The synthesis of a sialic acid dimer derivative, Neu5AcR(2f5)Neu5Gc, is described. The synthetic ... more The synthesis of a sialic acid dimer derivative, Neu5AcR(2f5)Neu5Gc, is described. The synthetic strategy is based on the use of allyl alcohol to achieve an exclusive R-sialylation product. The allyloxy group is also a latent glycolic acid that provides the subsequent coupling with neuraminate with minimal protection-deprotection manipulations.
A series of new conjugated compounds with a -SCH 2 -linkage were synthesized by chemical methods ... more A series of new conjugated compounds with a -SCH 2 -linkage were synthesized by chemical methods from imidazole and coumarin derivatives. The experimental results indicate that of the twenty newly synthesized imidazole-coumarin conjugates, three of them exhibited appealing EC 50 values (5.1-8.4 µM) and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1) position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents.
International Journal of Molecular Sciences, Jul 11, 2022
Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected... more Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC 50 = 6.46 µM, low toxicity with CC 50 = 59.7 µM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4anilinoquinazoline derivative improved the anti-CHIKV potency to EC 50 = 3.84 µM, CC 50 = 72.3 µM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.
Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected... more Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazol...
Herein, we report a bifunctional sulfo‐fluorous affinity (SOFA) tag‐assisted enzymatic synthesis ... more Herein, we report a bifunctional sulfo‐fluorous affinity (SOFA) tag‐assisted enzymatic synthesis and purification strategy for the facile preparation of bioactive glycans using fluorous solid‐phase extraction (FSPE). The incorporation of a sulfonate moiety onto the heavy fluorous tag significantly increases its water solubility, which allows the broad use of the inherently hydrophobic fluorous tag in aqueous buffers. In addition, the SOFA tag contains a photocleavable linker, enabling the easy release of amino‐functionalized oligosaccharides by UV irradiation. The SOFA tag was used in the synthesis of both negatively charged and neutral glycans to demonstrate its broad utility as an acceptor toward six different glycosyltransferases, significantly improving the feasibility of the preparation of complex glycans using FSPE. All the reactions were performed in an aqueous buffer, a minimum amount of methanol was used to purify the products, and the SOFA tag was easily recovered after ph...
Our work highlights DHB@MNP-induced pseudo-MS/MS for oligosaccharide characterization, with some ... more Our work highlights DHB@MNP-induced pseudo-MS/MS for oligosaccharide characterization, with some insights on this nanoparticle-mediated energy transfer dynamics.
Chikungunya virus (CHIKV) is an arbovirus that was first recognized in an epidemic form in East A... more Chikungunya virus (CHIKV) is an arbovirus that was first recognized in an epidemic form in East Africa in 1952-1953. The virus is primarily transmitted through mosquitoes and the resulting disease, chikungunya fever, is found in nearly 40 countries. Neither an effective vaccine nor a specific antiviral drug exists for treatments of chikungunya fever. Thus 22 new conjugated compounds of uracilcoumarinarene were designed and synthesized as potential inhibiting agents. Their chemical structures were determined unambiguously by spectroscopic methods, including single-crystal X-ray diffraction crystallography. The three units in these conjugates were connected by specially designed SCH2 and OSO2 joints. Five of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 10.2-19.1 μM) and showed low toxicity (CC50 = 75.2-178 μM). The selective index values were 8.8-11.5 for three conjugates. By analysis of the data from the anti-viral assays, the struct...
The CBr 4 -photoirradiation in methanol generates a controlled source of HBr, which can chemosele... more The CBr 4 -photoirradiation in methanol generates a controlled source of HBr, which can chemoselectively deprotect commonly used hydroxyl-protecting groups in saccharides and nucleosides, such as tert-butyldimethylsilyl, isopropylidene, benzylidene and triphenyl ethers in the presence of other acid-labile functional groups.
Phytosphingosine was synthesized from the commercially available D-2,3-O -isopropylidene-D-lyxofu... more Phytosphingosine was synthesized from the commercially available D-2,3-O -isopropylidene-D-lyxofuranose in 28% overall yield by a six-step procedure. This procedure is expedient and flexible for introduction of other lipid moieties on the phytosphingosine structure to make a variety of derivatives that can support the further exploration of their related biological functions.
Journal of the American Society for Mass Spectrometry, 2010
Efficient structural characterization is important for quality control when developing novel mate... more Efficient structural characterization is important for quality control when developing novel materials. In this study, we demonstrated the soft ionization capability of the hybrid of immobilized silica and 2,5-dihydrobenzoic acid (DHB) on iron oxide magnetic nanoparticles in MALDI-TOF MS with a clean background. The ratio between SiO 2 and DHB was examined and was found to affect the surface immobilization of DHB on the nanoparticle, critically controlling the ionization efficiency and interference background. Compared with commercial DHB, the functionalized nanoparticle-assisted MALDI-TOF MS provided superior soft ionization with production of strong molecular ions within 5 ppm mass accuracy on a variety of new types of synthetic materials used for solar cells, light emitting devices, dendrimers, and glycolipids, including analytes with either thermally labile structures or poor protonation tendencies. In addition, the enhancements of the molecular ion signal also provided highquality product-ion spectra allowing structural characterization and unambiguous small molecule identification. Using this technique, the structural differences among the isomers were distinguished through their characteristic fragment ions and comprehensive fragmentation patterns. With the advantages of long-term stability and simple sample preparation by deposition on a regular sample plate, the use of DHB-functionalized nanoparticles combined with high-resolution MALDI-TOF MS provides a generic platform for rapid and unambiguous structure determination of small molecules. (
The synthesis of a sialic acid dimer derivative, Neu5AcR(2f5)Neu5Gc, is described. The synthetic ... more The synthesis of a sialic acid dimer derivative, Neu5AcR(2f5)Neu5Gc, is described. The synthetic strategy is based on the use of allyl alcohol to achieve an exclusive R-sialylation product. The allyloxy group is also a latent glycolic acid that provides the subsequent coupling with neuraminate with minimal protection-deprotection manipulations.
A simple and efficient protocol for the preparative-scale synthesis of various lengths of oligo-N... more A simple and efficient protocol for the preparative-scale synthesis of various lengths of oligo-N-acetyllactosamine (oligo-LacNAc) and its multi-sialylated extensions.
(1) Materials. N-(5-Hexynyl) phthalimide (Aldrich), acetonitrile (CH 3 CN, Merck), toluene (Merck... more (1) Materials. N-(5-Hexynyl) phthalimide (Aldrich), acetonitrile (CH 3 CN, Merck), toluene (Merck), sodium borohydride (NaBH 4 , Acros), iso-propanol (i-PrOH, Merck), hydrochloric acid (HCl, Acros), acetic acid (HOAc, Acros), dimethyl formaldehyde (DMF, Merck), triethyl amine (NEt 3 , Merck), 4-dimethylaminopyridine (DMAP, Acros), 4-nitrophenyl chloroformate (NPCC, Acros), O-(7-azabenzotriazol-1-yl)- 3-tetramethyluronium hexafluorophosphate (HBTU, Anaspec), copper(I) iodide (CuI, Acros), copper(II) sulfate (CuSO 4 , Merck), sodium ascorbate (Acros), ethanol (EtOH, Merck), tert-butanol (t-BuOH, Acros), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma), decaborane (B 10 H 14 , CMS), and sodium borocaptate (Na 2 B 12 H 11 SH or BSH, Katchem Ltd., Prague, Czech Republic) were used as received. The P2 gel was purchased from Bio-Rad. Analytical thin-layer chromatography (TLC) and reverse-phase TLC were performed using pre-coated plates (Silica Gel 60 F 254 and 60 RP-18F 254S , respectively, Merck). Silica gel 60 and C-18 reverse-phase gel (Merck) were used for flash chromatography. All reactions were carried out in oven-dried glassware (120 °C) under a nitrogen atmosphere unless indicated otherwise. All solvents were dried and distilled using standard techniques. (2) General Measurements. 1 H-, 13 C-and 11 B-NMR spectra were recorded using a Bruker AV-400 or a DMX-600 MHz spectrometer. Chemical shifts are expressed in ppm and were referenced to the residual CDCl 3 (7.24 ppm) or CD 3 OD (3.31 ppm) resonances, which served as internal standards. The coupling constants, J, are reported in Hz.
An efficient synthesis of a P k trisaccharide with a functionalized side arm at the reducing end ... more An efficient synthesis of a P k trisaccharide with a functionalized side arm at the reducing end for conjugation to other molecules is presented. Construction of the P k trisaccharide with a high a-selectivity was achieved in high yield by coupling a reactive galactosyl phosphite donor with a lactosyl acceptor.
Elucidation of protein-protein interactions (PPIs) are often very challenging and yields complex ... more Elucidation of protein-protein interactions (PPIs) are often very challenging and yields complex and unclear results. Lectin-glycoprotein interactions are especially difficult to study due to the noncovalent nature of the interactions and inherently low binding affinities of proteins to glycan ligands on glycoproteins. Here, we report a "ligand-directed labeling probe (LLP)"-based approach to fabricate protein probes for elucidating protein-glycoprotein interactions. LLP was designed with dual photoactivatable groups for introduction of an alkyne handle proximal to the carbohydrate-binding pocket of lectins, Ricinus communis agglutinin 120 (RCA 120 ) and recombinant human Siglec-2-Fc. In proof-of-principle studies, alkynylated lectins were conjugated with the photoreactive diazirine crosslinker and environmentsensitive fluorophore, respectively, by the bioorthogonal click reaction. The modified RCA 120 or Siglec-2-Fc was used for detecting the interaction with target glycoprotein in solution or endogenously expressed glycoproteins on live HeLa cells. We anticipate that the fabrication of these protein probes will accelerate the discovery of novel PPIs.
Background In endothelial cells, phospholipase C (PLC) β1-activated Ca2+ is a crucial second mess... more Background In endothelial cells, phospholipase C (PLC) β1-activated Ca2+ is a crucial second messenger for the signaling pathways governing angiogenesis. PLCβ1 is inactivated by complexing with an intracellular protein called translin-associated factor X (TRAX). This study demonstrates specific interactions between Globo H ceramide (GHCer) and TRAX, which highlight a new angiogenic control through PLCβ1 activation. Methods Globo-series glycosphingolipids (GSLs), including GHCer and stage-specific embryonic antigen-3 ceramide (SSEA3Cer), were analyzed using enzyme-linked immunosorbent assay (ELISA) and Biacore for their binding with TRAX. Angiogenic activities of GSLs in human umbilical vein endothelial cells (HUVECs) were evaluated. Molecular dynamics (MD) simulation was used to study conformations of GSLs and their molecular interactions with TRAX. Fluorescence resonance energy transfer (FRET) analysis of HUVECs by confocal microscopy was used to validate the release of PLCβ1 from ...
Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T ... more Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T (iNKT) cells constitute an emerging class of immunomodulatory agents in development for numerous biological applications. Variations in lipid chain length and/or fatty acids in these glycoceramides selectively trigger specific pro-inflammatory responses. Studies that would link a specific function to a structurally distinct α-GalCer rely heavily on the availability of homogeneous and pure materials. To address this need, we report herein a general route to the diversification of the ceramide portion of α-GalCer glycolipids. Our convergent synthesis commences from common building blocks and relies on the Julia–Kocienski olefination as a key step. A cleavable fluorous tag is introduced at the non-reducing end of the sugar that facilitates quick purification of products by standard fluorous solid-phase extraction. The strategy enabled the rapid generation of a focused library of 61 α-GalCer...
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Papers by Chun-Cheng Lin