Metal Organic Frameworks for Natural Gas Storage in Vehicles

With the increasing demand for alternative fuels the storage of natural gas (NG) in adsorbents like metal organic frameworks (MOFs) will become more important. In order to use MOFs as storage media in fuel delivery systems, the optimization of mass and energy transfer of the system is crucial. For rapid NG filling of a tank, molecules need to reach the adsorption sites within a reasonable time while the heat of adsorption should be dissipated to the environment. In this article, mass transfer in shaped bodies of MOFs was determined by permeability measurements and pulsed field gradient (PFG) NMR spectroscopy. The heat dissipation was also experimentally measured and both data sets were used to set up a theoretical density function theory model to predict the behavior of MOFs for NG storage.     

The Discovery of Phenylbenzamide Derivatives as Grb7‐Based Antitumor Agents

Grb7 is a non‐catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells. Virtual screening strategies involving a shape‐based similarity search, molecular docking, and 2D‐similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide‐based antagonists of the Grb7 SH2 domain. Moderate binding affinities were observed, ranging from K_d=32.3 μM for lead phenylbenzamide NSC 104999 ( 1 ) to K_d=1.1 μM for a structurally related compound, NSC 57148 ( 2 ). Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1 ) to enthalpically driven (NSC 100874 ( 3 ), NSC 55158 ( 4 ), and compound 2 ). Finally, the lead compound 1 was found to decrease the growth of MDA‐MB‐468 breast cancer cells, with an IC₅₀ value of 39.9 μM . It is expected that these structures will serve as novel leads in the development of Grb7‐based anticancer therapeutics.     

Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents

Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC₅₀ values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine.     

Small‐Molecule APOBEC3G DNA Cytosine Deaminase Inhibitors Based on a 4‐Amino‐1,2,4‐triazole‐3‐thiol Scaffold

APOBEC3G (A3G) is a single‐stranded DNA cytosine deaminase that functions in innate immunity against retroviruses and retrotransposons. Although A3G can potently restrict Vif‐deficient HIV‐1 replication by catalyzing excessive levels of G→A hypermutation, sublethal levels of A3G‐catalyzed mutation may contribute to the high level of HIV‐1 fitness and its incurable prognosis. To chemically modulate A3G catalytic activity with the goal of decreasing the HIV‐1 genomic mutation rate, we synthesized and biochemically evaluated a class of 4‐amino‐1,2,4‐triazole‐3‐thiol small‐molecule inhibitors identified by high‐throughput screening. This class of compounds exhibits low‐micromolar (3.9–8.2 μM ) inhibitory potency and remarkable specificity for A3G versus the related cytosine deaminase, APOBEC3A. Chemical modification of inhibitors, A3G mutational screening, and thiol reactivity studies implicate C321, a residue proximal to the active site, as the critical A3G target for this class of molecules.     

Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase,Tumor Cell Growth Inhibition,and Interactions with Proteins

Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di‐ and tri‐n‐butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT‐29 and MCF‐7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di‐n‐butyltin(IV) complex as an example.     

Efficient Stacking on Protein Amide Fragments

The less polar π‐surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on amide groups of a large number of heteroarenes that are relevant to medicinal chemistry. From this study, we discern that the stacking energy of an aromatic ligand substituent can be improved by: 1) orienting the fragment dipole vector such that it is aligned in an antiparallel fashion with the dipole of the interacting protein amide group, 2) increasing its dipole moment, and 3) decreasing its π‐electron density. These guidelines should be helpful to more rationally exploit this interaction type in future structure‐based drug design.