•Novel thiouracil derivatives containing a triazolo-thiadiazole moiety were synthesized.•Most of the compounds showed strong antibacterial activities.•Compound 7d significantly inhibited SecA ATPase activity.•Compound 7d binds at a pocket close to the ATP-binding domain.•The triazole-thiadiazole moiety was of benefit to their SecA inhibitory activity.A series of novel thiouracil derivatives containing a triazolo-thiadiazole moiety (7a-7l) have been synthesized by structural modifications on a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7d and 7g were also tested for their inhibitory activities against SecA ATPase due to their promising antimicrobial activities. The inhibitory activity of compound 7d was found to be higher than that of 2. Molecular docking work suggests that compound 7d might bind at a pocket close to the ATPase ATP-binding domain.A series of novel thiouracil derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications of a lead SecA inhibitor. Compound 7d showed high inhibitory activity against the SecA ATPase.Download high-res image (291KB)Download full-size image

A series of novel thiouracil derivatives containing an acyl thiourea moiety (7a–7x) have been synthesized by structural modification of a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7c, 7m, 7u, 7v exhibited promising activities against above bacteria. Such four compounds were further tested for their inhibitory activity against SecA ATPase, and the results showed that compounds 7c and 7u had higher inhibitory activities than that of compound 2. Molecular docking work suggests that compound 7u might bind at a pocket close to the ATPase ATP-binding domain.Download high-res image (74KB)Download full-size image

Cell surface carbohydrates of the Lewis blood group antigens, Lewis X (Lex), Lewis Y (Ley), Lewis A (Lea), and their sialylated derivatives, such as sialy Lewis X (sLex) and sialy Lewis A (sLea), play important roles in various recognition processes. These cell surface carbohydrates have also been associated with the development and progression of many types of cancers. Recently, we synthesized four anthracene-based fluorescent bisboronic acid sensors (compounds 2a–d) linked by ‘click’ chemistry with tethers of different lengths to match the epitope of various Lewis group of sugars. Among the four compounds, 2a appears to have both high sensitivity and selectivity for Ley among other carbohydrate antigens.Download high-res image (82KB)Download full-size image

Sensors capable of recognizing cell surface carbohydrates, such as sialyl Lewis X (sLex), are invaluable research tools and for the diagnosis and early detection of many forms of cancer. In this paper, we report the design and synthesis of a series of bisboronic acids 6(a–f) as fluorescent sensors towards mono-/oligosaccharides. Among them, compounds 6d and 6e showed strong binding affinities with glucose and fructose, while compound 6c, in which two anthracene-based boronic acid units were linked by a hexamethylene spacer, was able to recognize sLex selectivity and stained HEPG2 cells at 1 μmol/L.Download high-res image (116KB)Download full-size imageAnthracene-based bisboronic acids as fluorescent sensors for mono-/oligosaccharides were designed and synthesized.

A series of novel N,N-bis(3-aminopropyl)methylamine-bridged bis-naphthalimide derivatives NI1–6 were designed and synthesized. Their cytotoxic activities against Hela, MCF-7, SGC-7901 and A549 cells were investigated. Compounds NI1–6 exhibited selectively cytotoxic activities in the tested cell lines and lower cytotoxic activities against MCF-7 cells were found except for compound NI1. NI1, the N-(2-hydroxyethyl)piperazine-modified naphthalimide, showed potent cytotoxic activity in the tested cell lines with IC50 values of 2.31, 2.94, 0.88 and 1.21 μM, respectively, better than the control drug (amonafide). Furthermore, its DNA binding properties, fluorescence imaging and collective apoptosis were investigated. Interestingly, NI1 as a DNA intercalator showed fluorescence enhancement upon binding with Ct-DNA and exhibited different impacts on the cell cycle compared with amonafide. Moreover, compound NI1 showed no significant hematoxicity and cardiotoxicity.

Several novel C-pseudonucleosides containing thiazolidin-4-one and phenyl connected by acetamide bond were rationally designed and easily synthesized at room temperature by using the unprotected sugar aldehyde as the starting material. The effects of the compounds on Con A-induced T cell proliferation were evaluated at five concentrations of 5, 10, 25, 50, and 100 μmol/L Interestingly, compounds 7a and 8a (n = 2, R = H) exhibited immunostimulating activities, while compounds 5a, 6a (n = 1, R = H) and 7b, 8b (n = 2, R = CH3) showed immunosuppressive activities. Another two compounds 5b and 6b (n = 1, R = CH3) had no immunomodulating activities. These initial biological results suggested that subtle structural changes to the phenyl and acetamide bond of C-pseudonucleosides could have a significant effect on T cell proliferation bias, although it was difficult to formulate a rigorous structure-activity relationship based on the observed activities.Novel C-pseudonucleosides containing thiazolidin-4-one were rationally designed and easily synthesized from the unprotected sugar aldehyde at room temperature. Some of the C-pseudonucleosides showed significant effect on Con A-induced T cell proliferation. The subtle structural changes in the C-pseudonucleosides could have a significant effect on T cell proliferation bias.

Several aza-C-pseudonucleosides bearing 1,3-benzothiazin-4-one (6 and 7) were prepared by the one-pot three-component condensation from the iminosugar aldehyde 3, amino acid ethyl/methyl ester hydrochlorides 4(a–c), and 2-mercaptobenzoic acid 5. After removal of Boc and the isopropylidene groups, the target novel tetracyclic iminosugars fused benzo[e][1,3]thiazin-4-one 1(a–c) and 2(a–b) were first afforded by the intramolecular cyclo-amidation reaction. Their structures were determined by their 1H, 13C NMR, and HRMS (ESI) spectra and X-ray. The tetracyclic iminosugars 1(a–c) and 2(a–b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 2a was the best one with the IC50 value of RT inhibitory activity of 0.82 μM. Structure–activity relationship analysis suggested that 1′R configuration in the tetracyclic azasugars was of benefit to their anti-HIV RT activity.

•Seven-membered iminosugars fused thiazolidin-4-one and benzthiazinan-4-one synthesized by Staudinger/aza-Wittig/Cyclization shows significant anti-HIV-RT activity.Novel seven-membered iminosugars fused thiazolidin-4-one and benzthiazinan-4-one were conveniently synthesized by the tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation. Benzoyl group (Bz) migrations were found in the synthesis of 8c and 9b using D-galactoside or D-mannoside as starting materials, respectively, which was suggested by HMBC and X-ray. The new bi/tricyclic iminosugars 3~4(a–d) and 5(b–d) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds except 5b could effectively inhibit RT activity. Among them, compounds 3c and 4c were the best ones with the IC50 values of RT inhibitory activities of 2.11 µM and 2.73 µM, respectively. Structure–activity relationship analysis suggested that the phenyl group in the tricyclic azasugars was beneficial for their anti-HIV RT activity.Novel seven-membered iminosugars fused thiazolidin-4-one and benzthiazinan-4-one were conveniently synthesized by the tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation. Most compounds exhibited significant anti-HIV-RT inhibitory activity.

Controllable supramolecular chirality based on the self-assembly of the perylene bisimide-carbohydrate conjugates was achieved, which exhibited right-handed chirality under the triazole as the linker, and left-handed chirality with the amide bond as the linker, because of the difference of the chirality transfer induced by the different π⋯π stacking interactions and the additional hydrogen-bonds of the amide bond.

Novel chiral pyrrolidinols modified naphthalimide derivatives NI1–4 were synthesized, which showed potent cytotoxic activities against Hela, MCF-7, SGC-7901 and A549 cells. The compounds exhibited strong fluorescence enhancement on binding to Ct-DNA and very good fluorescence imaging with A549 cells, providing a potent application of naphthalimide derivatives in developing novel dual therapeutic and imaging agents.

A series of novel naphthalimide derivatives modified by amino acids and their dichloroacetamide derivatives at the 3-position have been synthesized. Their cytotoxic activities were preliminarily evaluated against Hela, A549 and K562 cells, which showed that the length of the side chains of the amino acids influenced the cytotoxic activities. Moreover, compound 7d showed a very good cytotoxic activity against A549 cells with an IC50 value of 4.78 μmol L−1. Furthermore, the UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation experiment indicated that compounds 6a, 6d and 7a, 7d, as DNA intercalators, exhibited binding affinities with calf-thymus DNA (Ct-DNA).A series of novel dichloroacetamide and amino acid modified naphthalimide derivatives have been synthesized, which showed potent anticancer activities against A549 cells, as the DNA intercalators.

Novel bi-/tricyclic azasugars fused thiazinan-4-one were conveniently synthesized by the tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation. The aryl group (phenyl or pyridyl) in mercaptan acid had an important effect on the formation of the diastereomers of the tricyclic hybrids 12b–15b. The new bi/tricyclic azasugars 3a–8a, 4b, 6b, 8b and the known ones 2a, 2b were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that compounds 2a–b, 4a, 4b, 5a, and 6a could effectively inhibit RT activity. Among them, the tricyclic azasugar 5a was the best one with the IC50 value of 0.49 μM. Structure–activity relationship analysis suggested that the phenyl group in the tricyclic azasugars was benefit for their anti-HIV RT activity.

Novel triphenylethylene–coumarin hybrids containing two amino side chains were designed and synthesized. Some of these 3,4-diphenyl coumarins, 7b–c (the double chains at 4-position on 3-,4-phenyl, respectively), and 13b–f (the double chains at 4-position on 3-phenyl and 7-position, respectively), showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b (R = piperidinyl), 7e (R = NEt2), and 7f (R = 4-methylpiperazinyl) had significant interactions with Ct-DNA by the intercalative mode of binding. Structure activity relationships (SARs) analysis suggested that the location of the two amino alkyl chains would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA.

Novel dimers of triphenylethylene–coumarin hybrid containing one amino side chain were designed and synthesized by the condensation of four dicarboxylic acids with the amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. The adding order of the reactants had a significant effect on the condensation reaction when the malonic acid was used. The dimeric compounds 7a and 7b linked by the malonic acid, showed a broad-spectrum and good anti-proliferative activity against four tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b, 8b, 9b, and 10b had significant interactions with Ct-DNA by the intercalative mode of binding. Both the DNA binding properties and the anti-proliferative activities would be enhanced by dimerization of the monomeric hybrid with one amino side chain, and were significantly affected by the length of the linker (dicarboxylic acids).

A series of novel, azasugar-modified 2-monosubstituted, 2,6- and 2,7-bissubstituted anthraquinone derivatives have been synthesized by the nucleophilic substitution of N-alkylamino azasugar with mono-, bis(2-chloroacetamido)anthraquinones. Their cytotoxic activities against HeLa and MCF-7 cells were preliminarily evaluated and compound 9a with mono-azasugar pendant at 2-position showed similar activity to the control drug (Cisplatin).A series of novel, azasugar-modified anthraquinone derivatives have been synthesized through six steps, and their cytotoxic activities preliminarily evaluated.

•Novel aza-C-disaccharide analogues.•Tandem multi-step reactions through catalytic hydrogenation with Pd(OH)2/C.•Establish compounds’ configuration by NMR analysis.Novel aza-C-disaccharide analogues have been conveniently synthesized by using the isoxazoline-linked C-disaccharide derivatives as the intermediates. Firstly, the CN of isoxazoline was reduced to C–N by using DIBAL-H as reducing agent, then followed by the tandem multi-step reactions through catalytic hydrogenation with Pd(OH)2/C involving debenzylated, reductive cleavage of the N–O, condensation–cyclization of the aldehyde and the in situ generated amine group to form imine CN and then CN hydrogenation to form C–N, thus providing a practical and new access to the synthesis of novel aza-C-disaccharide analogues.

•A novel biocompatible glycocluster based on perylene bisimides PBI-12-Man was designed and synthesized, which showed fluorescent turn-on sensing of Concanavalin A (Con A).•The carbohydrate-protein interaction induced fluorescence enhancement possessed application in the fluorescence imaging of macrophage cell.•Such fluorescence turn-on sensing of protein based on carbohydrate-protein interactions would facilitate the development of new protein-specific fluorescent probe for diagnosis and molecular imaging under live cell conditions.A new water-soluble glycocluster based on perylene bisimides PBI-12-Man has been designed and synthesized, and its specific and selective binding property with Concanavalin A (Con A) has been investigated by fluorescence spectroscopy and circular dichroism (CD) spectroscopy, which showed strong binding affinity for Con A with the binding constant of 8.2×105 M−1 for monomeric mannose unit, two orders of magnitude higher than the corresponding monosaccharide ligand. Most interestingly, a fluorescence enhancement of PBI-12-Man was observed upon binding with Con A because of deaggregation of the self-assembly of PBI-12-Man induced by carbohydrate–protein interaction, and the further study of the fluorescence enhancement with macrophage cells showed that PBI-12-Man as a biocompatible agent had fluorescence imaging of the surface mannose receptor of the cells. Such fluorescence turn-on sensing of protein based on carbohydrate–protein interactions would facilitate the development of new protein-specific fluorescent probe for diagnosis and molecular imaging under live cell conditions.

Water-soluble perylene bisimide derivative 7 modified with six mannoses was synthesized and its self-assembled properties were studied by UV-Vis and CD spectroscopy, which revealed an interesting self-assembly with a solvent-tuning chiral conformation in H2O–DMSO solution. As H2O was added to the DMSO solution until a 60% (or 70%) v/v proportion was achieved, the self-assembly of the mannose functionalized compound 7 exhibited a left-handed helical conformation. More interestingly, when the volume of H2O constituted beyond 85% of the solution, the conformation of the self-assembly turned out to be a right-handed helical conformation. Furthermore, the binding interactions between the self-assembly of compound 7 and Con A were investigated by turbidity assay, CD spectra, TEM and SEM images, and ELLA experiment, which indicated that the self-assembly of compound 7 as multivalent glycoclusters exhibited specific binding to Con A with an IC50 value of 24 μM (144 μM, valency corrected), 10 times stronger than the reference compound (α-MMP).

A water-soluble fluorescent perylene bisimide derivative, PBI-Cl-Man, grafted with six mannose groups was synthesized. Its optical properties were investigated by UV-vis and fluorescence spectra, which indicated that compound PBI-Cl-Man exists in the monomer state at low concentrations and exhibits high fluorescence with a fluorescence quantum yield of 59.9% in water. Furthermore, the binding interactions of PBI-Cl-Man with Con A were studied by fluorescence spectra, CD spectra, turbidity assays and ELLA experiments. The almost complete quenching of the fluorescence upon binding with Con A was observed, with a binding constant of 2.4 × 107 M−1 (4.0 × 106 M−1 for monomeric mannose, valency corrected), nearly 3 orders of magnitude higher than that of monovalent mannose ligands (α-MMP). The ELLA experiments indicated that PBI-Cl-Man, as a multivalent glycocluster, exhibits a strong binding interaction with Con A with an IC50 value of 34 μM (204 μM, valency corrected), 7 times stronger than that of the reference compound (α-MMP).

A series of novel N-linked diglycose derivatives 9 and 10 were conveniently and directly synthesized based on the key step of one-pot tandem Staudinger/aza-Wittig/reduction reaction from the azido sugar and sugar-derived aldehyde followed by deprotection. The biological activities against glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and HIV-RT and antitumor activity of these compounds were preliminarily evaluated.A series of novel N-linked diglycose derivatives were conveniently and directly synthesized based on the key step of one-pot tandem Staudinger/aza-Wittig/reduction reaction followed by deprotection. Some compounds exhibited good cytotoxicity to A-549.

A novel triazatruxene-based fluorescent glycocluster was synthesized and its selective binding interactions with PNA lectin were investigated by fluorescence spectroscopy, CD spectroscopy, and a turbidity assay. The glycocluster exhibited a strong binding affinity for PNA lectin with a Stern–Volmer quenching constant of 5.8 × 105 mol−1 L.A new triazatruxene-based fluorescent glycocluster has been synthesized, which exhibited fluorescence quenching upon binding with peanut agglutinin lectin.

Novel triphenylethylene–coumarin hybrid derivatives containing different amounts of amino side chains were designed and synthesized in good yields under microwave radiation. The derivatives 5b–d which possessed two amino side chains (except morpholinyl) showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 10c, 5c, and 13c bearing amino side chain (except morpholinyl) on 4-phenyl had significant interactions with Ct-DNA by the intercalative mode of binding. Structure–activity relationships (SARs) analysis suggested that the amino alkyl chain would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA.

An efficient and practical synthesis of kifunensine thioanalogs 1a–c was reported. The bicyclic azasugars fused thiazolidin-4-one 4a–c as key intermediates were first synthesized in good yields of 74–80% via one-pot tandem Staudinger/aza-Wittig/cyclization by using the pivotal azidosugars 3a and 3b derived from d-mannose. Followed by double Pummerer rearrangements and deprotection, the target thiokifunensine 1a and its epimers 1b and 1c were obtained in good yields. Compounds 1a–c were preliminary evaluated for their HIV-RT and α-mannosidase (Jack bean) inhibitory activities. The results showed that such compounds exhibited significant anti-HIV-RT inhibitory activity but poor inhibitory against α-mannosidase. To gain further insight into the inhibitory mechanism of compounds 1a–c, the analog compounds 9a–c were also prepared after deprotection from 4a–c, respectively. Activity comparison between compounds 1a–c and 9a–c suggests that the better activities of 1a–c than those of the 9a–c is possibly due to the additional carbonyl at thiazolidine-4-one ring in fused bicyclic azasugars.Graphical abstractAn efficient and practical synthesis of kifunensine thioanalogs via the intramolecular Staudinger/aza-Wittig/cyclization and double Pummerer rearrangements was reported. These compounds exhibited significant anti-HIV-RT inhibitory activity but poor inhibition against α-mannosidase.Highlights► Kifunensine thioanalogs. ► Staudinger/aza-Wittig/cyclization. ► Double Pummerer rearrangement. ► Significant anti-HIV-RT activity.

Novel thiazolidin-4-one linked pseudo-aza-disaccharides and thiazolidin-4-ones containing C-pseudo-aza-nucleosides were synthesized via a one-pot three component reaction. The former was synthesized stereoselectively by the tandem Staudinger/aza-Wittig/cyclization reaction of azasugar aldehyde 1, an azidosugar, and mercaptoacetic acid. The reaction was structure and temperature controlled, and could be performed stereospecifically under 40 °C. It was the first report of a stereospecific synthesis of thiazolidin-4-one linked derivatives. However, these derivatives were synthesized with low stereoselectivity by involving the condensation reaction of azasugar aldehyde 1, aniline, and mercaptoacetic acid.(3aR,6S,7R,7aS)-6-(Azidomethyl)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-olC9H16N4O3[α]D25=+32.6 (c 1.0, CHCl3)Source of chirality: d-mannoseAbsolute configuration: (3aR,6S,7R,7aS)(3aR,6S,7R,7aS)-tert-Butyl 6-(azidomethyl)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylateC14H24N4O5[α]D25=+28.4 (c 1.0, CHCl3)Source of chirality: d-mannoseAbsolute configuration: (3aR,6S,7R,7aS)(R)-3-(((2R,3S,4R,5R)-3,4-Dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl)-2-((2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl)thiazolidin-4-oneC13H22N2O7S[α]D25=+12.4 (c 1.0, MeOH)Source of chirality: d-mannose, d-ribose, and asymmetric synthesisAbsolute configuration: (2R,3S,4R,5R), (R)thiazolidin-4-one, (2R,3S,4R)(S)-3-(((2R,3S,4R,5R)-3,4-Dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl)-2-((2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl)thiazolidin-4-oneC13H22N2O7S[α]D25=-26.0 (c 1.0, MeOH)Source of chirality: d-mannose, d-ribose, and asymmetric synthesisAbsolute configuration: (2R,3S,4R,5R), (S)thiazolidin-4-one, (2R,3S,4R)(R)-2-((2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl)-3-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)thiazolidin-4-oneC14H24N2O8S[α]D25=+123 (c 1.0, MeOH)Source of chirality: d-mannose, d-glucose, and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (R)thiazolidin-4-one, (2R,3S,4S,5R,6S)(R)-2-((2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl)-3-(((2S,3S,4R)-3,4-dihydroxypyrrolidin-2-yl)methyl)thiazolidin-4-oneC12H21N3O5S[α]D25=+31.1 (c 1.0, H2O)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (R)thiazolidin-4-one, (2S,3S,4R)(R)-2-((2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl)-3-(((2S,3R,4R,5R)-3,4,5-trihydroxypiperidin-2-yl)methyl)thiazolidin-4-oneC13H23N3O6S[α]D25=+55.4 (c 1.0, H2O)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (R)thiazolidin-4-one, (2S,3S,4R,5R)(R)-2-((2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl)-3-phenylthiazolidin-4-oneC13H16N2O3S[α]D25=+115.1 (c 1.0, MeOH)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (R)thiazolidin-4-one(S)-2-((2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl)-3-phenylthiazolidin-4-oneC13H16N2O3S[α]D25=-130.1 (c 1.0, MeOH)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (S)thiazolidin-4-one(R)-3-(4-Chlorophenyl)-2-((2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl)thiazolidin-4-oneC13H15ClN2O3S[α]D25=+64.1 (c 1.0, MeOH)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (R)thiazolidin-4-one(S)-3-(4-Chlorophenyl)-2-((2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl)thiazolidin-4-oneC13H15ClN2O3S[α]D25=-67.0 (c 1.0, MeOH)Source of chirality: d-mannose and asymmetric synthesisAbsolute configuration: (2R,3S,4R), (S)thiazolidin-4-one

A chiral self-assembly has been constructed from a D-lactose functionalized perylene bisimide derivative, showing right-handed supramolecular stacking induced by the chiral D-lactose moieties. Benefiting from the grafting of D-lactose, the self-assembled multivalent glycoclusters exhibited specific binding with PNA lectin.

δ-Glyconolactams were first synthesized by the intramolecular Schmidt–Boyer reaction using corresponding δ-azidosugars as starting material. The reaction could be efficiently performed in good yields of 61–69% under microwave radiation in acid condition, providing an alternative protocol to iminosugar δ-lactam.δ-Glyconolactams were first synthesized in good yields of 61–69% under microwave radiation in acid condition by intramolecular Schmidt–Boyer reaction.

Novel bicyclic iminosugar derivatives fused thiazolidin-4-one were conveniently synthesized by double Pummerer rearrangements, and their HIV reverse transcriptase (RT) inhibitory activities were preliminary examined. The notable anti-HIV-RT activity demonstrated that such bicyclic azasugars hold potential as a new kind of HIV-RT inhibitors.

A series of novel naphthalimide derivatives modified with various hydroxyl-alkylamines at 4-position have been synthesized. Their DNA binding properties were investigated by UV–Vis, fluoescence, and circular dichroism (CD) spectroscopies and thermal denaturation. The results showed that compounds 3a–e as the DNA intercalator exhibited middle binding affinities with Ct-DNA. The anticancer activities of 3a–e were preliminarily evaluated, compounds 3c and 3e exhibited potent anticancer activities against Bel-7402 cell line with IC50 values of 5.57 and 9.17 μM, respectively. More interestingly, enhancement of the fluorescence emission was found in the complexes of 3a–e with Ct-DNA, especially for 3c. This would make these compounds as potential DNA staining agents.

A series of novel isoxazoline linked pseudodisaccharide derivatives were regiospecifically synthesized by 1,3-dipolar cycloaddition of α-allyl-C-glycopyranosides and sugar-derived nitrile oxides with good yields. The structures of the compounds were characterized by NMR spectroscopy and MS spectrometry and confirmed by the X-ray crystallographic analysis of compound ((5S)-3-(2,3-O-isopropylidene-5-deoxy-d-lyxofuranose-4-yl)isoxazoline-5-yl) methyl α- C-d-galactopyranoside. Their biological activities against glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and HIV-RT, and antitumor activity were preliminarily evaluated. Some of them exhibited potent inhibitory activity to HIV-RT.Graphical abstractA series of novel isoxazoline linked pseudodisaccharide derivatives have been regiospecifically synthesized in good yields by 1,3-dipolar cycloaddition. Some compounds exhibited very good inhibitory activity to HIV-RT.Highlights► Novel isoxazoline linked pseudodisaccharide derivatives. ► 1,3-Dipolar cycloaddition reaction of α-allyl-C-glycopyranosides to nitrile oxides. ► Establish compounds configuration by NMR analysis and X-ray crystallography. ► Very good HIV-RT inhibitors.

A convenient synthesis of novel bi/tricyclic azasugars fused thiazolidin-4-one and thiazinan-4-one by the one-pot tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation was demonstrated. The reactions were carried out with the azidosugar 1 and mercaptan acids via a key intermediate Schiff base and stereoselectively afforded the titled bi/tricyclic azasugars in good yield. All the dominant products were in the 1,2-trans form and the reaction stereoselectivity mainly depended upon the steric hindrance of the neighboring rigid cyclic isopropylidene groups on C-2, 3 which favors the exo-attack of the sulfur atom (in mercaptan acids) to the intermediate imine. The preliminary biological evaluation of the compounds 10–17 showed that compounds 10b, 11a, 12b, 14b, 16b, 17a, and 17b were found to active the natural killer (NK) cells significantly (immunopotentiating activity) and compounds 10a, 10b, 12a, 16b, and 17b exhibited weak inhibitory activity against β-glucosidase. Yet none of these tested compounds have obvious effects on T cell proliferation, or show inhibition against α-amylase and α-glucosidase.

Novel thiazolidin-4-one-linked pseudodisaccharides 3–6 were synthesized by the one-pot tandem Staudinger/aza-Wittig/cyclization reaction at room temperature. The deacetylation of 3–6 afforded compounds 7–10, respectively. The structures of the new compounds were determined using single crystal X-ray crystallography, 1H, 13C, and 2D NMR spectroscopy, and HR mass spectrometry. The preliminary biological evaluation of compounds 7–10 showed that compounds 7aa, 8aa, 7ab, 8ab, 7bb and 8bb were found to have significant immunopotentiating activity. Yet none of these tested compounds have obvious inhibition against glycosidases or HIV reverse transcriptase, or show cancer cell growth inhibition.

A series of 2-aryl-3-(4,5,6-trimethylpyrimidin-2-yl) thiazolidin-4-ones (1a–1c) and their derivatives bearing a lipophilic substituent, like acetoxy group (3a–3c), propionyloxy group (4a–4c), methyl (5d and 5e) at C-5 on thiazolidin-4-one ring were designed, synthesized and evaluated for their HIV-RT inhibitory activity. Using selfcatalyzed Pummerer reaction, compounds 3a–3c and 4a–4c were obtained in good yield (63.1%–75.2%). Preliminary anti-HIV-RT test of these derivatives indicated that compounds 1a–1c, 4b (propionyloxy group at C-5) showed moderate HIV-RT inhibitory activity and compounds 5d and 5e with methyl at C-5 showed a weak HIVRT inhibitory activity. Structure activity relationship analysis suggested that the substituted groups on C-5 would be unfavorable to anti-HIV-RT activity and that the steric effect might play a critical role in the anti-HIV RT activity.

The catalysis of montmorillonite K10 (MK10) for aryl O-glycosylation of glycosyl trichloroacetimidates was investigated. It was found that the catalyst MK10 is deactivated gradually in the recycle glycosylation. The fresh and the deactivated catalysts were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Thermogravimetric analysis (TGA), and N2 adsorption-desorption. The results show that the eliminated trichloroacetamide molecule deposits on the MK10, which blocks and poisons the active sites, resulting in the deactivation of the catalyst. The regeneration of the deactivated MK10 by calcination was studied preliminarily.

A series of novel thiazolidin-4-ones bearing a hydrophobic substituent at 5-position on the 4,6-dimethyl-pyrimidine ring at N-3 (5c–i and 6c–i) were designed on the prediction of QSAR studies, synthesized in good yields of 60.1–85.3% by microwave-assisted one-pot protocol with the combination of using dicyclohexylcarbonimide (DCC) as the promotor, and evaluated as HIV-1 reverse transcriptases inhibitors. The results of in vitro HIV-1 RT kit assay showed that some of the new compounds, such as 5c, 6c, 5d, 6d, 5g, 5h and 6i, could effectively inhibit RT activity. Among them, compounds 5c and 6c where ethyl group existed at 5-position on N-3 pyrimidine ring were the best ones with the IC50 value of 0.26 μM and 0.23 μM, respectively. Structure-activity relationship analysis of these analogues suggested that the overall hydrophobicity and steric factor were important to the anti-HIV RT activity. The mechanism of the intramolecular cycloamidation promoted by DCC was also investigated with the key uncyclized intermediate 13.A series of novel thiazolidin-4-ones bearing a hydrophobic substituent at 5-position on the 4,6-dimethyl-pyrimidine ring at N-3 (5c–i and 6c–i) were designed on the prediction of QSAR studies, synthesized in good yields of 60.1–85.3% by improved microwave-assisted one-pot protocol with the combination of using dicyclohexylcarbonimide (DCC), and evaluated as HIV-1 reverse transcriptases inhibitors.

2-aryl-3-(naphthalene-1 or 2-yl)-1, 3-thiazolidin-4-ones 4 and 5 were synthesized in 41%–67% yield by using microwave-assisted one-pot protocol. The structures of the new compounds 4l, 4m, 5c, 5e, 5g, 5h, and 5j–5m were confirmed by IR, NMR, MS, and elemental analysis. The antimicrobial activities of the compounds against Pseudomonas syringae pv. lachrymans (Smith et Bryan) Young, Dye & Wilkie, Botrytis cinerea Pers., and Sphaerotheca fusca Blum. were examined. Some of the compounds showed good antifungical activity against Sphaerotheca fusca Blum.

Some novel 2-aryl-3-[5-deoxy-1,2-O-isopropylidene-α-d-xylofuranose-5-C-yl] thiazolidin-4-ones were synthesized by the three-component condensation of an amino sugar 1, an aromatic aldehyde 2, and mercaptoacetic acid 3 in the presence of DCC and DMAP at room temperature. Two diastereoisomers 4 and 5 were afforded as the main products in totally isolated yields of 25.4–70%. The reaction was carried out with almost no observed stereoselectivity except in the case of 2c, which showed a moderate stereoselectivity. The structures of the new compounds were determined by NMR spectroscopy and mass spectrometry (MS), and the configuration of the newly generated chiral carbon (C-2) in the thiazolidin-4-one ring was tentatively assigned based on the X-ray crystallographic structure of 5d and the comparison of their corresponding NMR signals. The antitumor (human cervical cancer cells) activity and the inhibition against the glycosidases (α-glucosidase, β-glucosidase, α-amylase) have been evaluated for the new compounds, some of which exhibited antitumor activity.

Novel trimers of triphenylethylene–coumarin hybrid containing two amino side chains (5a–d and 6a–d) were designed and synthesized by the condensation of 1,3,5-benzenetricarboxylic acid with the varied amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. The extended trimeric compound 6a (R = piperidinyl) exhibited significant anti-proliferative activity against three cancer cells at IC50 of near 10 μmol/L. UV–vis, fluorescence (lifetime) and thermal denaturation exhibited that 6a had significant interaction with Ct-DNA by the intercalative mode of binding. The order of their anti-proliferative activities was 6(a, d) > 5(a, d) and (5–6)a > (5–6)d, respectively, in accordance with that of their DNA binding properties, which suggested that the prolonged linker (six carbons) and piperidinyl group on the side chains are beneficial to DNA binding and the anti-tumor activity.Novel trimers of triphenylethylene–coumarin hybrid containing two amino side chains were designed and synthesized. Some compounds exhibited significant anti-proliferative activity against cancer cells. Both the length of the linker and the basic amino group had important effects on their anti-proliferative activity.

A chiral self-assembly has been constructed from a D-lactose functionalized perylene bisimide derivative, showing right-handed supramolecular stacking induced by the chiral D-lactose moieties. Benefiting from the grafting of D-lactose, the self-assembled multivalent glycoclusters exhibited specific binding with PNA lectin.

Water-soluble perylene bisimide derivative 7 modified with six mannoses was synthesized and its self-assembled properties were studied by UV-Vis and CD spectroscopy, which revealed an interesting self-assembly with a solvent-tuning chiral conformation in H2O–DMSO solution. As H2O was added to the DMSO solution until a 60% (or 70%) v/v proportion was achieved, the self-assembly of the mannose functionalized compound 7 exhibited a left-handed helical conformation. More interestingly, when the volume of H2O constituted beyond 85% of the solution, the conformation of the self-assembly turned out to be a right-handed helical conformation. Furthermore, the binding interactions between the self-assembly of compound 7 and Con A were investigated by turbidity assay, CD spectra, TEM and SEM images, and ELLA experiment, which indicated that the self-assembly of compound 7 as multivalent glycoclusters exhibited specific binding to Con A with an IC50 value of 24 μM (144 μM, valency corrected), 10 times stronger than the reference compound (α-MMP).