2)Cl(2), 2,3,11,12-tetrachloro-6,8,15,17-tetramethyldibenzo-5,9,14,18-tetraazacyclotetradecinatonickel(II). When crystallized with C(60) in carbon disulfide, the crystalline, well-ordered, host-guest compounds Ni(NapTMTAA).C(60).2CS(2) and Ni(Cl(4)TMTAA).C(60).2CS(2) were formed. The compounds were characterized by X-ray crystallography. The crystal structures of the precursor host molecules showed very strong host-host interactions, particularly in the case of Ni(Cl(4)TMTAA), which had short Ni...Ni interactions of 3.3860(11) and 3.5888(11) A in the two different dimers in the asymmetric unit; yet, these host-host interactions were entirely destroyed in the resultant host-guest compounds, and C(60) molecules were shown to make use of both cusps of the host macrocycle in the formation of a shape-selective arrangement.

Bis[1-(1-adamantyliminomethyl)-2-naphtholato-κN,O]cobalt(II).

The title compound, [Co(C(21)H(22)NO)(2)], crystallizes with two mol-ecules in the asymmetric unit. The coordination environments of the two Co(II) ions are distorted tetra-hedral. The primary structural difference between the two independent complex mol-ecules lies in the orientations of their adamantyl groups.

A large scale virtual screen of DprE1.

Tuberculosis continues to plague the world with the World Health Organization estimating that about one third of the world's population is infected. Due to the emergence of MDR and XDR strains of TB, the need for novel therapeutics has become increasing urgent. Herein we report the results of a virtual screen of 4.1 million compounds against a promising drug target, DrpE1. The virtual compounds were obtained from the Zinc docking site and screened using the molecular docking program, AutoDock Vina. The computational hits have led to the identification of several promising lead compounds.

A structural comparative approach to identifying novel antimalarial inhibitors.

Malaria continues to affect millions of people annually. With the rise of drug resistant strains, the need for alternative treatments has become increasingly urgent. Recently, PfUCHL3 was identified as an essential deubiquitinating enzyme. The increasing number of drug target structures being solved has increased the feasibility of utilizing a structural comparative approach to identifying novel inhibitors. Using AutoDock Vina, we recently screened the NCI library of about 320,000 compounds against the crystal structure of PfUCHL3. The top hits were subsequently screened against its human ortholog UCHL3 as to identify compounds that could specifically target the PfUCHL3 over its human counterpart. This method was used to identify small molecule inhibitors that can preferentially inhibit the parasitic enzyme. Several compounds were identified that demonstrated significant binding affinity preference for the malaria target over the human enzyme. Two of these compounds demonstrated ng/mL activity.