Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor.

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

Probing Site-Selective Conjugation Chemistries for the Construction of Homogeneous Synthetic Glycodendriproteins.

Methods that site-selectively attach multivalent carbohydrate moieties to proteins can be used to generate homogeneous glycodendriproteins as synthetic functional mimics of glycoproteins. Here, we study aspects of the scope and limitations of some common bioconjugation techniques that can give access to well-defined glycodendriproteins. A diverse reactive platform was designed via use of thiol-Michael-type additions, thiol-ene reactions, and Cu(I)-mediated azide-alkyne cycloadditions from recombinant proteins containing the non-canonical amino acids dehydroalanine, homoallylglycine, homopropargylglycine, and azidohomoalanine.

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition.

Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 µM.

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution.

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1'-NR1 R2 and 1'-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Fluorinated triazole-containing sphingosine analogues. Syntheses and in vitro evaluation as SPHK inhibitors.

Sphingosine analogues with a rigid triazole moiety in the aliphatic chain and systematic modifications in the polar head and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently ring opened in a regioselective manner in acidic medium. Up to 16 sphingosine analogues were prepared in a straightforward manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying comparable activity to that of DMS.

Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis.

Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine.

Highly reactive 2-deoxy-2-iodo-d-allo and d-gulo pyranosyl sulfoxide donors ensure ß-stereoselective glycosylations with steroidal aglycones.

The preparation of well-defined d-xylo and d-ribo glycosides represents a synthetic challenge due to the limited configurational availability of starting materials and the laborious synthesis of homogeneous 2-deoxy-ß-glycosidic linkages, in particular that of the sugar-steroid motif, which represents the "stereoselective determining step" of the overall synthesis. Herein we describe the use of 2-deoxy-2-iodo-glycopyranosyl sulfoxides accessible from widely available d-xylose and d-ribose monosaccharides as privileged glycosyl donors that permit activation at very low temperature. This ensures a precise kinetic control for a complete 1,2-trans stereoselective glycosylation of particularly challenging steroidal aglycones.

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate.

Chemical Access to d-Sarmentose Units Enables the Total Synthesis of Cardenolide Monoglycoside N-1 from Nerium oleander.

Herein we present a chemical approach for the ready preparation of d-sarmentosyl donors enabling the first total synthesis and structure validation of cardenolide N-1, a challenging 2,6-dideoxy-3-O-methyl-ß-d-xylo-hexopyranoside extracted from Nerium oleander twigs that displays anti-inflammatory properties and cell growth inhibitory activity against tumor cells. The strategy highlights the synthetic value of the sequential methodology developed in our group for the synthesis of 2-deoxyglycosides. Key steps include Wittig-Horner olefination of a d-xylofuranose precursor, [I+]-induced 6-endo cyclization, and 1,2-trans stereoselective glycosylation.

Enantioselective Formal Synthesis of Nectrisine Using a Palladium-Catalyzed Asymmetric Allylic Amination and Cross-Metathesis as Key Steps.

A formal enantioselective synthesis of nectrisine, a potent α-glucosidase inhibitor, was carried out starting from butadiene monoepoxide through a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, dihydroxylation, and cyclization.

Rhodium-catalyzed regio- and stereoselective oxyamination of dienes via tandem aziridination/ring-opening of dienyl carbamates.

The reaction of dienyl carbamates with PhI(OR)2 in the presence of rhodium catalysts affords vinyl aziridines which are in situ regio- and stereoselectively opened to afford oxyamination products resulting from a selective S(N)2 (Rh2(OAc)4/PhI(OPiv)2) or S(N)2' (Rh2(OPiv)4/PhI(OAc)2) opening. The scope and limitations of this tandem process are described.

Chemo-, regio-, and stereoselective silver-catalyzed aziridination of dienes: scope, mechanistic studies, and ring-opening reactions.

Silver complexes bearing trispyrazolylborate ligands (Tp(x)) catalyze the aziridination of 2,4-diene-1-ols in a chemo-, regio-, and stereoselective manner to give vinylaziridines in high yields by means of the metal-mediated transfer of NTs (Ts = p-toluensulfonyl) units from PhI═NTs. The preferential aziridination occurs at the double bond neighboring to the hydroxyl end in ca. 9:1 ratios that assessed a very high degree of regioselectivity. The reaction with the silver-based catalysts proceeds in a stereospecific manner, i.e., the initial configuration of the C═C bond is maintained in the aziridine product (cis or trans). The degree of regioselectivity was explained with the aid of DFT studies, where the directing effect of the OH group of 2,4-diene-1-ols plays a key role. Effective strategies for ring-opening of the new aziridines, deprotection of the Ts group, and subsequent formation of ß-amino alcohols have also been developed.

Tuning the stereoelectronic properties of 1-sulfanylhex-1-enitols for the sequential stereoselective synthesis of 2-deoxy-2-iodo-ß-D-allopyranosides.

The preparation of challenging 2-deoxy-2-iodo-ß-D-allo precursors of 2-deoxy-ß-D-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I(+)]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

Advances in the enantioselective synthesis of carbocyclic nucleosides.

Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3- to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (C=C and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4- and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.

Phosphine-free Suzuki-Miyaura cross-coupling in aqueous media enables access to 2-C-aryl-glycosides.

A general strategy for the synthesis of 2-aryl-glycals and their elaboration to 2-C-aryl-α-glycosides and 1,5-anhydro-2-C-aryl-2-deoxy alditols are described. The use of reliable, efficient phosphine-free Suzuki-Miyaura cross-coupling of 2-iodoglycals in aqueous media as a key step proceeds with complete regioselectivity at C-2 and enables access to 2-aryl-glycals with different configurations in excellent yields.

Sequential directed epoxydation-acidolysis from glycals with MCPBA. A flexible approach to protected glycosyl donors.

4,6-Di-O-protected glucal and allal derivatives react with MCPBA to afford manno- and allo-1-O-m-chlorobenzoate derivatives, respectively, as a result of a syn epoxidation directed by the allylic hydroxyl group, and consecutive ring-opening by m-ClBzOH. When glucal and allal derivatives are fully protected, initial epoxidation proceeds mainly anti to the allylic group to give, after ring-opening, the corresponding pyranosyl chlorobenzoates. Stereoselectivity in the reaction of fully protected galactal derivatives was complete, although only a moderate increase in the syn epoxidation product was observed in 4,6- and 3,4-di-O-protected derivatives. 1-O-m-Chlorobenzoate 18 was selectively protected and activated as donor in the synthesis of disaccharide 21.

Studies on the Zn(II)-mediated electrophilic selenocyclization and elimination of 3,4-O-isopropylidene-protected hydroxyalkenyl sulfides: synthesis of a 2-phenylselenenyl glycal.

Herein, we describe a mild and efficient Zn(II)-mediated electrophilic selenocyclization reaction of readily available and stable 3,4-O-isopropylidene-protected hydroxyalkenyl sulfides to 2-deoxy-2-phenylselenenyl-1-thio-glycosides. This material was transformed into a 2-phenylselenenyl glycal in a controlled manner using an activation-elimination sequence.

Short and general procedure for synthesizing cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives.

Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives have been prepared by treatment of the corresponding 1,2-anhydrosugars with potassium thiocyanate, potassium selenocyanate, and sodium cyanamide, respectively. The procedure is compatible with several protecting groups such as acyl, benzyl, and silyl and also with sugars of different configurations.

An efficient and general enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives.

A general and efficient protocol for the enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives was established. These compounds were obtained from a common intermediate prepared from butadiene monoepoxide by a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, and dihydroxylation.