Acyclic Chain Research Articles

New Chain-Extended Analogues of Salacinol and Blintol and Their Glycosidase Inhibitory Activities. Mapping the Active-Site Requirements of Human Maltase Glucoamylase

The synthesis of new chain-extended sulfonium and selenonium salts of 1,4-anhydro-4-thio-(or 4-seleno)-d-arabinitol, analogues of the naturally occurring glycosidase inhibitor salacinol, is described. Nucleophilic attack at the least hindered carbon atom of 4,6-O-benzylidene-2,5-di-O-p-methoxybenzyl-d-mannitol-1,3-cyclic sulfate by 2,3,5-tri-O-p-methoxybenzyl-1,4-anhydro-4-thio-(or 4-seleno)-d-arabinitol gave the sulfonium and selenonium sulfates, respectively. Subsequent deprotection with trifluoroacetic acid yielded the target compounds. In these analogues, an extended polyhydroxylated aliphatic side chain has been incorporated while maintaining the stereochemistry of C-2' and C-3' of salacinol or blintol. These compounds were designed to probe the premise that they would bind with higher affinity to glucosidases than salacinol because the extra hydroxyl groups in the acyclic chain would make favorable polar contacts within the active site. Both target compounds inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range. Comparison of these values to those of related compounds synthesized in previous studies has provided a better understanding of structure-activity relationships and the optimal stereochemistry at the different stereogenic centers required of an inhibitor of this enzyme. With respect to chain extension, the configurations at C-2' and C-4' are critical for activity, the configuration at C-3', bearing the sulfate moiety, being unimportant. The desired configuration at C-5' is also specified. However, comparison of the activities of the chain-extended analogues with those of salacinol and blintol indicates that there is no particular advantage of the chain-extension relative to salacinol or blintol. These results are similar to those reported earlier for kotalanol, a 7-carbon-extended derivative, versus salacinol against rat intestinal maltase, sucrase, and isomaltase.

Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters

Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines

To discover new potent and selective anti-human immunodeficiency virus (HIV) acyclic nucleoside phosphonate (ANP) drugs with in vivo antiretroviral activity. New acyclic pyrimidine nucleoside phosphonate derivatives that mimic the structure of the anti-HIV purine nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA, tenofovir) were designed by linking the acyclic side chain of the ANPs through an ether bond to the C-6 position instead of the N-1 position of the pyrimidine ring. The compounds were evaluated against HIV and Moloney murine sarcoma virus (MSV) in cell culture, including a broad variety of HIV-1 clade clinical isolates and relevant mutant (drug-resistant) HIV-1 isolates. Their antiviral activities were correlated and investigated in an in vivo model consisting of MSV-infected newborn mice. MSV-induced tumour formation and associated death were recorded in drug-treated animals. Several 5-substituted 6-[2-(phosphonomethoxy)ethoxy]-2,4-diaminopyrimidine (PMEO-DAPy) analogues were found to inhibit a broad variety of HIV-1 clinical isolates. They showed a more favourable cross-resistance profile to mutant virus isolates than adefovir and tenofovir. There was a close correlation between inhibition of MSV in C3H/3T3 cells and inhibition of HIV-1 in CEM cells. The PMEO-DAPy derivatives potently inhibited MSV-induced tumour cell formation in newborn mice. The 5-methyl analogue PMEO-5-Me-DAPy proved markedly more inhibitory to MSV-induced tumour cell formation and associated animal death than its unsubstituted parent PMEO-DAPy derivative. When compared with adefovir, PMEO-5-Me-DAPy was less toxic and more antivirally active in MSV-infected mice. PMEO-5-Me-DAPy deserves further (pre)clinical investigations as a candidate anti-HIV drug.

Design and synthesis of selenonium and sulfonium ions related to the naturally occurring glucosidase inhibitor salacinol

Four series of analogues of the naturally occurring glucosidase inhibitor salacinol were synthesized for structure–activity studies with different glycosidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack at the least-hindered carbon atom of the 1,3-cyclic sulfates derived from D-glucose and D-mannose by the isopropylidene-protected 1,4-anhydro-4-thio- and seleno-D-allitols and the 4-thio- and seleno-L-allitols. Deprotection of the coupled products afforded the novel sulfonium and selenonium ions containing polyhy droxylated acyclic chains of four and six carbons, with different stereochemistry at the stereogenic centers and with 1,4-anhydro-4-seleno or 4-thio-D- or L- alditol heterocyclic rings. The compounds showed no significant activity against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself.Key words: glycosidase inhibitors, zwitterionic, selenonium salts, sulfonium salts, cyclic sulfates, L-ascorbic acid, D-gulonic-γ-lactone.

The first example of samarium diiodide-promoted intramolecular ketone–ester coupling of ketones tethering acyloxyalkyl side chains producing 2-hydroxy cyclic hemiacetals

The reaction of samarium diiodide with some cyclic and acyclic ketones tethering acyloxyalkyl side chains produced 2-hydroxy cyclic hemiacetals in moderate to good yields, in which an intramolecular addition of samarium ketyl radicals to distant ester carbonyls would be involved.

Oxidation of A2E Results in the Formation of Highly Reactive Aldehydes and Ketones

It has been reported that the photo-oxidation of A2E, a component of human retinal lipofuscin, leads to products that are toxic to cells via dark reactions. Because these compounds have been implicated in the development of various maculopathies such as age-related macular degeneration (AMD), it is important to determine the structures of those deleterious compounds. Both the photo-oxidation and auto-oxidation of A2E lead to the same complex mixture of products, some of which have lower molecular weights than the staring material. Because A2E is homologous to beta-carotene, it was hypothesized that its oxidation would lead to products analogous to those found in oxidized beta-carotene, namely, a series of cleavage products along the acyclic chain with the concomitant formation of aldehydes. This was found to be the case based upon 1) the formation of all of the aldehydes predicted from the oxidation of beta-carotene, 2) the loss of 28 amu (carbonyl moiety) from the molecular ion, 3) the facile reaction of the aldehydes with nitrophenylhydrazines to form nitrophenylhydrazones and 4) the subsequent MS/MS cleavage of those derivatives at the N-N bond. If formed in vivo, these aldehydes would have toxic effects on any cell. Finally, the similarity in product mixtures from both the photo-oxidation and auto-oxidation strongly suggests that the intermolecular photo-oxidation of A2E results primarily from a radical process without the involvement of singlet oxygen. Any formation of singlet oxygen most likely arises from sensitization by the aldehyde oxidation products, as this process is well known for aldehydes, in general, and retinal, specifically.

Reductive Opening of Glycal Derived Highly Functionalized 2,3‐Epoxy‐1‐iodides with Zinc Dust: An Efficient Method for the Synthesis of Acyclic Long Chain Polyhydroxylated Terminal Alkenic Alcohols.

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Synthesis of thioswainsonine as a potential glycosidase inhibitor

The synthesis of a bicyclic sulfonium-ion analogue of a naturally occurring glycosidase inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multi-step synthesis starting from 1,4-anhydro-2,3-di- O-benzyl-4-thio- d-lyxitol. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt will serve as a candidate to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.

Synthesis of New 5‐Substituted Pyrimidine Acyclonucleosides

Acyclonucleosides of pyrimidine were prepared by condensing appropriately silylated 5‐substituted pyrimidines with an acyclic side chain in the form of an acetylated haloalkoxyalcohol and subsequent removal of the protecting acetyl group in base. Also, acyclonucleosides with a 1‐ethoxymethyl side chain have been investigated. The activity against hepatitis B virus (HBV) has been tested.

Synthesis and ring opening metathesis polymerisation of isoxazolino- and isoxazolidino-norbornenes

Isoxazolino- and isoxazolidino-norbornenes, prepared by cycloaddition to norbornadiene of nitrile oxides and nitrones, respectively, undergo ring opening metathesis polymerisation (ROMP) initiated by the Grubbs ruthenium alkylidenes 1 and 2. The structures of the resulting polymeric isoxazolines were established from their NMR spectra by comparison to polynorbornene and to model isoxazolines prepared by nitrile oxide cycloaddition to cyclopentene. The average degree of polymerisation was regulated using an acyclic chain transfer agent (hex-1-ene) affording products with av DP=4–157, and with narrow molecular weight distributions (PDI=1.45–1.65). Oligomeric analogues (n=4,16) with saturated backbones were prepared by reduction with p-toluenesulfonyl hydrazide.

Synthesis of zwitterionic selenonium and sulfonium sulfates from D-mannose as potential glycosidase inhibitors

Four chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol were synthesized for structure–activity studies with different glycosidase enzymes. The syntheses involved the reaction of isopropylidene-protected 1,4-thio- and 1,4-seleno-D-talitols and 1,5-thio- and 1,5-seleno-L-gulitols, derived from D-mannose, with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, also derived from D-mannose. Deprotection of the products afforded the novel selenonium and sulfonium sulfates composed of heterocyclic five- and six-membered ring core structures with pendant polyhydroxylated, acyclic chains of six carbon atoms.Key words: glycosidase inhibitors, zwitterionic selenonium and sulfonium sulfates, cyclic sulfate

A New Class of Glucosidase Inhibitor: Analogues of the Naturally Occurring Glucosidase Inhibitor Salacinol with Different Ring Heteroatom Substituents and Acyclic Chain Extension

Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes.

Reductive opening of glycal derived highly functionalized 2,3-epoxy-1-iodides with zinc dust: an efficient method for the synthesis of acyclic long chain polyhydroxylated terminal alkenic alcohols

The synthesis of densely functionalized acyclic long chain terminal alkenic alcohols was achieved by reductive opening of glycal derived 2,3-epoxy-1-iodides, with commercial zinc dust alone in a short reaction time with excellent yields involving a simple reaction procedure and easy work-up. A mechanism involving an organometallic intermediate is proposed.

Synthesis of Sulfonium Sulfate Analogues of Disaccharides and Their Conversion to Chain-Extended Homologues of Salacinol: New Glycosidase Inhibitors

Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol with cyclic sulfate derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium sulfate derivatives of D-glucose, D-galactose, D-arabinose, and D-xylose that are of interest in their own right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range, of approximately the same magnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.

Synthesis of Aminopropyl Phosphonate Nucleosides with Purine and Pyrimidine Bases

The synthesis and antiviral evaluation of new acyclic phosphonate nucleosides related to HPMPC (Cidofovir) has been described. These aminopropyl phosphonate nucleosides 1-3 have an amino function within either the acyclic chain (series 2 and 3) or as substituent (series 1). Both purine and pyrimidine nucleotide analogues have been synthesized. In contrast to HPMPC the oxygen analogue of 2c, only a weak antiherpes virus activity could be demonstrated for 2b and 2c.

A simple method for simultaneous estimation of Wiener (W) and Szeged (Sz) indices of benzenoids

This paper describes a simple method for the simultaneous estimation of Wiener (W) and Szeged (Sz) indices for benzenoid systems using elementary cut method. The method is extended to cyclic graphs containing acyclic (tree-like) side chains.

An Efficient Synthesis Of Acyclic N7- and N9-Adenine Nucleosides Via Alkylation With Secondary Carbon Electrophiles to Introduce Versatile Functional Groups At the C-1 Position of Acyclic Moiety

The introduction of versatile functional groups, allyl and ester, at the C-1 position of the acyclic chain in acyclic adenine nucleosides was achieved for the first time directly by alkylation of adenine and N6-protected adenine. Thus, the C-1′-substituted N9-adenine acyclic nucleoside, adenine-9-yl-pent-4-enoic acid ethyl ester (11), was prepared by direct alkylation of adenine with 2-bromopent-4-enoic acid ethyl ester (6), while the corresponding N7-regioisomer, 2-[6, (dimethylaminomethyleneamino)-purin-7-yl]-pent-4-enoic acid ethyl ester (10), was obtained in one step by the coupling of N,N-dimethyl-N′- (9H-purin-6-yl)-formamidine (9) with 2-bromopent-4-enoic acid ethyl ester (6). The functional groups, ester and allyl, were converted to the desired hydroxymethyl and hydroxyethyl groups, and subsequently to phosphonomethyl derivatives and corresponding pyrophosphorylphosphonates.

Synthesis of a Sulfonium Ion Analogue of the Glycosidase Inhibitor Swainsonine

The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-thiolane. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt provides a candidate with which to further probe the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.

Chemistry of Anthracene–Acetylene Oligomers. II. Synthesis, Structure, and Properties of 1,8-Anthrylene–Ethynylene Cyclic Tetramers and Related Acyclic Oligomers

Abstract The title π-conjugated oligomers consisting of anthracene and acetylene units were synthesized to construct a new type of three-dimensional organic architecture. An acyclic chain was extended by the sequence of the Sonogashira coupling and the desilylation from 1,8-diethynylanthracene derivatives and 1,8-diiodoanthracene to form a tetramer, which was then coupled intramolecularly to afford a cyclic tetramer as orange crystals. It is characteristic that a substituent free cyclic tetramer shows the hypochromic effect in the UV spectrum and the presence of an excimer-type emission in the fluorescence spectrum. X-ray analysis revealed that the cyclic tetramer took a diamond prism structure of nearly C2 symmetry, and the skeletal swing between the two enantiomeric forms via a square prism form was observable by dynamic NMR spectroscopy (barrier: ca. 38 kJ mol−1). The structural and spectral properties as well as some reactivities of the cyclic tetramer and related acyclic oligomers up to heptamer are reported.

Design and Studies of Novel 5-Substituted Alkynylpyrimidine Nucleosides as Potent Inhibitors of Mycobacteria

We herein report a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of mycobacteria. A series of 5-alkynyl derivatives of 2'-deoxyuridine (1-8), 2'-deoxycytidine (9-14), uridine (15-17), and 2'-O-methyluridine (18, 19) were synthesized and evaluated for their antimycobacterial activity in vitro. 5-Decynyl, 5-dodecynyl, and 5-tetradecynyl derivatives showed the highest antimycobacterial potency against M. bovis and M. avium, with the 2'-deoxyribose derivatives being more effective than the ribose analogues. Nucleosides bearing short alkynyl side chains 5-ethynyl, 5-propynyl, 5-pentynyl, and 5-heptynyl were mostly not inhibitory. Incorporation of a phenylethynyl function at the 5-position diminished the antimicrobial effect. Furthermore, related bicyclic analogues (20-24) were devoid of antimycobacterial activity, indicating that an acyclic side chain at the C-5 position of the pyrimidine ring is essential for potent activity. Compounds 1-17 were synthesized by the Pd-catalyzed coupling reactions of respective alkynes with 5-iodo derivatives of 2'-deoxyuridine, 2'-deoxycytidine, and uridine. Intramolecular cyclization of 1 and 3-6 in the presence of Cu afforded the corresponding bicyclic compounds 20-24. The investigated nucleosides are recognized here for the first time to be potent inhibitors of mycobacteria. This class of compounds could be of interest for lead optimization as antimycobacterial agents.