Current Organic Chemistry - Volume 13, Issue 14, 2009

In order to improve the biological and pharmacological properties of antisense oligonucleotides, we have been recently focused our efforts on synthesis of DNA-peptide conjugates and biological evaluation of them. Oligonucleotides can be covalently linked to peptides composed of any sequence of amino acids by Solid Phase Fragment Condensation (SPFC). The peptides incorporated into the conjugates include nuclear localizing signals (NLS), nuclear export signals (NES), membrane fusion domain of some viral proteins and some designed cationic α-helical or β-sheet peptides with amphipathic character. Some polyamines and sugars were also conjugated with oligonucleotides by SPFC in good yields. Evaluation of biological properties of DNA-peptide conjugates indicated that (a) the conjugates could bind to target RNA and dsDNA with increased affinity, (b) the conjugates were more resistant to cellular nuclease degradation, (c) the conjugates- RNA hybrids could activate RNase H as effective as native oligonucleotides, (d) the conjugates with fusion peptides showed largely enhanced cellular uptake, (e) the conjugates with NLS could be predominantly delivered into cell nucleus, (f) the conjugates with NES could be localized in cytoplasm. As a result, antisense oligonucleotides conjugated with NLS could inhibit human telomerase in human leukemia cells much more strongly than phosphorothioate oligonucleotides.

The use of lipid monolayers to bind and adsorb proteins is an attractive and increasingly important method for generating high localized concentrations of oriented proteins and protein complexes. These bound proteins can be imaged directly, or they may form 2-D crystalline arrays that are amenable to structure determination by single particle analysis or 2-D electron crystallography. 2-D crystals grown by this technique can also be used to initiate the growth of 3-D crystals for X-ray diffraction analysis. Many derivatized lipids have been prepared for use with this technique, incorporating a diverse range of ligands to enable binding to specific proteins. Synthetic lipids containing functionalized head groups that chelate Ni2+ or Cu2+ have also been prepared to bind and orient expressed proteins that contain His-tags. Protein-binding monolayer-forming lipids generally consist of two distinct components: (1) a branched hydrocarbon tail to confer fluidity to the monolayer and (2) a functionalized hydrophilic head group to facilitate binding of protein molecules at the air-water interface. Newer examples of these compounds also incorporate perfluorinated hydrocarbon moieties to confer detergent resistance to these lipids. This review focuses on synthetic approaches to functionalized lipids for protein monolayer crystallizations.

The use of allene derivatives in the 1,3-dipolar cycloaddition either as dipolarophiles or 1,3-dipole precursors is discussed. Allenes participate in cycloadditions with a variety of 1,3-dipoles namely nitrile oxides, nitrones, carbonyl ylides, nitrile imines, azides and diazocompounds. They also react as the 2??-component in other annulation reactions such as the cycloaddition of ambident 1,3-dipolar species generated from benzimidazole carbenes and isothiocyanates, palladium- catalyzed overall intramolecular [3+2] cycloaddition with alkylidenecyclopropanes and rhodium(I)-catalyzed formal [3+2] annulation reaction of chromium alkenyl(methoxy)carbene complexes. The reactivity of allenes as 1,3-dipole precursors and the subsequent annulation reactions are also covered. Allenes can be used to generate nitrones and other dipolar species can be obtained from allenylazines, via π-allylPd intermediates generated from allenes and from the reaction of allenes with phosphines.

Since the rediscovery of proline in 2000 as catalyst in aldol reaction by List, Barbas and Lerner and, soon after, the development of iminium catalysis by D. W. C. MacMillan, the emergence of organocatalysis as an important tool in organic synthesis is outstanding. During the last years, several research groups have worked in the development of new and powerful methodologies that allow us to build difficult molecules with high yields and enantioselectivities in a metal-free environment. Moreover, the possibility to join two or more organocatalytic reactions in one process has become one challenging goal for chemists, probably due to the costly protecting groups and time-consuming purification procedures after each synthetic step that are one of the common issues in organic synthesis. To circumvent these problems, tandem, domino, cascade or multicomponent organocatalytic reactions have been utilized for the efficient diastereo- and enantioselective construction of complex molecules from simple precursors in simple processes. For example, different tandem organocatalytic reactions such as cyclopropanation, aziridination, Michael-aldol, Michael-α-alkylation, etc. have been developed since 2006 with excellent yields and stereoselectivities. Herein, we describe the last trends and examples of organocatalytic domino reactions. This review aims to cover and discuss the current development of this fast growing field.

This review deals with synthesis and reactions of 3-acetylindoles as well as their biological activities. The data published over the last few years on the methods of synthesis and chemical properties of 3-acetylindoles are reviewed here for the first time.