Carbohydrates in diversity-oriented synthesis: challenges and opportunities.

Over the last decade, Diversity-Oriented Synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways, and to provide a larger array of the chemical space. Drug discovery and chemical biology are taking advantage of DOS approaches to exploit highly-diverse and complex molecular platforms, producing advances in both target and ligand discovery. In this view, carbohydrates are attractive building blocks for DOS libraries, due to their stereochemical diversity and high density of polar functional groups, thus offering many possibilities for chemical manipulation and scaffold decoration. This review will discuss research contributions and perspectives on the application of carbohydrate chemistry to explore the accessible chemical space through appendage, stereochemical and scaffold diversity.

Use of click-chemistry in the development of peptidomimetic enzyme inhibitors.

Cu(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) is often utilized in medicinal chemistry to make the triazole moiety as it acts as a non-classical bioisostere of the peptide bond. This useful technique can also be applied in the fragment-based assembly of molecular libraries for high-throughput screening. This minireview outlines the application of click-chemistry in the synthesis of enzyme inhibitors with the triazole moiety.

Heterocyclic HIV-protease inhibitors.

In the panorama of HIV protease inhibitors (HIV PIs), many efforts have been devoted to the development of new compounds with reduced peptidic nature in order to improve pharmacokinetics and pharmacodynamics features. The introduction of cyclic scaffolds in the design of new chemical entities reduces flexibility and affords more rigid inhibitors. Specifically, common dipeptide isosteres are replaced by a central cyclic scaffold designed to address the key interactions with catalytic aspartic acids and residues belonging to the flap region of the active site. The current interest in cyclic chemotypes addressing key interactions of HIV protease is motivated by the different nature of interactions formed with the enzyme, although maintaining key structural resemblance to a peptide substrate, hopefully giving rise to novel HIV-1 PIs displaying an improved profile towards multidrug resistant strains. This approach has been demonstrated for Tipranavir, which is a potent FDA approved HIV-1 PI representing the most famous example of heterocyclic aspartic protease inhibitors.

Cyclic DGR-peptidomimetic containing a bicyclic reverse turn inducer as a selective alpha(v)beta (5) integrin ligand.

3-Aza-6,8-dioxabicyclo[3.2.1]octane-based amino acids as reverse turn inducers have been introduced into cyclic peptidomimetics containing the RGD or DGR retro-sequence, in order to achieve a stereochemical scanning of the binding capability of the resulting molecules towards alpha(v)beta(3) and alpha(v)beta(5) integrins, resulting in retro-inverso DGR peptides as micromolar ligands. A comparative analysis between the conformational preferences of 4 and of its isomer 3, having the opposite RGD sequence, was reported with respect to the binding activity, giving insight into the factors affecting the preferential binding of 4 to the alpha(v)beta(5) integrin.

Synthesis of a bicyclic delta-amino acid as a constrained Gly-Asn dipeptide isostere.

Delta-amino acids are very attractive in drug discovery, especially in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein we report the synthesis of a rigid delta-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivatives, and the intramolecular trans-acetalization of the oxidized adduct to give the bicyclic delta-amino acid. Starting from L-tartaric acid derivative, it was achieved the corresponding Gly-D-Asn isostere, whereas from the enantiomeric D-tartaric acid derivative the corresponding Gly-L-Asn isostere could be obtained, thus giving access to both enantiomeric dipeptide sequences.

Structural diversity of bicyclic amino acids.

Over the years biomedical research has been constantly oriented towards the development of new therapeutics based on bioactive peptides and their analogues. In particular, the generation of compounds having structures and functions similar to bioactive peptides, named "peptidomimetics", raised much interest among organic and medicinal chemists due to the possibility by using such compounds to improve both potency and stability of peptidic lead compounds. In the context of this research area, unnatural amino acids are of great interest in drug discovery, and their use as new building blocks for the development of peptidomimetics with high diversity level and possessing high-ordered structures is of special interest. In particular, medicinal chemistry has taken advantage of the use of amino acid homologues and of cyclic and polycyclic templates to introduce elements of diversity for the generation of new molecules as drug candidates. Bicyclic amino acids have been developed as reverse turn mimetics and dipeptide isosteres, and the constraint imposed by their structures has been reported as a tool for controlling the conformational preferences of modified peptides. Moreover, synthetic efforts have been driven to the generation of diverse structures based on the modulation of ring size and scaffold decoration by suitable functional groups. Herein is reported an overview of different classes of bicyclic amino acids, taking into account the strategies to achieve structurally diverse templates, and some implications in medicinal chemistry are also disclosed.

Effect of C-ring modifications in benzo[c]quinolizin-3-ones, new selective inhibitors of human 5 alpha-reductase 1.

The synthesis and the inhibition potency of octahydro- and decahydrobenzo[c]quinolizin-3-one derivatives 3--7, as new non-steroidal selective inhibitors of human enzyme 5 alpha-reductase type 1, are reported. These compounds differ from the recently reported benzo[c]quinolizin-3-one inhibitors 2 by the presence of a fully or partially saturated C-ring. Compounds 3 and 4, with a double bond in the C-ring, were prepared by sequential rearrangement-annulation of isoxazolines 19 and 20. C-ring saturated compounds 5--7 were prepared by the Lewis acid-promoted Mannich-Michael tandem reaction of Danishefsky diene with the appropriate N-t-Boc iminium ion. Inhibition experiments were carried out on 5 alpha R-1 and 5 alpha R-2 expressed by CHO cells. Among the prepared compounds, octahydrobenzo[c]quinolizin-3-one 3, with a double bond at the position 6a--10a, was a potent and selective inhibitor of human 5 alpha R-1 (IC(50)=58 nM). The introduction of a tert-butylcarboxyamide at the position 8 (compound 4) was deleterious for the inhibition activity. The lack of the double bond in the C-ring reduced strongly the inhibition activity of compounds 5--7. The extended planarity of the most potent benzo[c]quinolizin-3-ones as well as favorable interactions of the C-ring unsaturation with the enzyme active site could account for the inhibition activity of these compounds.

Introduction of the new dipeptide isostere 7-endo-BtA as reverse turn inducer in a Bowman-Birk proteinase inhibitor: synthesis and conformational analysis.

Two dipeptide isosteres 7-exo-BTG (1) and 7-endo-BtA (2), belonging to the new class of gamma/delta-bicyclic amino acid BTAa, were inserted into an 11-residue peptide deriving from the Bowman Birk Inhibitor (BBI) class of serine protease inhibitors, and the conformational properties of these modified peptides have been studied by NMR and molecular modelling. The dipeptide isostere 7-endo-BtA [(1R,4S,5R,7R)-4-endo-methyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-endo-carboxylic acid] (2), derived from L-alanine and meso tartaric acid, gave rise to the modified BBI peptide 5 whose structure was very similar to that of the original peptide 3, suggesting a possible reverse turn inducing property for this dipeptide isostere.

Suzuki reaction of vinyl triflates from six- and seven-membered N-alkoxycarbonyl lactams with boronic acids and esters.

The Pd(0)-catalyzed reaction of vinyl triflates from N-alkoxycarbonyl lactams with different boron compounds has been studied. The coupling reaction of alkenylboronates and arylboronic acids with six- and seven-membered lactam-derived N-alkoxycarbonyl vinyl triflates was feasible under very mild conditions in THF-water employing (Ph3P)2PdCl2 as a catalyst and Na2CO3 as a base, which provided in high yields the corresponding 6- or 7-substituted N-alkoxycarbonyl-3,4-dihydro-2H-pyridines and N-alkoxycarbonyl-2,3,4,5-tetrahydroazepines. Allylboronates reacted slower but, with vinyl triflates from delta-valerolactam, still gave acceptable yields of the coupling product. Alkylboronic acids required different reaction conditions, in particular the presence of Ag2O together with a base in anhydrous toluene and (dppf)PdCl2 as a catalyst, affording the corresponding 6-alkyl-N-alkoxycarbonyl-3,4-dihydro-2H-pyridines in high yields.

Pd(0)-catalyzed cross-coupling reactions of boron derivatives with a lactam-derived N-Boc enol triflate

[formula: see text] The cross-coupling reaction of 2-(1-alkenyl)-1,3,2-benzodioxaboroles, obtained from alkynes and catecholborane, and other boron derivatives with a lactam-derived N-Boc enol triflate occurred under very mild conditions in a THF-water medium employing (Ph3P)2PdCl2 as a catalyst, providing the corresponding 6-substituted N-Boc 3,4-dihydro-2H-pyridines in high yields.