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1.
J Nat Prod ; 87(4): 713-721, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38417168

RESUMO

PD-1/PD-L1 monoclonal antibodies exhibit promising therapeutic effectiveness in multiple cancers. However, developing a simple and efficient non-antibody treatment strategy using the PD-1/PD-L1 signaling pathway still remains challenging. In this study, we developed a flow cytometry assay to screen bioactive compounds with PD-L1 inhibitory activity. A total of 409 marine natural products were screened, and sokotrasterol sulfate (SKS) was found to efficiently suppress the IFN-γ-induced PD-L1 expression. SKS sensitizes the tumor cells to antigen-specific T-cell killing in the T cell-tumor cell coculture system. Mechanistically, SKS directly targeted Janus kinase (JAK) to inhibit the downstream activation of signal transducer and activator of transcription (STAT) and the subsequent transcription of PDL1. Our findings highlight the immunological role of SKS that may act as a basis for a potential immunotherapeutic agent.


Assuntos
Antígeno B7-H1 , Interferon gama , Janus Quinases , Interferon gama/farmacologia , Humanos , Janus Quinases/metabolismo , Esteróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estrutura Molecular , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linhagem Celular Tumoral
2.
Bioorg Chem ; 143: 107057, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38150934

RESUMO

Pyridoxal kinase (PDXK) is an essential enzyme in the synthesis of pyridoxal 5-phosphate (PLP), the active form of vitamin B6, which plays a pivotal role in maintaining the enzyme activity necessary for cell metabolism. Thus, PDXK has garnered attention as a potential target for metabolism regulation and tumor therapy. Despite this interest, existing PDXK inhibitors have faced limitations, including weak suppressive activity, unclear mechanisms of action, and associated toxic side effects. In this study, we present the discovery of a novel PDXK inhibitor, luteolin, through a high-throughput screening approach based on enzyme activity. Luteolin, a natural product, exhibits micromolar-level affinity for PDXK and effectively inhibits the enzyme's activity in vitro. Our crystal structures reveal that luteolin occupies the ATP binding pocket through hydrophobic interactions and a weak hydrogen bonding pattern, displaying reversible characteristics as confirmed by biochemical assays. Moreover, luteolin disrupts vitamin B6 metabolism by targeting PDXK, thereby inhibiting the proliferation of leukemia cells. This research introduces a novel screening method for identifying high-affinity and potent PDXK inhibitors and sheds light on clarification of the structural mechanism of PDXK-luteolin for subsequent structure optimization of inhibitors.


Assuntos
Luteolina , Piridoxal Quinase , Humanos , Piridoxal Quinase/química , Piridoxal Quinase/metabolismo , Luteolina/farmacologia , Fosfato de Piridoxal/metabolismo , Vitamina B 6/farmacologia , Vitamina B 6/metabolismo , Inibidores de Proteínas Quinases/farmacologia
3.
Org Biomol Chem ; 18(15): 2938-2948, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32242600

RESUMO

Two myo-inositol derivatives having an Nα,Nε-diacetyl-l-lysine (Ac2Lys) moiety linked to the inositol 1-O-position through a self-cleavable linker and a metabolically stable 2-azidoethyl group linked to the inositol 3-O- and 4-O-positions, respectively, were designed and synthesized. The Ac2Lys moiety blocking the inositol 1-O-position required for GPI biosynthesis was expected to be removable by a combination of two enzymes, histone deacetylase (HDAC) and cathepsin L (CTSL), abundantly expressed in cancer cells, but not in normal cells, to transform these inositol derivatives into biosynthetically useful products with a free 1-O-position. As a result, it was found that these inositol derivatives could be incorporated into the glycosylphosphatidylinositol (GPI) biosynthetic pathway by cancer cells, but not by normal cells, to express azide-labeled GPIs and GPI-anchored proteins on cell surfaces. Consequently, this study has established a novel strategy and new molecular tools for selective metabolic labeling of cancer cells, which should be useful for various biological studies and applications.


Assuntos
Corantes Fluorescentes/química , Proteínas Ligadas por GPI/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Inositol/química , Lisina/química , Engenharia Metabólica , Imagem Óptica , Células Cultivadas , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Proteínas Ligadas por GPI/química , Glicosilfosfatidilinositóis/química , Células HEK293 , Humanos , Inositol/síntese química , Inositol/metabolismo , Lisina/síntese química , Lisina/metabolismo , Microscopia de Fluorescência
4.
J Am Chem Soc ; 138(5): 1684-8, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26784371

RESUMO

The first total synthesis of a major component of marine glycolipid vesparioside B ( Scheme 1 , 1, R1 = n-C22H45, R2 = n-C14H29) has been accomplished through a convergent [4 + 3] coupling strategy. Key steps included stereoselective installment of a set of challenging 1,2-cis-glycoside bonds. A 2-quinolinecarbonyl-assisted α-galactosylation and a novel ß-arabinosylation were developed, respectively, to synthesize the α-galactofuranosidic and the ß-arabinopyranosidic linkages. Furthermore, a 4,6-O-benzylidene-controlled α-galactopyranosylation reaction allowed the efficient connection of the left tetrasaccharide donor 2 with the right disaccharide lipid acceptor 3, hence leading to the total synthesis of 1.


Assuntos
Glicoesfingolipídeos/síntese química , Poríferos/química , Animais , Glicoesfingolipídeos/química , Glicosilação , Ligação de Hidrogênio , Espectroscopia de Prótons por Ressonância Magnética
5.
Front Pharmacol ; 15: 1355507, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720778

RESUMO

Introduction: Solute carrier (SLC) transport proteins play a crucial role in maintaining cellular nutrient and metabolite homeostasis and are implicated in various human diseases, making them potential targets for therapeutic interventions. However, the study of SLCs has been limited due to the lack of suitable tools, particularly cell-based substrate uptake assays, necessary for understanding their biological functions and for drug discovery purposes. Methods: In this study, a cell-based uptake assay was developed using a stable isotope-labeled compound as the substrate for SLCs, with detection facilitated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay aimed to address the limitations of existing assays, such as reliance on hazardous radiolabeled substrates and limited availability of fluorescent biosensors. Results: The developed assay was successfully applied to detect substrate uptakes by two specific SLCs: L-type amino acid transporter 1 (LAT1) and sodium taurocholate co-transporting polypeptide (NTCP). Importantly, the assay demonstrated comparable results to the radioactive method, indicating its reliability and accuracy. Furthermore, the assay was utilized to screen for novel inhibitors of NTCP, leading to the identification of a potential NTCP inhibitor compound. Discussion: The findings highlight the utility of the developed cell-based uptake assay as a rapid, simple, and environmentally friendly tool for investigating SLCs' biological roles and for drug discovery purposes. This assay offers a safer alternative to traditional methods and has the potential to contribute significantly to advancing our understanding of SLC function and identifying therapeutic agents targeting SLC-mediated pathways.

6.
Cell Death Discov ; 10(1): 360, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39134539

RESUMO

Ferroptosis is a specific form of cell death characterized by excessive accumulation of cellular lipid peroxides. Ferroptosis is closely associated with various diseases, inhibition of which may help alleviate multi-organ injury caused by ischemia-reperfusion and enhance the anti-tumor effect by promoting the immunity of T cells. However, clinical approved drugs targeting ferroptosis process remain rare. In this study, we unexpectedly found that (R)-crizotinib, the first-generation ALK inhibitor, has potent inhibitory activity against ferroptosis across various cell lines. Moreover, its chiral molecule (S)-crizotinib, which was considered to share no common targets with (R)-crizotinib, also suppresses ferroptosis with an efficacy similar to that of (R)-crizotinib. We further demonstrated that both crizotinib enantiomers inhibit ferroptosis independently of their known targets, but through a common mechanism involving the targeting of AGPAT3-mediated synthesis of ether-linked polyunsaturated fatty acids (PE-O-PUFA), which are known to promote lipid-ROS generation and ferroptosis. In line with their activity in cell lines, (R)-crizotinib and (S)-crizotinib effectively mitigate renal ischemia-reperfusion injury in mice. Furthermore, the two compounds also inhibit lipid-ROS accumulation in CD8+ T cells in draining lymph nodes of B16-F10 subcutaneous xenograft mice, thereby promoting anti-tumor effects. Collectively, our study firstly reports a common activity shared by (R)-crizotinib and (S)-crizotinib in ferroptosis regulation. As a clinically approved drug, (R)-crizotinib has well-established pharmacokinetics and safety, which makes it a promising candidate for repurposing. Given the current lack of FDA-approved ferroptosis inhibitors, our findings suggest therapeutically repurposing (R)-crizotinib as well as its enantiomer (S)-crizotinib for treating ferroptosis-related diseases.

7.
J Org Chem ; 75(16): 5764-7, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20666429

RESUMO

The total synthesis of batatoside L (1), a resin glycoside possessing cytotoxicity against laryngeal carcinoma cells, has been completed in a highly convergent manner. The most crucial step in this total synthesis was the efficient construction of the 18-membered macrolactone framework through the Corey-Nicolaou macrolactonization approach.


Assuntos
Convolvulaceae/química , Oligossacarídeos/síntese química , Resinas Vegetais/síntese química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Conformação Molecular , Oligossacarídeos/química , Resinas Vegetais/química , Estereoisomerismo
8.
J Med Chem ; 63(8): 4227-4255, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32216347

RESUMO

Heparanase cleaves polymeric heparan sulfate (HS) molecules into smaller oligosaccharides, allowing for release of angiogenic growth factors promoting tumor development and autoreactive immune cells to reach the insulin-producing ß cells. Interaction of heparanase with HS chains is regulated by specific substrate sulfation sequences. We have synthesized 11 trisaccharides that are highly tunable in structure and sulfation pattern, allowing us to determine how heparanase recognizes HS substrate and selects a favorable cleavage site. Our study shows that (1) N-SO3- at +1 subsite and 6-O-SO3- at -2 subsite of trisaccharides are critical for heparanase recognition, (2) addition of 2-O-SO3- at the -1 subsite and of 3-O-SO3- to GlcN unit is not advantageous, and (3) the anomeric configuration (α or ß) at the reducing end is crucial in controlling heparanase activity. Our study also illustrates that the α-trisaccharide having N- and 6-O-SO3- at -2 and +1 subsites inhibited heparanase and was resistant toward hydrolysis.


Assuntos
Ativação Enzimática/fisiologia , Glucuronidase/metabolismo , Glicosídeos/metabolismo , Heparitina Sulfato/metabolismo , Oligossacarídeos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Glicosídeos/síntese química , Heparina/farmacologia , Heparitina Sulfato/antagonistas & inibidores , Humanos , Camundongos , Simulação de Acoplamento Molecular/métodos , Oligossacarídeos/síntese química
9.
Chem Sci ; 10(45): 10475-10480, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-32110337

RESUMO

Studies of S-linked glycoconjugates have attracted growing interest because of their enhanced chemical stability and enzymatic resistance over O-glycoside counterparts. We here report a facile approach to access α-1,2-cis-S-linked glycosides using triflic acid as a catalyst to promote the glycosylation of a series of thiols with d-glucosamine, galactosamine, glucose, and galactose electrophiles. This method is broadly applicable for the stereoselective synthesis of S-linked glycopeptides, oligosaccharides and glycolipids in high yield and excellent α-selectivity. Many of the synthetic limitations associated with the preparation of these S-linked products are overcome by this catalytic method.

10.
Org Lett ; 19(12): 3063-3066, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28541706

RESUMO

A new strategy has been developed for GPI glycan-peptide conjugate synthesis based upon a traceless Staudinger reaction between a peptide phosphinothioester and a GPI glycan azide. The strategy was first studied and optimized with simple peptides and GPI glycans, which offered excellent yields of the desired conjugates in both organic and aqueous solvents. It was then used to successfully synthesize an analogue of the human CD52 antigen containing the whole CD52 peptide sequence and the conserved trimannose motif of all GPI anchors.


Assuntos
Peptídeos/química , Polissacarídeos/química , Azidas , Humanos , Estrutura Molecular , Água
11.
Org Lett ; 15(16): 4154-7, 2013 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-23898788

RESUMO

The first total synthesis of batatin VI, an architecturally novel resin glycoside dimer, has been achieved via a convergent [5 + 3] glycosidic coupling approach. An improved protocol for the construction of the key 18-membered macrolactone core using a Keck macrolactonization method was introduced. However, the synthesized compound was not identical to the natural batatin VI.


Assuntos
Macrolídeos/síntese química , Oligossacarídeos/síntese química , Macrolídeos/química , Estrutura Molecular , Oligossacarídeos/química , Resinas Vegetais/química , Estereoisomerismo
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