The exquisite chemoselectivity and the intrinsic compatibility of enzymes have been widely exploited during the past decade for the development of multi-step biocatalytic reactions in one-pot. In this context, hydrogen-borrowing cascades permit to maximise the atom-efficiency through the internal recycling of redox equivalents, which avoids the use of additional oxidants or reductants. Here, we describe the state-of-the-art in the field of biocatalytic hydrogen-borrowing cascades and provide a future perspective for a wider implementation in organic synthesis.

G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that are involved in the regulation of a wide range of physiological functions and constitute the most common target for therapeutic intervention. Due to the paucity of crystal structures, homology modeling has become a widespread technique for the construction of GPCR models, which have been applied to the study of their structure-function relationships and to the identification of lead ligands through virtual screening. Rhodopsin has been for years the only available template. However, recent breakthroughs in GPCR crystallography have led to the solution of the structures of a few additional receptors. In light of these newly elucidated crystal structures, we have been able to produce a substantial amount of data to demonstrate that accurate models of GPCRs in complex with their ligands can be constructed through homology modeling followed by fully flexible molecular docking. These results have been confirmed by our success in the first blind assessment of GPCR modeling and docking, organized in coordination with the solution of the X-ray structure of the adenosine A(2A) receptor. Taken together, these data indicate that: a) the transmembrane helical bundle can be modeled with considerable accuracy; b) predicting the binding mode of a ligand, although doable, is challenging; c) modeling of the extracellular and intracellular loops is still problematic.

A long standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a suitable linker to form highly efficacious drug-conjugates. These conjugates can deliver potent cytotoxic drugs specifically to tumors and cancer cells with minimal systemic toxicity. This article describes the design, development and application of novel taxoid-based tumor-targeting drug-conjugates, which possess excellent specificity and efficacy in vitro and in vivo.

We discuss a peptide that targets cells in the acidic tissues that result from a range of pathological states, including tumours, and that can also translocate cell-impermeable cargo molecules across cell membranes in a pH-dependent manner. The technology is based on the interactions of a water-soluble membrane peptide, which we call pHLIP (pH (Low) Insertion Peptide), with the lipid bilayers of cell membranes. at the normal pH of healthy tissue it binds to cell surfaces, but at low pH pHLIP inserts as a monomer across the cell membrane to form a stable transmembrane helix. pHLIP holds promise for imaging and drug delivery applications.

Cellular membrane affinity chromatography (CMAC) columns have been created through the immobilization of cellular membrane fragments on liquid chromatographic supports. A CMAC column containing the human organic cation transporter, CMAC(hOCT1) column, has been used to study the stereoselective binding of competitive inhibitors. The chromatographic data obtained using the CMAC(hOCT1) column was to develop a pharmacophore model that described the stereoselectivity. The results indicate that a dynamic chiral recognition model based upon conformational adjustments between the inhibitors and hOCT1 is responsible for the observed steroeselectivity.

Peptide synthesis has been developed into one of the most efficient synthetic procedures in organic chemistry. The problems of orthogonal functional group protection and amide bond formation without racemization have been developed in a number of ingenious strategies. Optimization, in particular, has been achieved in stepwise solid phase synthesis. This in turn made possible the development of combinatorial synthesis allowing the synthesis of millions of peptide compounds of high purity in a few days. A variety of methodologies and strategies have been developed and continue to be developed to determine structures and to evaluate peptides and peptidomimetics. The development of methods for solid phase synthesis of a variety of organic and inorganic structures using similar strategies as in peptide synthesis are being vigorously pursued. However, existing instrumentation and technology is not sufficient to cover current demands for peptides, and thus new approaches and technologies for cost-effective synthesis of peptide arrays are needed.

A new technology for high-speed solution-phase parallel synthesis has been developed by the combination of microwave heating and fluorous tagging strategies. This article highlights several applications of this technology in the synthesis of library scaffolds involving Pd-catalyzed cross-coupling and multicomponent reactions.