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The synthesis and a preliminary evaluation of the pairing properties of ribo-cyclohexanyl nucleic acids (r-CNA) is herein reported. Incorporation of a single r-CNA nucleotide into natural duplexes did not enhance their stability, while a very high pairing selectivity for RNA was found. As deduced by comparative analysis of Tm and NMR data, a relationship between pairing selectivity and conformational preferences of the "sugar" moiety of r-CNA (and more generally of six-membered nucleic acids) was suggested.

A DDQ-mediated domino reaction (up to six steps in a single process) has been developed to selectively provide substituted dihydrofurans from a common starting material containing a cyclic bis-thioenol ether. Study of the reaction mechanism highlighted a role played by the sulfur-containing moiety in influencing reaction rate and stereoselectivity.

The development of tumor-targeting drug delivery systems, able to selectively transport cytotoxic agents into the tumor site by exploiting subtle morphological and physiological differences between healthy and malignant cells, currently stands as one of the most attractive anticancer strategies used to overcome the selectivity problems of conventional chemotherapy. Owing to frequent overexpression of folate receptors (FRs) on the surface of malignant cells, conjugation of cytotoxic agents to folic acid (FA) via suitable linkers have demonstrated to enhance selective drug delivery to the tumor site. Herein, the chemical synthesis and biological evaluation of two novel folate-conjugates bearing the anticancer agent chlorambucil (CLB) tethered to either an aminoether (4,7,10-trioxa-1,13-tridecanediamine) or a pseudo-β-dipeptide (β-Ala-ED-β-Ala) linker is reported. The two drug delivery systems have been prepared in high overall yields (54% and 34%) through straightforward and versatile synthetic routes. Evaluation of cell specificity was examined using three leukemic cell lines, undifferentiated U937 (not overexpressing FRs, FR(-)), TPA-differentiated U937 (overexpressing FRs, FR(+)), and TK6 (FR(+)) cells. Both conjugates exhibited high specificity only to FR(+) cells (particularly TK6), demonstrating comparable antitumor activity to CLB in its free form. These data confirm the reliability of folate-based drug delivery systems for targeted antitumor therapy; likewise, they lay the foundations for the development of other folate-conjugates with antitumor potential.

The study of the base-pairing properties of nucleic acids with sugar moieties in the backbone belonging to the L-series (β-L-DNA, β-L-RNA, and their analogs) are reviewed. The major structural factors underlying the formation of stable heterochiral complexes obtained by incorporation of modified nucleotides into natural duplexes, or by hybridization between homochiral strands of opposite sense of chirality are highlighted. In addition, the perspective use of L-nucleic acids as candidates for various therapeutic applications, or as tools for both synthetic biology and etiology-oriented investigations on the structure and stereochemistry of natural nucleic acids is discussed., (Copyright © 2011 Verlag Helvetica Chimica Acta AG, Zürich.)

A novel route to 2',3'-dideoxy-β-l-erythro-hexopyranosyl nucleosides equipped with a 1'-(N(6)-benzoyladenin-9-yl) or a 1'-(thymin-1-yl) moiety has been developed. Synthesis of the enantiopure sugar moiety was carried out by a de novo approach based on a domino reaction as the key step. N-Glycosidation was explored via either nucleobase-transfer mechanism (B = T) or in situ anomerization (B = A or T), affording target nucleosides with high overall stereoselectivity.

Oligonucleotides composed of 1',5'-anhydro-arabino-hexitol nucleosides belonging to the L series (L-HNA) were prepared and preliminarily studied as a novel potential base-pairing system. Synthesis of enantiopure L-hexitol nucleotide monomers equipped with a 2'-(N(6)-benzoyladenin-9-yl) or a 2'-(thymin-1-yl) moiety was carried out by a de novo approach based on a domino reaction as key step. The L oligonucleotide analogues were evaluated in duplex formation with natural complements as well as with unnatural sugar-modified oligonucleotides. In many cases stable homo- and heterochiral associations were found. Besides T(m) measurements, detection of heterochiral complexes was unambiguously confirmed by LC-MS studies. Interestingly, circular dichroism measurements of the most stable duplexes suggested that L-HNA form left-handed helices with both D and L oligonucleotides.

Inhibition of carbohydrate processing enzymes is a topic of great interest, as these enzymes are involved in a plethora of key biochemical events, such as digestion, lysosomal catabolism of glycoconjugates and post-translational glycoprotein processing. Among the most potent inhibitors of such enzymes, iminosugars have emerged as versatile tools for medicinal chemists, especially those in quest for new therapeutic agents. Supply of iminosugars from natural sources or by chemical synthesis has provided excellent targets for medical intervention, ranging from antidiabetics and antivirals to inhibitors of genetic disorders. Although a huge body of literature has been reported around iminosugars, most data have focused on D-series iminosugars, whereas relatively little attention has been devoted to the corresponding L-enantiomers, due to their supposed lack of biological activity profile, as well as their scarce availability from natural sources. Notwithstanding, recent insights into the molecular details of enzyme-inhibitor interactions have led to a reassessment of L-iminosugars for pharmaceutical purposes. On one hand, they have been used as tools for intensive SAR (structure-activity-relationship) studies, in order to gain new information on the enzymatic inhibition mechanisms. Likewise, early reports on biological activity of L-iminosugars have led to reconsider their therapeutic skills. This review focuses on the most significant discoveries regarding medicinal chemistry of L-iminosugars. The important role L-iminosugars play in unravelling the inhibition mechanisms of specific enzymes is herein recognized; moreover, the high potential of this class of inhibitors as novel drug candidates is under discussion.

During recent years, quantitative proteome profiling has taken advantage of incorporating the traditional stable isotope dilution analysis into global scale or discovery-based proteomic experiments that use mass spectrometers as detectors to allow the pairwise study of differently expressed proteins. Quantitative protein analysis by means of the isotope-coded affinity tag (ICAT) method and tandem mass spectrometry (MS) enables the pairwise comparison of protein expression levels in biological samples. Herein, a modified ICAT reagent, named BAA-ICAT (beta-alanine-arm-ICAT) in which the polyether linker is replaced by a more water-soluble polyamide one, was investigated.

A highly convergent and efficient synthesis of a new sialyl Lewis(x) (sLe(x)) mimic, which was predicted by computational studies to fulfil the spacial requirements for a selectin antagonist, has been developed. With a beta(2,3)-amino acid residue l-galactose (bioisostere of the l-fucose moiety present in the natural sLe(x)) and succinate are linked, leading to a mimic of sLe(x) that contains all the required pharmacophores, namely the 3- and 4-hydroxy group of l-fucose, the 4- and 6-hydroxy group of d-galactose and the carboxylic acid of N-acetylneuraminic acid. The key step of the synthesis involves a tandem reaction consisting of a N-deprotection and a suitable O-->N intramolecular acyl migration reaction which is promoted by cerium ammonium nitrate (CAN). Finally, the new sialyl Lewis(x) mimic was biologically evaluated in a competitive binding assay.