[Show abstract][Hide abstract] ABSTRACT: Immune tolerance to tumor-associated carbohydrate antigens (TACAs) has severely restricted the usefulness of most TACAs. To overcome this problem, we selected a sialylated trisaccharide TACA, GM3, as a target antigen, and tested a new immunotherapeutic strategy by combining metabolic bioengineering with dendritic cell (DC) vaccination. We engineered cancer cells to express an artificial structure, N-phenylacetyl-D-neuraminic acid, in place of the natural N-acetyl-D-neuraminic acid of GM3 by using N-phenylacetyl-D-mannosamine (ManNPhAc) as a biosynthetic precursor. Next, we selectively targeted the bioengineered cancer cells by vaccination with DCs pulsed with the GM3 N-phenylacetyl derivative. Vaccination with GM3NPhAc- KLH-loaded DCs elicited robust GM3NPhAc-specific T cell-dependent immunity. The results showed that this strategy could significantly inhibit FBL3 tumor growth and prolong the survival of tumor-bearing mice; B16F10 lung metastases could also be reduced. These findings lay out a new strategy for overcoming immune tolerance to TACAs, such as GM3, for the development of effective tumor immunotherapies.
[Show abstract][Hide abstract] ABSTRACT: In previous studies undertaken by our group, a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-r), which were analogs of fluconazole, was designed and synthesized by click chemistry. In the study reported here, the in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compounds 1a, 1q, and 1r showed the more antifungal activity than the others.
Drug Design, Development and Therapy 03/2015; 9:1459-67. DOI:10.2147/DDDT.S74989 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of glycosylated derivatives of Tunicyclin D were synthesized through a highly efficient and versatile synthetic method. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. Biological studies of the synthetic Tunicyclin D derivatives showed monosaccharide-containing compounds exhibit improved or similar antifungal activities, whereas the compounds carrying disaccharide glycans, showed much weaker antifungal activities.
[Show abstract][Hide abstract] ABSTRACT: Design and synthesis of triazole library antifungal agents having piperazine side chains, analogues to fluconazole were documented. The synthesis highlighted utilization of the click chemistry on the basis of the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H-NMR, 13C-NMR, MS and IR. The influences of piperazine moiety on in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi.
[Show abstract][Hide abstract] ABSTRACT: A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).
Archives of Pharmacal Research 05/2014; 38(4). DOI:10.1007/s12272-014-0378-5 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F) can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π-π face-to-edge interactions.
Drug Design, Development and Therapy 04/2014; 8:383-90. DOI:10.2147/DDDT.S58680 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates as new analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these compounds, 2a-f and 3a-q exhibited higher activities than fluconazole against nearly all fungi tested except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3h-k, and 3o-q against Candida species were much better than those of fluconazole and ketoconazole. Also, 2a-d, 3a-d, 3e-f, 3h-k, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft.
European Journal of Medicinal Chemistry 01/2014; 74C:366-374. DOI:10.1016/j.ejmech.2014.01.009 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A mild and operationally simple procedure by Pd-catalyzed cross-coupling of acyl chlorides with in situ–generated alkynylzinc derivatives was developed, giving the corresponding ynones in good yields.
[Show abstract][Hide abstract] ABSTRACT: Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039μg/mL, followed by voriconazole, which has a MIC of 0.0625μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
[Show abstract][Hide abstract] ABSTRACT: TMSCl was shown to be an efficient reagent for selective deprotection of the anomeric position protected as N,O-dimethylhydroxylamine glycoside. This deprotection condition was proved to be compatible with a number of protecting groups, such as the TBDPS, acetyl, benzyl, benzylidene, and benzoyl groups.
[Show abstract][Hide abstract] ABSTRACT: Covalent attachment of glycosylphosphatidylinositols (GPIs) to the protein C-terminus is one of the most common posttranslational modifications in eukaryotic cells. In addition to anchoring surface proteins to the cell membrane, GPIs also have many other important biological functions, determined by their unique structure and property. This account has reviewed the recent progress made in disclosing GPI and GPI-anchored protein biosynthesis, in the chemical and chemoenzymatic synthesis of GPIs and GPI-anchored proteins, and in understanding the conformation, organization, and distribution of GPIs in the lipid membrane.
Current opinion in chemical biology 10/2013; 17(6). DOI:10.1016/j.cbpa.2013.09.016 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new series of 7-O-substituted pyridyl-4-methyl coumarin derivatives were synthesized and characterized based on their spectral data. All the target compounds were evaluated for their in vitro antifungal activity against eight important fungal pathogens. This study showed that the introduction of the substituted pyridyl moiety at the 7-hydroxy position of coumarin could enhance the antifungal activities. It also indicated that a bulky substituent was not beneficial to the antifungal activity of those coumarin derivatives.
Medicinal Chemistry Research 10/2013; 22(10). DOI:10.1007/s00044-013-0470-2 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of 11,12-cyclic carbonate azithromycin-4″-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity.
[Show abstract][Hide abstract] ABSTRACT: A series of 1-(1H-1,2,4-triazol-1-yl)- 2-(2,4-difluorophenyl)-3-[N- propyl-N-((1-substituted -1H-1,2,3-triazol-4-yl)methyl)amino]-2-propanols which are analogues of Fluconazole, have been designed and synthesized on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and HR ESI MS. The MIC80 values indicate that the target compounds 1a-o showed higher activities against nearly all the fungi tested to some extent except against A. fum. and T. rub.. All the target compounds exhibited higher activities against C. alb.SC5314 and C. alb. Y0109 than all six positive controls.
[Show abstract][Hide abstract] ABSTRACT: A series of fluconazole analogues containing 1,2,3-triazole fragment have been designed and synthesized on the basis of the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by (1)H NMR, (13)C NMR and LC-MS. The MIC80 values indicate that the target compounds 1a-r showed higher activities against nearly all the fungi tested to some extent except against Aspergillus fumigatus. Compounds 1c, e, f, l and p showed 128 times higher activity (with the MIC80 value of 0.0039 mg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls.
Archives of Pharmacal Research 05/2013; 36(10). DOI:10.1007/s12272-013-0063-0 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-o) which are analogues of fluconazole, have been designed and synthesized for the first time by the click reaction on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). Their structures were characterized by 1H NMR, 13C NMR and HRMS. The in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi.
Medicinal Chemistry Communication 03/2013; 4(4):704-708. DOI:10.1039/C3MD20086H · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the more active antitumor compounds, two series of new xanthones, containing 1,4-disubstituted-1,2,3-triazole moiety were designed and synthesized. Eaton's Reagent and "click reaction" were used in the synthesis. Most of the title compounds showed good inhibitory activity against the hepatoma carcinoma cell line (Bel-7402) and human cervical carcinoma cell line (HeLa) in vitro. Compounds 10a, 10e, 10f, 11r and 11t had potent activity with IC(50) values, ranging from 2.2 ± 0.17 to 7.1 ± 0.27 ∝M, which was equivalent to Doxorubicin.
Archives of Pharmacal Research 12/2012; 35(12):2093-104. DOI:10.1007/s12272-012-1206-4 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 3/4-[[N-alkyl-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1, 2, 4-triazole)] propylamino] benzylethyl carbonate were designed, synthesized and evaluated as antifungal agents. The MIC80 values indicate that all the compounds showed only moderate or even no antifungal activities against nearly all the tested fungal pathogens. Moreover, the interactions of the most active compounds in the drug binding site of CACYP51 were also explored with the help of docking studies.
[Show abstract][Hide abstract] ABSTRACT: In order to search for drugs with excellent anti-inflammatory activities, a series of novel sinomenine derivatives were designed, synthesized, and evaluated for their inhibition activities against NF-κB activation induced by lipopolysaccharide (LPS). Compared with the natural parent sinomenine, compounds 2a-w showed higher activity, while compounds 1a-o showed similar activity against NF-κB. Moreover, a molecular model for the binding between compound 2v and the active site of p50 was provided on the basis of the computational docking results.