Synthesis,Crystal Structure and Hydrolysis of a Novel Anhydrogalactosucrose: 2′‐Methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside

A novel anhydrogalactosucrose derivative 2′‐methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside ( 4 ) was prepared from 3,6:1′,4′:3′,6′‐trianhydro‐4‐chloro‐4‐deoxy‐galactosucrose ( 3 ) via a facile method and characterized by ¹H NMR, ¹³C NMR and 2D NMR spectra. The single crystal X‐ray diffraction analysis shows that the title molecule forms a two thee‐dimensional network structure by two kinds of hydrogen bond interactions [O(2) H(2)···O(7), O(5) H(5)···O(8)]. Its stability was investigated by acid hydrolysis reaction treated with sulfuric acid, together with the formation of 1,6‐Di‐O‐methoxy‐4‐chloro‐4‐deoxy‐β‐D‐galactopyranose ( 5 ) and 2,2‐Di‐C‐methoxy‐1,4:3,6‐dianhydromannitol ( 6 ). According to the result, the relative stability of the ether bonds in the structure is in the order: C(1) O C(5)≈C(3′) O C(6′)≈C(1′) O C(4′)>C(3) O C(6)≈C(1) O C(2′)>C(2′) O C(5′).     

Synthesis and Evaluation of Paromomycin Derivatives Modified at C(4′)

The 2‐amino‐2‐deoxy‐α‐D ‐glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4‐diamino‐2,4‐dideoxy‐α‐D ‐glucopyranosyl, 2,4‐diamino‐2,4‐dideoxy‐α‐D ‐galactopyranosyl, 2‐amino‐2‐deoxy‐α‐D ‐galactopyranosyl, or 3,4,5‐trideoxy‐4‐aza‐α‐D ‐erythro‐heptoseptanosyl moiety to investigate the effect of the substituent at C(4′) on the interaction with ribosomal RNA. The triflate 6 was prepared from the key intermediate pentaazido 3′,6′‐dibenzyl ether 5 , and the hexosulose 10 was obtained by oxidation of 5 with Dess–Martin's periodinane. Stereoselective reduction of 10 with NaBH₄ gave the alcohol 11 that was transformed into the triflate 12 . The epimeric hexaazides 7 and 13 were obtained by treating the triflates 6 and 12 , respectively, with tetrabutylammonium azide. Periodate cleavage of glycol 2 yielded the dialdehyde 24 that was reductively aminated with aniline and benzylamine to give the 3,4,5‐trideoxy‐4‐aza‐α‐D ‐erythro‐heptoseptanosides 25 and 26 , respectively. Standard azide reduction and debenzylation yielded 9 (2,4‐diamino‐2,4‐dideoxy‐α‐D ‐galactopyranosyl ring I), 13 (2‐amino‐2‐deoxy‐α‐D ‐galactopyranosyl ring I), 17 (2,4‐diamino‐2,4‐dideoxy‐α‐D ‐glucopyranosyl ring I), and 27 and 28 (3,4,5‐trideoxy‐4‐aza‐α‐D ‐erythro‐heptoseptanosyl ring I). The derivatives 9 and 13 possessing a D ‐galacto‐configured ring I were less active than the corresponding D ‐gluco‐analogues 17 and paromomycin ( 1 ), respectively. The C(4′)‐aminodeoxy derivative 17 (D ‐gluco ring I) and the known 4′‐deoxyparomomycin ( 23 ), prepared by a new route, displayed slightly lower antibacterial activities than paromomycin ( 1 ). Cell‐wall permeability is not responsible for the unexpectedly low activity for 17 , as shown by cell‐free translation assays. The results evidence that the orientation of the substituent at C(4′) is more important than its nature for drug binding and activity.     

Nucleic acid related compounds. 114. Synthesis of 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides and selected cytotoxic,anti‐hepatitis b,and adenosine deaminase substrate activities

Selected 2,6‐(disubstituted)purine 2′,3′‐didehydro‐2′,3′‐dideoxynucleosides and 2′,3′‐dideoxynucleosides were prepared and evaluated. Treatment of 5′‐protected ribonucleosides with phenoxythiocarbonyl chloride and 4‐(dimethylamino)pyridine, or under Schotten‐Baumann conditions, gave high yields of 2′,3′‐O‐thiono‐carbonates that underwent Corey‐Winter elimination. Treatment of unprotected ribonucleosides with α‐ace‐toxyisobutyryl bromide in “moist” acetonitrile gave trans 2′,3′‐bromohydrin acetate mixtures that underwent reductive elimination with zinc‐copper couple or zinc/acetic acid. Catalytic hydrogenation of the resulting 2′,3′‐enes gave 2′,3′‐dideoxynucleosides. Treatment of the 2‐amino‐6‐chloropurine and 6‐amino‐2‐fluoro‐purine derivatives with nucleophiles gave 2,6‐(disubstituted)purine 2′,3′‐dideoxynucleosides. 2′,3′‐Dideoxyguanosine and the 2‐amino‐6‐[amino ( 16d ), methoxy ( 16b ), ethoxy ( 16c ), and methylamino ( 16j )]purine 2′,3′‐dideoxynucleosides showed good anti‐hepatitis B activity with infected primary duck hepatocytes. Cytotoxic effects with selected analogues were evaluated in human T‐lymphoblastic and promyelocytic leukemia cell lines. The 2‐amino‐6‐fluoro derivative 16m was the most cytotoxic of the 2‐amino‐6‐(substituted)purine 2′,3′‐dideoxynucleosides, and 2‐fluoro‐2′,3′‐dideoxyadenosine ( 21a ) was the most cytotoxic compound. The order of efficiency of hydrolysis of the 6‐substituent from 2‐amino‐6‐(sub‐stituted)purine 2′,3′‐dideoxynucleosides (V_max/K_m) with adenosine deaminase from calf intestine was: 2‐amino‐6‐[amino ( 16d ) > methoxy ( 16b ) > ethoxy ( 16c )], all of which were ≤3% of the efficiency with adenosine. The 6‐methylamino derivative 16j , as well as 16b , 16c , and 16d were readily converted into 2′,3′‐dideoxyguanosine by duck cell supernatants.     

Synthesis and Conformational Analysis of 1′‐ and 3′‐Substituted 2‐Deoxy‐2‐fluoro‐D‐ribofuranosyl Nucleosides

Convergent syntheses of the 9‐(3‐X‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranosyl)adenines 5 (X=N₃) and 7 (X=NH₂), as well as of their respective α‐anomers 6 and 8 , are described, using methyl 2‐azido‐5‐O‐benzoyl‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranoside ( 4 ) as glycosylating agent. Methyl 5‐O‐benzoyl‐2,3‐dideoxy‐2,3‐difluoro‐β‐D ‐ribofuranoside ( 12 ) was prepared starting from two precursors, and coupled with silylated N⁶‐benzoyladenine to afford, after deprotection, 2′,3′‐dideoxy‐2′,3′‐difluoroadenosine ( 13 ). Condensation of 1‐O‐acetyl‐3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐β‐D ‐ribofuranose ( 14 ) with silylated N²‐palmitoylguanine gave, after chromatographic separation and deacylation, the N⁷‐β‐anomer 17 as the main product, along with 2′‐deoxy‐2′‐fluoroguanosine ( 15 ) and its N⁹‐α‐anomer 16 in a ratio of ca. 42 : 24 : 10. An in‐depth conformational analysis of a number of 2,3‐dideoxy‐2‐fluoro‐3‐X‐D ‐ribofuranosides (X=F, N₃, NH₂, H) as well as of purine and pyrimidine 2‐deoxy‐2‐fluoro‐D ‐ribofuranosyl nucleosides was performed using the PSEUROT (version 6.3) software in combination with NMR studies.     

The 7‐bromo derivative of 2‐amino‐2′‐deoxytubercidin fluorinated at the sugar moiety

The title compound, 2,4‐diamino‐5‐bromo‐7‐(2‐deoxy‐2‐fluoro‐β‐d ‐arabinofuranosyl)‐7H‐pyrrolo[2,3‐d]pyrimidine, C₁₁H₁₃BrFN₅O₃, shows two conformations of the exocyclic C4′—C5′ bond, with the torsion angle γ (O5′—C5′—C4′—C3′) being 170.1 (3)° for conformer 1 (occupancy 0.69) and 60.7 (7)° for conformer 2 (occupancy 0.31). The N‐glycosylic bond exhibits an anti conformation, with χ = −114.8 (4)°. The sugar pucker is N‐type (C3′‐endo; ³T₄), with P = 23.3 (4)° and τ_m = 36.5 (2)°. The compound forms a three‐dimensional network that is stabilized by several intermolecular hydrogen bonds (N—H...O, O—H...N and N—H...Br).     

2‐Amino‐8‐(2‐deoxy‐2‐fluoro‐β‐D‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one: Synthesis and Conformation of a 5‐Aza‐7‐deazaguanine Fluoronucleoside

Nucleobase‐anion glycosylation of 2‐[(2‐methyl‐1‐oxopropyl)amino]imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one ( 6 ) with 3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐α‐D ‐arabinofuranosyl bromide ( 8 ) furnishes a mixture of the benzoyl‐protected anomeric 2‐amino‐8‐(2‐deoxy‐2‐fluoro‐D ‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐ones 9 / 10 in a ratio of ca. 1 : 1. After deprotection, the inseparable anomeric mixture 3 / 4 was silylated. The obtained 5‐O‐[(1,1‐dimethylethyl)diphenylsilyl] derivatives 11 and 12 were separated and desilylated affording the nucleoside 3 and its α‐D anomer 4 . Similar to 2′‐deoxy‐2′‐fluoroarabinoguanosine, the conformation of the sugar moiety is shifted from S towards N by the fluoro substituent in arabino configuration.     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

Oligonucleotides Containing Novel 4′‐C‐ or 3′‐C‐(Aminoalkyl)‐Branched Thymidines

The synthesis of four novel 3′‐C‐branched and 4′‐C‐branched nucleosides and their transformation into the corresponding 3′‐O‐phosphoramidite building blocks for automated oligonucleotide synthesis is reported. The 4′‐C‐branched key intermediate 11 was synthesized by a convergent strategy and converted to its 2′‐O‐methyl and 2′‐deoxy‐2′‐fluoro derivatives, leading to the preparation of novel oligonucleotide analogues containing 4′‐C‐(aminomethyl)‐2′‐O‐methyl monomer X and 4′‐C‐(aminomethyl)‐2′‐deoxy‐2′‐fluoro monomer Y (Schemes 2 and 3). In general, increased binding affinity towards complementary single‐stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monomer Y in a 2′‐O‐methyl‐RNA oligonucleotide had a negative effect on the binding affinity of the 2′‐O‐methyl‐RNA oligonucleotide towards DNA and RNA. Starting from the 3′‐C‐allyl derivative 28 , 3′‐C‐(3‐aminopropyl)‐protected nucleosides and 3′‐O‐phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3′‐C‐(3‐aminopropyl)thymidine monomer Z or the corresponding 3′‐C‐(3‐aminopropyl)‐2′‐O,5‐dimethyluridine monomer W (Schemes 4 and 5). Incorporation of the 2′‐deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased binding affinity towards RNA, while the 2′‐O‐methyl monomer Z induced decreased binding affinity towards DNA as well as RNA complements (Table 2).     

Synthesis and Taste Properties of 4,1′,4′,6′‐Tetrahalodeoxysucrose Analogues

The synthesis of a series of 1,4,6‐trideoxy‐1,4,6‐trihalo‐β‐d‐hexulofuranosyl 4‐deoxy‐4‐halo‐α‐d‐hexopyranosides is described. The 4‐chloro‐, 4‐bromo‐ and 4‐iodo‐4‐deoxy‐β‐d‐fructofuranosyl analogues were synthesized from a 3′,4′‐lyxo‐epoxide using the respective alkali metal halides. The corresponding 4‐halodeoxytagatofuranosyl analogues, on the other hand, were obtained by direct halide displacement of the 4′‐O‐trifluoromethanesulfonyl derivative, which was derived by regioselective sulfonylation of 1,6‐di‐O‐trityl‐β‐d‐fructofuranosyl 6‐O‐trityl‐α‐d‐glucopyranoside via its stannylene acetal. The sweetness intensities of these tetrahalodeoxy compounds strongly suggest that both size and configuration of the halogen substituents at C‐4 and C‐4′ are critical for sweetness enhancement.     

Nucleosides XII.1 Synthesis of 5‐Modified Isoguanosines and Reinvestigation of 5′‐Deoxy‐N3,5′‐cycloisoguanosine

Isoguanosine ( 3 ) underwent a coupling reaction with diaryl disulfides in the presence of tri‐n‐butylphosphine when its 6‐amino group was protected by N,N‐dimethylaminomethylidene. The synthesis of 5′‐deoxy‐N³,5′‐cycloisoguanosine ( 6 ) and its 2′,3′‐O‐isopropylidene derivative ( 11 ) were accomplished in excellent yields from isoguanosines ( 3 & 10 ) in the presence of triphenylphospine and carbon tetrachloride in pyridine. Chlorination at the 5′‐position of isoguanosine ( 3 ) with thionyl chloride followed by the aqueous base‐promoted cyclization afforded the same product 6 . The structures were elucidated by spectroscopic analysis including IR, UV, 1‐D and 2‐D NMR.     

Synthesis of the Branched Trisaccharide L‐Glycero‐α‐D‐manno‐heptopyranosyl‐(1 → 3)‐ [β‐D‐glucopyranosyl‐(1 → 4)]‐L‐glycero‐α‐D‐manno‐heptopyranose,Protected to Allow Flexible Access to Neisseria and Haemophilus LPS Inner Core Structures

Abstract

An efficient synthesis of the protected branched trisaccharide (2′S,3′S)‐(7‐O‐benzyl‐6‐O‐chloroacetyl‐3,4‐O‐(2′,3′‐dimethoxybutane‐2′,3′‐diyl)‐2‐O‐p‐methoxybenzyl‐L‐glycero‐α‐D‐manno‐heptopyranosyl)‐(1 → 3)‐[(2,3,4,6‐tetra‐O‐benzoyl‐β‐D‐glucopyranosyl)‐(1 → 4)]‐7‐O‐acetyl‐1,6‐anhydro‐2‐O‐benzyl‐L‐glycero‐β‐D‐manno‐heptopyranose, which is a key intermediate in the synthesis of inner core structures of Haemophilus and Neisseria LPSs, is described. The heptoses were formed by Grignard reactions using a benzyloxymethyl chloride or a commercial vinyl reagent. The anhydro bridge was formed by treatment of a 6‐OH methyl α‐heptoside precursor with FeCl₃. The protecting group pattern allows modifications at the 2‐, 3‐, 4‐, and 6‐positions of the second heptose moiety and also, after acetolysis of the anhydro bridge, elongation at the reducing end, all known alterations found in the bacterial LPSs.     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

Intricacies of ligand coordination in tricarbonylchromium(0) complexes with ortho‐ and para‐fluorobiphenyls

The steric and electronic factors that influence which of the two rings of a substituted biphenyl ligand coordinates to chromium are of interest and it has been suggested that haptotropic rearrangements within these molecules may be limited if the arene–arene dihedral angle is too large. Two tricarbonylchromium(0) complexes and their respective free ligands have been characterized by single‐crystal X‐ray diffraction. In the solid state, tricarbonyl[(1′,2′,3′,4′,5′,6′‐η)‐2‐fluoro‐1,1′‐biphenyl]chromium(0), [Cr(C₁₂H₉F)(CO)₃], (I), exists as the more stable isomer with the nonhalogenated arene ring ligated to the metal center. Similarly, tricarbonyl[(1′,2′,3′,4′,5′,6′‐η)‐4‐fluoro‐1,1′‐biphenyl]chromium(0) crystallizes as the more stable isomer with the phenyl ring bonded to the Cr⁰ center. The arene–arene dihedral angles in these complexes are 55.77 (4) and 52.4 (5)°, respectively. Structural features of these complexes are compared to those of the DFT‐optimized geometries of ten tricarbonyl[(η⁶‐C₆H₅)(4‐F‐C₆H₄)]chromium model complexes. The solid‐state structures of the free ligands 2‐fluoro‐1,1′‐biphenyl and 4‐fluoro‐1,1′‐biphenyl, both C₁₂H₉F, exhibit arene–arene dihedral angles of 54.83 (7) and 0.71 (8)°, respectively. The molecules of the free ligands occupy crystallographic twofold axes and exhibit positional disorder. Weak intermolecular C—H…F interactions are observed in all four structures.     

Ring‐opening polymerization of benzylated 1,6‐anhydro‐β‐D‐lactose and specific biological activities of sulfated (1→6)‐α‐D‐lactopyranans

A new anhydro disaccharide monomer, 1,6‐anhydro‐2,3‐di‐o‐benzyl‐4‐o‐(2′,3′,4′,6′‐tetra‐o‐benzyl‐β‐D ‐galactopyranosyl)‐β‐D ‐glucopyranose (benzylated 1,6‐anhydro lactose (LSHBE)), was synthesized from D ‐lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring‐opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 → 6)‐α‐D ‐lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH₂Cl₂ solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6‐anhydro‐β‐D ‐glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti‐HIV (EC₅₀ = 5.9 and 1.3 μg/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti‐HIV and blood anticoagulant activities of 0.3 μg/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti‐HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913–924, 2009     

Cyclic‐Disulfide‐Based Prodrugs for Cytosol‐Specific Drug Delivery

The cytosolic conversion of therapeutically relevant nucleosides into bioactive triphosphates is often hampered by the inefficiency of the first kinase‐mediated step. Nucleoside monophosphate prodrugs can be used to bypass this limitation. Herein we describe a novel cyclic‐disulfide class of nucleoside monophosphate prodrugs with a cytosol‐specific, reductive release trigger. The key event, a charge‐dissipating reduction‐triggered cyclodeesterification leads to robust cytosolic production of the cyclic 3′,5′‐monophosphate for downstream enzymatic processing. The antiviral competence of the platform was demonstrated with an O‐benzyl‐1,2‐dithiane‐4,5‐diol ester of 2′‐C‐methyluridine‐3′,5′‐phosphate. Both in vitro and in vivo comparison with the clinically efficacious ProTide prodrug of 2′‐deoxy‐2′‐α‐fluoro‐β‐C‐methyluridine is provided. The cytosolic specificity of the release allows for a wide range of potential applications, from tissue‐targeted drug delivery to intracellular imaging.     

芳环缩合核苷衍生物的合成

A novel efficient synthetic route to 1,3-dihydrobenzo[c]furan glycone was developed and the corresponding 5-fluoro, 5-iodo uracil and guanosine derivatives, the aromatic analogues of the well known antiviral 2＇,3＇-dideoxy-2＇,3＇-dihydronucleosides （d4N）, were synthesized.     

Synthesis of (5′S)‐5′‐C‐Alkyl‐2′‐deoxynucleosides

We describe the synthesis of (5′S)‐5′‐C‐butylthymidine ( 5a ), of the (5′S)‐5′‐C‐butyl‐ and the (5′S)‐5′‐C‐isopentyl derivatives 16a and 16b of 2′‐deoxy‐5‐methylcytidine, as well as of the corresponding cyanoethyl phosphoramidites 9a , b and 14a , b , respectively. Starting from thymidin‐5′‐al 1 , the alkyl chain at C(5′) is introduced via Wittig chemistry to selectively yield the (Z)‐olefin derivatives 3a and 3b (Scheme 2). The secondary OH function at C(5′) is then introduced by epoxidation followed by regioselective reduction of the epoxy derivatives 4a and 4b with diisobutylaluminium hydride. In the latter step, a kinetic resolution of the diastereoisomer mixture 4a and 4b occurs, yielding the alkylated nucleoside 2a and 2b , respectively, with (5′S)‐configuration in high diastereoisomer purity (de=94%). The corresponding 2′‐deoxy‐5‐methylcytidine derivatives are obtained from the protected 5′‐alkylated thymidine derivatives 7a and 7b via known base interconversion processes in excellent yields (Scheme 3). Application of the same strategy to the purine nucleoside 2′‐deoxyadenine to obtain 5′‐C‐butyl‐2′‐deoxyadenosine 25 proved to be difficult due to the sensitivity of the purine base to hydride‐based reducing agents (Scheme 4).     

Semi‐synthesis and NMR spectral assignments of flavonoid and chalcone derivatives

Previous investigations of the aerial parts of the Australian plant Eremophila microtheca and Syzygium tierneyanum resulted in the isolation of the antimicrobial flavonoid jaceosidin ( 4 ) and 2′,6′‐dihydroxy‐4′‐methoxy‐3′,5′‐dimethyl chalcone ( 7 ), respectively. In this current study, compounds 4 and 7 were derivatized by acetylation, pivaloylation, and methylation reactions. The final products, 5,7,4′‐triacetoxy jaceosidin ( 10 ), 5,7,4′‐tripivaloyloxy jaceosidin ( 11 ), 5,7,4′‐trimethoxy jaceosidin ( 12 ), 2′,6′‐diacetoxy‐4′‐methoxy‐3′,5′‐dimethyl chalcone ( 13 ), 2′‐hydroxy‐4′‐methoxy‐6′‐pivaloyloxy‐3′,5′‐dimethyl chalcone ( 14 ), and 2′‐hydroxy‐4′,6′‐dimethoxy‐3′,5′‐dimethyl chalcone ( 15 ) were all fully characterized by NMR and MS. Derivatives 10 and 13 have been previously reported but were only partially characterized. This is the first reported synthesis of 11 and 14 . The natural products and their derivatives were evaluated for their antibacterial and antifungal properties, and the natural product, jaceosidin ( 4 ) and the acetylated derivative, 5,7,4′‐triacetoxy jaceosidin ( 10 ), showed modest antibacterial activity (32–128 µg/ml) against Staphylococcus aureus strains. Copyright © 2016 John Wiley & Sons, Ltd.     

Reliable Synthesis of Various Nucleoside Diphosphate Glycopyranoses

A reliable and high yielding synthetic pathway for the synthesis of the biologically highly important class of nucleoside diphosphate sugars (NDP‐sugars) was developed by using various cycloSal‐nucleotides 1 and 9 as active ester building blocks. The reaction with anomerically pure pyranosyl‐1‐phosphates 2 led to the target NDP‐sugars 20 – 45 in a nucleophilic displacement reaction, which cleaves the cycloSal moiety in anomerically pure forms. As nucleosides cytidine, uridine, thymidine, adenosine, 2′‐deoxy‐guanosine and 2′,3′‐dideoxy‐2′,3′‐didehydrothymidine were used while the phosphates of D ‐glucose, D ‐galactose, D ‐mannose, D ‐NAc‐glucosamine, D ‐NAc‐galactosamine, D ‐fucose, L ‐fucose as well as 6‐deoxy‐D ‐gulose were introduced.