Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2alpha phosphorylation-dependent pathway mediated by stress and the eIF2alpha phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2alpha, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAi(Met) ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.

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Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.

Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1.

Silanethione 2a and silaneselenone 2b—stabilized by intramolecular Si ← N coordination— are obtained as shown below. The X‐ray structure analysis of 2a, 1‐naphthyl instead of phenyl, reveals strong zwitterionic character, which might explain the unexpectedly low reactivity toward nucleophiles and electrophiles (a, X = S; b, X = Se).

Natural products that act as highly specific, small-molecule protein-binding agents and as modulators of protein-protein interactions are highly complex and exhibit functional groups with three-dimensional and stereochemical diversity. The complex three-dimensional display of chiral functional groups appears to be crucial for exhibiting specificity in protein binding and in differentiating between closely related proteins. The development of methods that allow a high-throughput access to three-dimensional, skelatally complex, polycyclic compounds having few asymmetric diversity sites is essential and a highly challenging task. In the postgenomic chemical biology age, in which there is a great desire to understand protein-protein interactions and to dissect protein networking-based signaling pathways by small molecules, the need for developing "stereocontrolled, diversity-oriented synthesis" methods to generate natural product-like libraries is of utmost importance.

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Palladium complexes immobilized onto generation 0-3 PAMAM dendrimers supported on silica were used as catalysts for the carbonylation of iodobenzene in methanol to form methyl benzoate. High yields were obtained and the catalyst was recycled 4-5 times without significant loss of activity. The carbonylation reaction was found to be applicable to a variety of iodoarenes regardless of the nature of the substituent. IntroductionThe carbonylation of haloarenes has been extensively investigated in the liquid phase.1 Most of the work reported in this area has involved bromo-and iodoarenes as starting materials, and metal complexes as catalysts which are capable of oxidative addition to a C-X bond (e.g. Pd or Rh). Phosphine-modified palladium complexes such as dichlorobis(triphenylphosphine)palladium(II) or bromoarylbis(triphenylphosphine)palladium(II) are catalytically active for the carbonylation of iodobenzene or bromobenzene to produce benzoic acid derivatives.2 The carbonylation of haloarenes with Pd catalysts and phase transfer systems, (e.g., poly(ethylene glycol) and watersoluble catalysts 3 ) gave satisfactory yields of benzoic acids. The carbonylation reaction can proceed in a different manner if the intermediate is intercepted by another species. An example is the novel approach for the one-pot preparation of R-amino amides by Pdcatalyzed double carbohydroamination of haloarenes. 4 The preparation of polyesters and polyamides by palladium-catalyzed alkoxycarbonylation of haloarenes 5 is also noteworthy. Different strategies have been successfully pursued to overcome the low reactivity of chloroarenes toward oxidative addition. Milstein et al. 6 described the use of Pd complexes containing electron-rich and bulky chelating diphosphines. Also, Osborn et al. 7 and Alper and Grushin 8 demonstrated that Pd complexes with phosphines possessing both high basicity (pK a > 6.5) and substantial steric hindrance are useful catalysts (e.g. (Cy 3 P) 2 PdCl 2 ) for the carbonylation of chlorobenzene under mild conditions. Other methods of functionalizing chloroaromatics include photochemical activation 9 or the use of tricarbonyl(chloroarene)chromium complexes which react in a stoichiometric fashion. 10Heterogeneous catalysts have advantages of heat stability and ease of separation from the product when compared with homogeneous catalysts. Application of solid catalysts for the carbonylation of haloarenes has been examined by the use of NiCl 2 on pumice 11 or on SiO 2 . 12 A study on the use of solid catalysts for the carbonylation of haloarenes concluded that Pd supported on charcoal was the most active system. 13Transition metal catalysis based on functionalized dendrimers has become an interesting and promising way of using a heterogeneous catalytic system. From a catalytic point of view the ideal catalyst should be highly active and selective under mild conditions, stable and easy to separate from the product by using a simple process such as filtration. 14 Dendrimer metal catalysts can, in principle, fill the gap...