N-Fluoroalkylated Morpholinos - a New Class of Nucleoside Analogues.

The first concise and efficient synthesis of some fluorine-containing morpholino nucleosides has been developed. One synthetic strategy was based on the oxidative ring cleavage of the vicinal diol unit of uridine, cytidine adenosine and guanosine derivatives, followed by cyclisation of the dialdehyde intermediates by double reductive amination with fluorinated primary amines to obtain various N-fluoroalkylated morpholinos. Another approach involved cyclisation of the diformyl intermediates with ammonia source, followed by dithiocarbamate formation and desulfurization-fluorination with diethylaminosulfur trifluoride yielding the corresponding morpholine-based nucleoside analogues with a N-CF3 element in their structure.

Triaza-tricyclanos - synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation.

Herein, we report a stereoselective synthesis of a novel type of conformationally constrained nucleoside analogue in which the sugar part is replaced by a new symmetrical tricycle consisting of a morpholine ring condensed with two imidazolidines. 1,5-Dialdehydes obtained from trityl- and dimethoxytrityl-protected uridine, ribothymidine, inosine, cytidine, adenosine and guanosine by metaperiodate oxidation were reacted with N1,N3-dibenzyl-1,2,3-triaminopropane; the latter reactant was produced using a new method that avoids explosive intermediates. Reactions of dialdehydes with propane-triamine via cascade tricyclization resulted in the corresponding triaza-tricyclic derivatives bearing three new stereogenic centers in high yields. Out of the eight possible diastereoisomers, one stereoisomer was formed in each case due to the chiral control of the starting nucleoside-dialdehydes and the steric constraint of the condensed ring system. The absolute configuration of the new stereotriad was determined by X-ray diffraction and NMR experiments. A mechanistic study performed under reductive conditions to trap the presumed bicyclic intermediate showed that the triamine reactant first attacks the 2'-aldehyde group, followed by a rapid bicyclization to form the imidazolidino-morpholine unit.

Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues.

The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5'-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to the N-alkylated tertiary amine structure of the morpholino unit.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions.

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.

Stereoselective Thioconjugation by Photoinduced Thiol-ene Coupling Reactions of Hexo- and Pentopyranosyl d- and l-Glycals at Low-Temperature-Reactivity and Stereoselectivity Study.

A comprehensive optimization and mechanistic study on the photoinduced hydrothiolation of different d- and l- hexo- and pentoglycals with various thiols was performed, at the temperature range of RT to -120 °C. Addition of thiols onto 2-substituted hexoglycals proceeded with complete 1,2-cis-α-stereoselectivity in all cases. Hydrothiolation of 2-substituted pentoglycals resulted in mixtures of 1,2-cis-α- and -ß-thioglycosides of varying ratio depending on the configuration of the reactants. Hydrothiolation of unsubstituted glycals at -80 °C proceeded with excellent yields and, except for galactal, provided the axially C2-S-linked isomers with high selectivity. Cooling was always beneficial to the efficacy, increased the yields and in most cases significantly raised the stereoselectivity. The suggested mechanism explains the different conformational preferences of the intermediate carbon-centered radicals, which is a crucial factor in the stereoselectivity of the reactions.

Reperfusion-induced injury and the effects of the dithioacetate type hydrogen sulfide donor ibuprofen derivative, BM-88, in isolated rat hearts.

Hydrogen sulfide (H2S) plays an important role in cardiac protection by regulating various redox signalings associated with myocardial ischemia/reperfusion (I/R) induced injury. The goal of the present investigations is the synthesis of a newly designed H2S-releasing ibuprofen derivative, BM-88, and its pharmacological characterization regarding the cardioprotective effects in isolated rat hearts. Cytotoxicity of BM-88 was also estimated in H9c2 cells. H2S-release was measured by an H2S sensor from the coronary perfusate. Increasing concentrations of BM-88 (1.0 to 20.0 µM) were tested in vitro studies. Preadministration of 10 µM BM-88 significantly reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from its drug-free control value of 92% to 12%. However, no clear dose dependent reduction in the incidence of reperfusion-induced VF was observed while different concentrations of BM-88 were used. It was also found that 10 µM BM-88 provided a substantial protection and significantly reduced the infarct size in the ischemic/reperfused myocardium. However, this cardiac protection was not reflected in any significant changes in coronary flow and heart rates. The results support the fact that H2S release plays an important role mitigating reperfusion-induced cardiac damage.

In vitro and in vivo antiplasmodial evaluation of sugar-modified nucleoside analogues.

Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf3D7 and PfRKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation.

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions-Synthesis and Antibacterial Studies.

Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19-C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.

A simple method for the preparation of propargylamines using molecular sieve modified with copper(II).

A new, heterogeneous, 4 A molecular sieve-supported copper(ii) catalyst was developed and was used successfully in the A(3) coupling of alkynes, aldehydes and amines under simple reaction conditions.

Synthesis and photoinitiated thiol-ene reactions of exo-mannals - a new route to C-ß-d-mannosyl derivatives.

Syntheses of acyl protected exo-mannal derivatives were developed starting from O-peracylated mannopyranoses via the corresponding anhydro-aldose tosylhydrazones under modified Bamford-Stevens conditions. The synthesis of analogous O-peralkylated (benzylated and isopropylenated) derivatives was carried out from pyranoid and furanoid mannonolactones using methylene transfer reagents. Photoinitiated thiol-ene additions of these exo-mannals resulted in the corresponding C-(mannopyranosyl/mannofuranosyl)methyl sulfides in medium to good yields with exclusive regio- and ß(d) stereoselectivities.