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Molecular docking of N-1,4-disubstituted-1,2,3-triazole tethered carboxymethylated thymidine and uridine with ribonuclease A, indicated their possible binding with the P

Ribonuclease A is used as a model enzyme system for the design of RNase inhibitors. Previous studies have established that the geometric nature of the active site cleft is an important feature for the accommodation of crescent-shaped compounds in the active site of RNase A. In the current research, benzene-based triazolylated semicircular hybrid molecules carrying different polar functionalities were synthesized and screened for their RNase A inhibitory potency. An additional carboxylic acid group at the C1-position of the 1,3,5-trisubstituted benzene ring enhanced the inhibitory properties significantly. Furthermore, the studies revealed that the reduced arm lengths of 3,5-substituents result in a better geometric complementarity that makes the molecules fit favorably in the semicircular cavity of the active site as visualized by docking studies. In a series of ten such new compounds, the 3,5-bis[4-(sulfomethyl)-1H-1,2,3-triazol-1-yl]benzoic acid exhibited, the highest inhibition efficiency with a K

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

Seven new carbohydrate–bistriazole hybrid molecules were designed taking into consideration the crescent shaped active site of ribonuclease A (RNase A). In this case, the β-D-ribofuranose structure was used as the basic building unit; both the C1 and C4 arms protruding out towards the β-face of the tetrahydrofuran moiety of the ribose sugar provided an overall “U” shape to the basic building block. Several combinations of bistriazole moieties were constructed on the two arms of this basic building block. These mono- and/or bis-substituted 1,2,3-triazole units were linked to acidic functional groups because of the overall basic nature of the hydrolytic site of RNase A. All these compounds were efficient competitive inhibitors of RNase A with inhibition constants (Ki) in the micromolar range. In contrast to the carboxylic acid-modified hybrid molecules, molecules carrying sulfonic acids were found to be more potent because of the stronger interactions with the positively charged active site. The most efficient inhibitor of the series was the disulfonic acid-functionalized carbohydrate-bis-triazole hybrid molecule. Docking studies disclosed that the molecule, because of its well defined “U” shape with flexible arms, fits effectively in the active site; moreover, in all cases, besides the acid groups, the triazole and sugar rings also actively participated in creating the hydrogen bonding network in the cavity of the enzyme active site.

1,5-Regioisomeric triazole linked disaccharides have been synthesized and screened for their inhibitory properties against ribonuclease A (RNase A). The angular constraint-driven 'crescent shaped' inhibitors accommodated themselves into the enzyme active site. An improved enzyme inhibition was observed with increased H-bonding ability of polar functional groups in the modified disaccharides. In this series, introduction of two carboxyl groups in the furanose rings elicited the best result with an inhibition constant of 50 ± 3 µM. This is the first ever report on the use of disaccharides as RNase A inhibitors.

A single carbohydrate-derived molecule consisting of a masked aldehyde, a Michael acceptor and a number of cleavable bonds has been designed. The adducts generated from this Michael acceptor and a series of β-dicarbonyl compounds and related reagents after acid treatment afforded a new class of furo[2,3-c]piperidine, furo[2,3-d]azepine and oxa-aza-tricyclic scaffolds to form up to three fused rings and seven stereocenters. In-built chirality centers of the sugar derivative controlled the diastereoselectivity of formation of all new stereocenters without the requirement of any external reagent for asymmetric induction. Simple variations of reaction conditions and reagents afforded diverse polycyclic aza-ring systems containing six and seven membered nitrogen heterocycles, which are privileged structures in numerous pharmaceuticals. A less known but unique 1,2-sulfone migration generated seven membered skeleton. In essence this work manifests the power of carbohydrate-based synthetic chemistry for generating complex oxa-aza molecular scaffolds with stereochemical diversity.

Department of Chemistry, Indian Instituteof Technology Kharagpur, Kharagpur-721 302, West Bengal, India E-mail: tpathak@chem.iitkgp.ac.in Manuscript received online 27 December 2019, revised and accepted 09 January 2020 A powerful, flexible, and stereoselective general strategy for the construction of chirally pure six-membered carbocycles from easily available vinyl nitro-modified hexofuranosides is described. By using a Michael addition reaction followed by ring opening and ring closure, densely functionalized carbasugars decorated with multiple chiral centers are obtained in good overall yields.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since C S bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

A metal-free alternative to the regioselective synthesis of carboxylated 1,4-disubstituted 1,2,3-triazoles (1,4-cDTs) has been accomplished. A methoxycarbonyl-substituted vinyl sulfone on reactions with organic azides resulted in the formation of 1,4-cDTs in an operationally simple route. The reaction, carried out with a variety of organic azides containing free alcohol, acid, Boc-protected amine, ester, protected sugars, long-chain alkanes, benzyl, 9-methylanthracenyl, and cholesteryl groups, was found to be general in nature, which afforded a plethora of new chemical entities; reactions of diazides generated mostly the desired and a few unexpected products. This article reports for the first time the targeted metal-free synthesis of any 1,4-disubstituted 1,2,3-triazole using the cycloaddition reactions of an appropriately functionalized vinyl sulfone.

The strained epoxide ring of oxirane-derived furanoside and pyranoside of d-fructose are regioselectively opened by various primary and secondary amines as well as azide to yield C4-alkylamino-C4-deoxy and the corresponding azido derivatives. The epoxide ring of a furanoside derived from l-sorbose, a C-5 epimer of d-fructose also afforded C4-amino and C4-azido analogues. All three epoxides generated piperazine linked disaccharides. These epoxides are also easily opened by p-tolylthiol to access thiosugars. One such thiosugar was converted to vinylsulfone-modified fructofuranoside and subjected to nucleophillic addition. A suitably designed vinyl sulfone-modified fructofuranoside having a leaving group at C-6, act as an efficient substrate for MIRC (Michael Initiated Ring Closure) reactions to construct cyclopropane skeleton in d-fructose. The strategy is general in nature and provides an easy access to cyclopropanated sugar derivatives. Thus, the easily accessible "spring loaded" epoxides of d-fructose and l-sorbose have been used as pivotal starting point for the synthesis of hitherto unknown modified carbohydrates.

Sulfonic nucleic acids were identified as inhibitors of ribonuclease A (RNase A). The incorporation of a strongly acidic group (sulfonic, –SO3H) at the 3′-end of pyrimidine nucleosides thymidine and uridine was prompted by the low inhibition constant (Ki) values recorded for carboxymethylsulfonyl (–SO2CH2CO2H) and –CO2H functionalized nucleosides. It was envisaged that the sulfonic acid-modified pyrimidines would bind effectively with the positively charged P1 site of ribonuclease A. Typical harsh conditions used for SO3H incorporation were replaced with milder reaction conditions. The uridine analogue showing a Ki value of 0.96 μM elicited a better result than the thymidine-modified inhibitor. Notably, it was also the best result among all modified non-phosphate acidic nucleosides reported and screened so far as RNase A inhibitors.

1,4- and 1,5-Disubstituted 1,2,3-triazole scaffolds as surrogate of amide with large dipole moment have been utilized to access two isomeric naphthylthiourea-based chemosensors 1 and 2 in appreciable overall yields. The easily synthesizable chemosensors 1 and 2 are designed to recognize anions and also to realize a comparative view on their sensing potentials. Different inorganic phosphates and a group of phosphorylated nucleosides such as ATP, ADP and AMP are selectively recognized by these chemosensors in semi aqueous system. The fluorometric study revealed that both the sensors sensed ATP selectively in CH3CN/H2O (4/1,v/v) by showing considerable increase in emission. 1,4-Disubstituted triazole-based sensor 1 has been established to be more effective than the 1,5-disubstituted triazole-based sensor 2 in selective sensing of ATP.

D-Fructose, an inexpensive biomass precursor available on a large scale, has been used for the generation of enantiomerically pure chemical entities. Construction of vinyl selenone moieties on cyclic skeletons of d-fructose led to the highly reactive synthetic intermediates comprising of an electron-deficient double bond along with an excellent leaving group. Reactions of these Michael acceptors with different nucleophiles afforded aziridines, thiiranes, cyclopropanes, dihydrofurans, dihydroisoxazole, dibenzyloxymethylfuran, and isonucleosides in moderate to good yields. This powerful and practical route provides a new platform for synthetic applications of renewable biomass precursors and adds to the toolbox for chemists interested in new chemical entities.

Hydrolysis of RNA by ribonuclease A crucially depends on the participation of the 2'-OH group as well as the positioning of the internucleotide bond at two different sites of the enzyme. Therefore, ribopyrimidines were modified with -SO2CH2CO2H, an acidic functional group, which was expected to interact with the phosphate binding site. These ribonucleosides were designed to understand the influence of the 2'-OH group of these inhibitors on ribonuclease A inhibition along with the effect of the -SO2CH2CO2H group. The "down" configuration of the 2'-OH group enhanced the inhibitory properties (Ki =1.75 μm) and also imparted important Val43 H-bonding with the furanose oxygen atom of the inhibitors. One of the most important aspects of this work is that there was no serendipitous discovery of the inhibitors. The inhibitors reported in this manuscript were obtained by design by employing chemical logic.

1,5-Disubstituted 1,2,3-triazole (1,5-DT) linked disaccharides have been synthesized from stable building blocks having both vinyl sulfone and azido groups using aqueous ionic-liquid media. These building blocks containing secondary azido groups do not undergo self-coupling but react with the externally delivered primary azidosugars. The disaccharides are coupled with appropriate building blocks for the preparation of the first ever 1,5-DT linked- and 1,4-/1,5-DT-linked trisaccharides using aqueous ionic-liquid and water–butanol based “click” chemistry, respectively.

Vinyl sulfones and vinyl sulfone-modified carbohydrates were subjected to 1,3-dipolar-cycloaddition reactions with four different azidofuranosides having azido groups at the C5 and C6-positions under refluxing conditions in aqueous media without any metal catalyst to afford the 1,5-disubstituted 1,2,3-triazolylated monofuranosides and difuranosides in high yields. These syntheses of 1,5-disubstituted triazolylated monosaccharides as well as 1,5-disubstituted 1,2,3-triazole linked disaccharides open up a new possibility of connecting furanosides with a stable-triazole backbone. Download : Download high-res image (55KB) Download : Download full-size image

A self-assembled monolayer (SAM) of 1-(3,5-epidithio-2,3,5-trideoxy-β-D-threo-pentofuranosyl)thymine (EFT) on a gold electrode was prepared and characterized by Raman spectral and electrochemical measurements. Voltammetric and electrochemical impedance measurements show that the SAM of EFT on a Au electrode impedes the electron-transfer reaction. The SAM of EFT was successfully used for the voltammetric sensing of urate in neutral solution. The coexisting ascorbate anion does not interfere and therefore the EFT-based electrode was able to quantify urate at the micromolar level in the presence of a large excess amount of ascorbate. To demonstrate the practical applications, the amount of urate in two different human serum samples was quantified by using the EFT-based electrode; the results are in good agreement with those determined by the clinical method. DFT calculations show that both ascorbate and urate have noncovalent interactions including hydrogen-bonding interactions with EFT.

Divinyl sulfones derived from pyranoside skeletons afforded 1,1-dioxothiomorpholine with predefined asymmetric environments. Although the exocyclic vinyl sulfone group easily reacts with primary amines, the intramolecular addition pattern of the secondary amine leading to the formation of the 1,1-dioxothiomorpholine derivative dramatically varied when benzylidene protection was replaced by benzyl protecting groups.

A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hydroxy groups in inhibiting RNase A activity. Uridines and cytidines modified with -SO 2 CH 2 COOH groups at the 2'- and 3'-positions show good inhibitory properties with low inhibition constant (K i ) values in the range of 109–17 μM. The present work resulted in a set of inhibitors that undergo more effective interactions with the RNase A active site, as visualized by docking studies.

5′-Carboxymethylsulfonyl-5′-deoxy-uridine, -cytidine and -adenosine were selected as a new class of potential RNase A inhibitors. The key step of the synthesis from the corresponding esters is crucially dependent on the nature of the base and only trimethyltin hydroxide afforded the desired products under extremely mild basic hydrolytic conditions. The cytidine analogue was found to be the best competitive inhibitor of RNase A in this series (Ki = 22 ± 2 μM).

A vinyl sulfone modified bicyclic sugar molecule undergoes efficient Michael addition of hetero- and carbon nucleophiles to afford single diastereomers. The same molecule consisting of two other masked functional groups, namely an aldehyde and an oxocarbonium ion, turned out to be a unique synthetic intermediate. The adducts generated from this Michael acceptor and a series of β-dicarbonyl compounds and related reagents after acid treatment afforded a new class of furo[2,3-c]pyrans, forming up to three new bonds and three stereocenters. In-built chirality centers of the sugar derivative controlled the diastereoselectivity of formation of all new bonds without the requirement for any external reagent for asymmetric induction. DFT calculations revealed the formation of furopyrans as the only possible products, which corroborates the experimentally observed results.

Enantiomerically pure 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfonyl)- and 2-hydroxymethylene substituted-2,5-dihydro-3-(arylsulfinyl)-furans have been prepared from easily accessible carbohydrate derivatives for the first time. The strategy for accessing both these sulfones and sulfoxides is more efficient than the methods reported so far for the synthesis of this type of compounds. Hydroxymethylene group is sufficient to impose diastereoselectivity on the addition of a wide range of nucleophiles to vinyl sulfone-modified tetrahydrofurans. The benzyl protected hydroxymethylene group also suppresses the influence of chirally pure sulfoxides as two diastereomeric vinyl sulfoxide-modified tetrahydrofurans afforded the Michael adducts with same configurations at C-3 and C-4; this has been established by oxidizing the adducts, which were found to be identical to the products obtained by adding the same nucleophiles to the corresponding vinyl sulfones. These highly reactive Michael acceptors may be considered as a new addition to the arsenals of synthetic chemists interested in the functionalization of tetrahydrofurans.

A single sugar molecule containing three functional groups, namely a masked aldehyde, a Michael acceptor and a leaving group, reacts with a series of β-dicarbonyl compounds and related reagents to form up to three new bonds and up to three new stereocenters. The configuration of the sugar derivative controls the diastereoselectivity in the formation of all the new bonds without a requirement for any external reagent for asymmetric induction. This "Chiral pool" based diversity-oriented synthetic strategy has led to the formation of a series of furofurans based on different scaffolds and with appendage variations, and also to a hitherto unknown family of bicyclic 3,8-dioxabicyclo[4.2.1]nonanes.

Enantiomerically pure 2-substituted-2,5-dihydro-3-(aryl) sulfonyl/sulfinyl furans have been prepared from the easily accessible carbohydrate derivatives. The orientation of the substituents attached at the C-2 position of furans is sufficient to control the diastereoselectivity of the addition of various nucleophiles to the vinyl sulfone/sulfoxide-modified tetrahydrofurans, irrespective of the size of the group. The orientation of the substituents at the C-2 center also suppresses the influence of sulfoxides on the diastereoselectivity of the addition of various nucleophiles. The strategy leads to the creation of appendage diversity, affording a plethora of enantiomerically pure trisubstituted furanics for the first time.

Vinyl sulfoxide-modified pent-2-enofuranosides and hex-2-enopyranosides have been synthesized by using a controlled oxidation of C-3-deoxy-C-3-thioaryl furanosides and pyranosides, respectively, followed by mesylation of the C-2-hydroxyl group and elimination. In the furanose system, both diastereomers were formed in almost equal ratio, whereas the pyranose ring imposed diastereoselectivity of oxidation of the sulfur atom to produce only Ss isomers in good overall yields. Vinyl sulfoxide-modified 2-enofuranosides were treated with NaCH2NO2 to obtain C-2 branched chain sugars. Furanosyl sulfoxides yielded products that were similar to the adducts obtained by treatment of the corresponding sulfones with nitromethane. The sulfinyl group in thepyranosides influenced the diastereoselectivity of addition to produce adducts that differed from the products obtained from the corresponding vinyl sulfones under similar reaction conditions.

A metal-free, vinyl sulfone-based synthesis of 1,5-disub- stituted-1,2,3-triazoles is reported for the first time. These triazoles are easily formed in a regioselective fashion by heating under reflux a mixture of a substituted vinyl sulfone and an organic azide 'on wa- ter'. This powerful and practical route has the potential to be ex- ploited for the synthesis of complex 1,5-disubstituted-1,2,3- triazoles.

Four 5'-deoxy-5'-nipecotic acid substituted pyrimidine nucleosides were synthesized and characterized. Their inhibitory activities towards ribonuclease A (RNase A) have been studied by enzyme kinetics and docking experiments. All inhibition constants obtained were in the sub-millimolar range. Biochemical analysis shows that the uridine derivative is more potent than the corresponding thymidine derivatives and that the inhibition is competitive in nature. For thymidine derivatives, the 3'-hydroxy group plays an important role in binding as well as in inhibition. Docking studies also support the experimental results. In the docking conformation the uridine derivative was found to bind to the P(1)P(2) subsite with the acid group within hydrogen bonding distance of the active site histidine residues.

Nucleophilic C-S bond formation using easily available β-hydroxysulfonate derivatives allowed direct access to new mono- and disubstituted divinyl sulfones. Our strategy uses thioethanol (HSCH(2)CH(2)OH) and its analogues such as HSCH(2)CH(Y)OH generated in situ. The strategy also allows the synthesis of modified divinyl sulfones attached to chiral appendages like carbohydrates. Bis-heteronucleophilic Michael addition reactions with 1 equiv of a primary amine afforded new generations of S,S-dioxothiomorpholine derivatives known for their therapeutic applications. Further synthetic manipulations of some of these cyclic compounds led to the synthesis of novel bicyclic derivatives.

This review describes the research by the authors on the synthesis of vinyl sulfone-modified carbohydrates and the application of this new class of Michael acceptors in the generation of a wide range of aminosugars, branched-chain sugars, cyclopropanted carbohydrates, densely functionalized cyclopropanes, isonucleosides and pyrroles.

1,5-Disubstituted 1,2,3-triazole (1,5-DT) linked disaccharides were used in the modified Tollens method for the synthesis and stabilization of silver nanoparticles (AgNPs) for the first time. The templating effect of the triazole ring is evident from the spectral data. Unlike the naturally occurring disaccharides these disaccharides are stable and the formation of the corresponding dicarboxylate was established. AgNPs obtained from one of the disaccharides showed promising antimicrobial activity. The formation, shapes and antimicrobial activity of the AgNPs strongly depend on the molecular structure of the 1,5-DTs used.

A powerful, flexible, and stereoselective general strategy for the construction of chirally pure six-membered heterocycles and carbocycles by utilizing a tandem Michael–SN2 sequence is described. The strategy avoids the tedious synthesis of separate starting materials prior to cyclization. The expedient and general strategy, which is virtually untapped until now, will enrich the arsenal of synthetic chemists for the preparation of cyclic compounds.

Divinyl sulfone-modified carbohydrates have been synthesized for the first time by reacting easily available carbohydrate epoxides with thioethanol in a regiospecific fashion. One of the modified divinyl sulfones initiated significant cell death in Entamoeba species and the influence of the anomeric configurations on the biological activities of these sugar-derived divinyl sulfones has been highlighted. The most active compound in this series was found to be devoid of any toxicity.

Pentosyl and hexosyl acyclic vinyl sulfones having a suitably positioned leaving group reacted with externally delivered carbon, nitrogen, oxygen, and sulfur nucleophiles to afford a series of five-membered carbocycles and heterocycles in a diastereoselective fashion. This diversity-oriented synthetic method generates a wide range of chirally pure cyclic compounds from easily accessible starting materials and reagents.

Although phenylmethylene-protected vinyl sulfone-modified carbohydrate 2alpha reacts with both primary and secondary amines in Michael fashion to afford aminated products, only primary amines react with the dibenzyl-protected 3alpha, 6-O-trityl-protected 4alpha, and unprotected 5alpha, highlighting for the first time the remarkable influence of protecting groups on the reaction patterns of vinyl sulfone-modified carbohydrates. The quantum chemical calculations suggest that the Michael addition of amines and proton transfer to vinyl sulfone-modified carbohydrates 2alpha and 5alpha are possible via relay process in a concerted mechanism. These calculations reveal that the addition of primary amines to vinyl sulfone-modified carbohydrate is preferential due to the low activation energy barriers, whereas the addition of secondary amines has relatively higher activation energy barriers. The theoretical conclusions are in line with the experimental observations.

In a departure from metal-based cyclopropanation reactions, 4-sulfonylhex-3-enopyranosides carrying a leaving group at either of the two γ-positions are used as efficient intermediates for the synthesis of C3–C4 and C4–C5 cyclopropanated pyranosides. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

We report the inhibition of the ribonucleolytic activity of ribonuclease A (RNase A) by nucleoside–dibasic acid conjugates for the first time. Agarose gel and precipitation assays show that the spacer length and the pKa of the carboxylic group have an important role in the inhibitory capacity. Kinetic experiments indicate a competitive mode of inhibition with inhibition constant (Ki) value of 132 ± 3 μM for Oxa-aT. Docking studies revealed that the carboxylic group of the most active compounds is within hydrogen bonding distance of His-12, Lys-41 and His-119.

Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine nucleosides have been synthesized and characterized. Their inhibitory action to ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are moderate inhibitors of RNase A with mid-to-upper micromolar inhibition constants (K(i)). The high resolution X-ray crystal structures of the RNase A-inhibitor complexes have shown that all inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1)R(2) subsites while the 5' group binds away from the main subsite P(1), where P-O(5') bond cleavage occurs, toward the solvent close to subsite P(0). Structure-activity relationship analysis has demonstrated that the compounds with the larger group in the 5' position are more potent. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes provides a structural explanation of their potency and suggests ways to improve their efficiency and selectivity. These inhibitors can be the starting point for the development of compounds that can be used as pharmaceuticals against pathologies associated with RNase A homologues such as human angiogenin, which is implicated in tumor induced neovascularization.

A wide range of vinyl sulfone-modified carbohydrates have been prepared as starting materials for the synthesis of polysubstituted chiral pyrroles. All these vinyl sulfones reacted efficiently with ethylisocyanoacetate to generate a plethora of new pyrrole derivatives. Furanosyl rings opened up during pyrrole synthesis, and pyranosyl rings were opened up by reacting the pyrrole with POCl(3)/DMF. This paper also reports one of the most efficient and practical routes for the synthesis of beta-substituted pyrroles.

Treatment of methyl 5-deoxy-2,3-O-isopropylidene-5-(benzylsulfonyl)-β-D-ribofuranoside with CBr(2)F(2)-KOH/Al(2)O(3) afforded the corresponding olefinic sugar. The methyl- and the isopropyl-analogues in contrast underwent epimerization at C-4 to generate the α-L-lyxo derivatives.

Michael-type addition reactions of planar N -heterocycles at the C-2 positions of vinyl sulfone-modified carbohydrates provide an efficient and general route for the carbon– N -heterocycle bond formation. Therefore, the addition pattern of planar heterocycles, such as imidazole, triazole, thymine, and adenine to 3- C -phenylsulfonyl-hex-2-enopyranosides ( 1α / 1β ) and 3- C - p -toluenesulfonyl-pent-2-enofuranosides ( 2α / 2β ) was studied for developing a general methodology for the synthesis of new classes of isonucleosides possessing a carbon– N -heterocycle linkage at C-2 positions of furanosyl and pyranosyl sugars. To a great extent, the anomeric configurations of the starting vinyl sulfones play crucial roles in deciding the diastereoselectivity of addition of heterocycles. However, the trityl protected 3- C - p -toluenesulfonyl-hex-2-enopyranosides ( 33α / 33β ) were judged to be more practical starting materials for desulfonylation and deprotection for the synthesis of a new class of thymine and adenine deoxyisonucleosides.

Analogues of 3'-C-methylidene-2',3'-dideoxy-5-meth­yluridine have been synthesized from the 3'-deoxy-3'-sulfonylated derivatives of thymidine using sulfur dioxide extrusion reaction.

This minireview describes syntheses of various vinyl sulfone-modified carbohydrates and their reactions with nitrogen and carbon nucleophiles for accessing a wide range of aminosugars and branched-chain sugars.

The synthesis and reactions of vinyl sulfone-modified pyranosides, furanosides, acyclic sugars, nucleosides and carbasugars are reviewed. Figure options Download full-size image Download as PowerPoint slide