InCl3-catalyzed intramolecular carbonyl-olefin metathesis.

An efficient and novel synthetic strategy for the generation of different carbocyclic moieties by ring closing carbonyl-olefin metathesis is reported. Herein, we describe a sustainably attractive protocol for one of the most powerful carbon-carbon bond-forming reactions, based on solvent-reduction, use of InCl3 catalyst, and microwave irradiation, affording target compounds with yields up to 96%.

Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-ß42 monomer.

A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aß42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aß42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aß42 aggregates. The early stage interaction between compound 7 and the Aß42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aß42 monomer and it helps preventing the formation of ß-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early "on-pathway" events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer's disease.

Molecular Diversity by Olefin Cross-Metathesis on Solid Support. Generation of Libraries of Biologically Promising ß-Lactam Derivatives.

The application of the reagent-based diversification strategy for generation of libraries of biologically promising ß-lactam derivatives is described. Key features are the versatility of the linker used and the cross-metathesis functionalization at the cleavage step. From an immobilized primary library, diversity was expanded by applying different cleavage conditions, leading to a series of cholesterol absorption inhibitor analogues together with interesting hybrid compounds through incorporation of a chalcone moiety.

New mimetic peptides inhibitors of Αß aggregation. Molecular guidance for rational drug design.

A new series of mimetic peptides possessing a significant Aß aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aß aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aß42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aß aggregation. Thus, significant alterations in the structure of our Aß42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the ß1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.

Solid-supported cross-metathesis and a formal alkane metathesis for the generation of biologically relevant molecules.

Solid-phase synthetic strategies toward the generation of libraries of biologically relevant molecules were developed using olefin cross-metathesis as a key step. It is remarkably the formal alkane metathesis based on a one-pot, microwave-assisted, ruthenium-catalyzed cross-metathesis and reduction to obtain Csp3-Csp3 linkages.

Synthesis of 3-aryl-1,2,4-benzotriazines via intramolecular cyclization of solid-supported o-hydrazidoanilines.

An efficient solid-phase protocol for the rapid generation of libraries of biologically promising 1,2,4-benzotriazines, including amino acid-derived components, is described.

Chemically engineered extracts: source of bioactive compounds.

Biological research and drug discovery critically depend on access to libraries of small molecules that have an affinity for biomacromolecules. By virtue of their sustained success as sources of lead compounds, natural products are recognized as "privileged" starting points in structural space for library development. Compared with synthetic compounds, natural products have distinguishing structural properties; indeed, researchers have begun to quantify and catalog the differences between the two classes of molecules. Measurable differences in the number of chiral centers, the degree of saturation, the presence of aromatic rings, and the number of the various heteroatoms are among the chief distinctions between natural and synthetic compounds. Natural products also include a significant proportion of recurring molecular scaffolds that are not present in currently marketed drugs: the bioactivity of these natural substructures has been refined over the long process of evolution. In this Account, we present our research aimed at preparing libraries of semisynthetic compounds, or chemically engineered extracts (CEEs), through chemical diversification of natural products mixtures. The approach relies on the power of numbers, that is, in the chemical alteration of a sizable fraction of the starting complex mixture. Major changes in composition can be achieved through the chemical transformation of reactive molecular fragments that are found in most natural products. If such fragments are common enough, their transformation represents an entry point for chemically altering a high proportion of the components of crude natural extracts. We have searched for common reactive fragments in the Dictionary of Natural Products (CRC Press) and identified several functional groups that are expected to be present in a large fraction of the components of an average natural crude extract. To date, we have used reactions that incorporate (i) nitrogen atoms through carbonyl groups, (ii) sulfur by transformation of -OH and amines, and (iii) bromine through double bonds and aromatic rings. The resulting CEEs had different composition and biomolecular properties than their natural progenitors. We isolated a semisynthetic ß-glucosidase inhibitor from a CEE prepared by reaction with benzenesulfonyl chloride, an antifungal pyrazole from a CEE prepared by reaction with hydrazine, and an acetylcholinesterase inhibitor from a CEE prepared through bromination. Our results illustrate how biological activity can be generated through chemical diversification of natural product mixtures. Moreover, the level of control that can be asserted in the process by judicious design and experimental choices underscores the potential for further development of CEEs in both basic research and drug discovery.

Brominated extracts as source of bioactive compounds.

The chemical composition and the biomolecular properties of a crude plant extract were altered through bromination leading to the discovery of an acetylcholinesterase inhibitor.

Exploring the solid-phase synthesis of 3,4-disubstituted beta-lactams: scope and limitations.

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.