Synthesis of triazole-functionalized 2-DOS analogues and their evaluation as A-site binders.

Aminoglycoside-antibiotics represent important tools for studying the biological functions of RNA. An orthogonal protection strategy applied on 2-deoxystreptamine (2-DOS) revealed a series of key intermediates that enable its regioselective functionalization. Our approach allowed the construction of selected representatives of triazole-containing analogues with diverse molecular frameworks for biological evaluation regarding their binding and antibacterial potencies.

Designed spiro-bicyclic analogues targeting the ribosomal decoding center.

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.

Design and synthesis of (13S)-methyl-substituted arachidonic acid analogues: templates for novel endocannabinoids.

Two novel methyl-substituted arachidonic acid derivatives were prepared in an enantioselective manner from commercially available chiral building blocks, and were found to be excellent templates for the development of (13S)-methyl-substituted anandamide analogues. One of the compounds synthesized, namely, (13S,5Z,8Z,11Z,14Z)-13-methyl-eicosa-5,8,11,14-tetraenoic acid N-(2-hydroxyethyl)amide, is an endocannabinoid analogue with remarkably high affinity for the CB1 cannabinoid receptor.

Feruloyl esterase-catalysed synthesis of glycerol sinapate using ionic liquids mixtures.

The ability of a feruloyl esterase (AnFaeA), either in free or immobilised (cross-linked enzyme aggregates) form, to catalyse the esterification of glycerol, a major by-product of the biodiesel industry, with sinapic acid was studied in four hexafluorophosphate anion-containing ionic liquids: ([Bmim][PF(6)], [Omim][PF(6)], [C(2)OHmim][PF(6)] and [C(5)O(2)mim][PF(6)]). Such ionic liquids are considered 'green' reaction systems. The synthetic reaction was optimised in [C(2)OHmim][PF(6)] and the highest conversion yield was 72.5+/-2.1%, while, at the same reaction conditions in [C(5)O(2)mim] [PF(6)], a similar conversion yield was obtained (76.7+/-1.5%). AnFaeA was active in its free and immobilised form, with the latter retaining a part of its synthetic activity after 5 consecutive 24h-period reaction cycles. Sinapic acid was esterified to one of the primary hydroxyl groups of glycerol and retained, after esterification, 63.1+/-0.3% and 89.5+/-1.1% of its antioxidant activity against low-density lipoprotein oxidation, when added at concentrations of 10 and 60muM, respectively, in the assay mixture.

C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols.

In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1'-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1'-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1'-cyclopropyl and C1'-cyclopentyl groups are optimal pharmacophores for both receptors while the C1'-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1'-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2'-C3' cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.

The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2.

A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.

Structural modifications of the cannabinoid side chain towards C3-aryl and 1',1'-cycloalkyl-1'-cyano cannabinoids.

The compounds reported in this study are Delta(8)-THC analogues in which the C3 five-carbon linear side chain of Delta(8)-THC was replaced with aryl and 1',1'-cycloalkyl substituents. Of the compounds described here analogues 2d (CB(1), K(i)=11.7 nM. CB(2), K(i)=9.39 nM) and 2f (CB(1), K(i)=8.26 nM. CB(2), K(i)=3.86 nM) exhibited enhanced binding affinities for CB(1) and CB(2), exceeding that of Delta(8)-THC. Efficient procedures for the synthesis of these novel cannabinoid analogues are described.