Duplex formation and secondary structure of γ-PNA observed by NMR and CD.

Peptide nucleic acids (PNAs) are non-natural oligonucleotides mimics, wherein the phosphoribose backbone has been replaced by a peptidic moiety (N-(2-aminoethyl)glycine). This peptidic backbone lends itself to substitution and the γ-position has proven to yield oligomers with enhanced hybridization properties. In this study, we use Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) to explore the properties of the supramolecular duplexes formed by these species. We show that standard Watson-Crick base pair as well as non-standard ones are formed in solution. The duplexes thus formed present marked melting transition temperatures substantially higher than their nucleic acid homologs. Moreover, the presence of a chiral group on the γ-peptidic backbone increases further this transition temperature, leading to very stable duplexes. PNA duplexes with a chiral backbone present a marked chiral secondary structure, observed by CD, and showing a common folding pattern for all studied structures. Nevertheless small differences are observed depending on the details of the nucleobase sequence.

DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules.

Fragment-based lead discovery has proven to be a powerful method in the drug discovery process. The combinatorial output that is accessible by combining fragments is very attractive; however, identifying fragment pairs that bind synergistically and linking them productively can be challenging. Several technologies have now been established to prepare and screen nucleic acid-encoded libraries (ssDNA, dsDNA, PNA), and it has been shown that pairs of molecules combined by hybridization can bind synergistically to a target. Herein we apply this concept to combinatorially pair two libraries of small molecule fragments, use the fittest fragments supplemented with closely related analogs to build a focused library covalently linking the fragments with different spacers, and apply this strategy to the discovery of a potent ligand for Hsp70.

Total Synthesis of Sanglifehrin A.

The immunosuppressive agent sanglifehrin A has been prepared for the first time by total synthesis. The construction of the macrocyclic unit of the target molecule was achieved through a selective intramolecular Stille coupling, and the spirolactam unit by Paterson-aldol reactions. The final steps involve an intermolecular Stille coupling and the opening of the internal acetal unit. This convergent synthesis opens the way for the synthesis of libraries of novel sanglifehrin analogues for biological screening.

[Hypertrophic osteopathy and acropachy associated with noncirrhotic alcoholic liver disease. Apropos a case]. / Osteoartropatía hipertrófica y acropaquia asociados a enfermedad hepática alcohólica no cirrótica. A propósito de un caso.

Hypertrophic osteoarthropathy (HOA) may be an idiopathic condition or may be secondary to other diseases, the most common of which is bronchogenic carcinoma. Among non neoplastic etiologies, it is commonly associated with chronic liver disease, usually cirrhosis and chronic active hepatitis. The concomitant occurrence of HOA and hepatic steatosis is another association that has recently been reported. We report here a 70-year-old male with periostitis, clubbing of the fingers and alcoholic hepatitis stenosis. We emphasize the need to perform observational studies to validate this association.

Combinatorial synthesis through disulfide exchange: discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.

Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

As described in the preceding article, utilizing a novel combinatorial disulfide exchange strategy, a library of psammaplin A (1) analogues was constructed and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of highly potent antibacterial agents (e.g. 17, 57, 58, 69, and 70), some possessing greater than 50-fold higher activities than the natural product. Evaluation of the selectivity and serum binding properties of some of the most promising compounds and preliminary studies directed at deciphering the mechanism of action of this novel class of antibacterial agents are also included.

Iodine(V) reagents in organic synthesis. Part 3. New routes to heterocyclic compounds via o-iodoxybenzoic acid-mediated cyclizations: generality, scope, and mechanism.

The discovery and development of the o-iodoxybenzoic acid (IBX) reaction with certain unsaturated N-aryl amides (anilides) to form heterocycles are described. The application of the method to the synthesis of delta-lactams, cyclic urethanes, hydroxy amines, and amino sugars among other important building blocks and intermediates is detailed. In addition to the generality and scope of this cyclization reaction, this article describes a number of mechanistic investigations suggesting a single electron transfer from the anilide functionality to IBX and implicating a radical-based mechanism for the reaction.