Progress in small-molecule inhibitors targeting PD-L1.

PD-L1 is a transmembrane protein overexpressed by tumor cells. It binds to PD-1 on the surface of T-cells, suppresses T-cell activity and hinders the immune response against cancer. Clinically, several monoclonal antibodies targeting PD-1/PD-L1 have achieved significant success in cancer immunotherapy. Nevertheless, their disadvantages, such as unchecked immune responses, high cost and long half-life, stimulated pharmacologists to develop small-molecule inhibitors targeting PD-1/PD-L1. After a batch of excellent inhibitors with a biphenyl core structure were firstly reported by BMS, more and more researchers focused on small-molecule inhibitors targeting PD-L1 rather than PD-1. Numerous small-molecule inhibitors were extensively designed and synthesized in the past few years. In this paper, the structural characteristics of PD-L1 and complexes of PD-L1 with its inhibitors are elaborated and small molecule inhibitors developed in the last decade are summarized as well. This paper aims to provide insights into further designing and synthesis of small molecule inhibitors targeting PD-L1.

Chemical approaches for the stereocontrolled synthesis of 1,2-cis-ß-D-rhamnosides.

In carbohydrate chemistry, the stereoselective synthesis of 1,2-cis-glycosides remains a formidable challenge. This complexity is comparable to the synthesis of 1,2-cis-ß-D-mannosides, primarily due to the adverse anomeric and Δ-2 effects. Over the past decades, to attain ß-stereoselectivity in D-rhamnosylation, researchers have devised numerous direct and indirect methodologies, including the hydrogen-bond-mediated aglycone delivery (HAD) method, the synthesis of ß-D-mannoside paired with C6 deoxygenation, and the combined approach of 1,2-trans-glycosylation and C2 epimerization. This review elaborates on the advancements in ß-D-rhamnosylation and its implications for the total synthesis of tiacumicin B and other physiologically relevant glycans.

Study on the chemical reactivity difference of primary hydroxyl groups in iridoid glycosides.

Iridoid glycoside, which belongs to the polyhydroxy compound, is a kind of active ingredient of traditional Chinese medicine with a wide range of sources, and has many pharmacological effects such as anti-cancer, anti-inflammatory, anti-virus, hypoglycemic and so on. Its structure contains many hydroxyl groups, including two primary hydroxyl groups. The chemical reactivity of primary hydroxyl groups has very little difference, so it is very important to control the selectivity of hydroxyl groups under certain conditions. In this paper, the difference between the two primary hydroxyl groups in iridoid glycoside was calculated based on computer simulation and verified this result through designed experiments. This study will provide an important way for site-directed modification of hydroxyl in iridoid glycoside in the future.

Design, Synthesis and Biological Evaluation of Novel Catalpol Derivatives as Potential Pancreatic Cancer Inhibitors.

A series of C10-position imidazole-modified catalpol derivatives are specifically designed and synthesized for serving as potential pancreatic cancer inhibitors, which are characterized by 1 H NMR, 13 C NMR and high-resolution mass spectrometry (HRMS). They were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) test on two human pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell HPDE6-C7, which showed the significant inhibitory effected on the growth of human pancreatic cancer cells of PANC-1 and BxPC-3, especially 91.6% efficacy on BxPC-3, and 73.1% on PANC-1. Simulation studies like molecular docking supported strong binding of vascular endothelial growth factor receptor 2 (VEGFR-2) protein tyrosine kinase (PDB ID: 4AGD), a target of pancreatic cancer. A novel imidazol-modified catalpol compound 3i with strong inhibitory effect on pancreatic cancer cells, which could potentially develop into anti-pancreatic cancer drug candidates in the future.

Design, synthesis and anticancer activities evaluation of novel pyrazole modified catalpol derivatives.

Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective, anti-inflammatory, choleretic, hypoglycemic and anticancer. However, there are some disadvantages for catalpol such as a short half-life in vivo, low druggability, stingy binding efficiency to target proteins and so on. It is necessary to make structural modification and optimization which enhance its performance on disease treatments and clinic applications. Pyrazole compounds have been reported to have excellent anticancer activities. Based on the previous research foundation of our research group on iridoids and the anticancer activities of catalpol and pyrazole, a series of pyrazole modified catalpol compounds were synthesized by principle of drug combination for serving as potential cancer inhibitors. These derivatives are characterized by 1H NMR, 13C NMR and HRMS. The efficacy of anti-esophageal cancer and anti-pancreatic cancer activities were evaluated by the MTT assay on two esophageal cancer cells Eca-109 and EC-9706, and two pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell line HPDE6-C7, which showed that the compound 3e had strong inhibitory activity against esophageal cancer cells, this providing a theoretical basis for the discovery of catalpol-containing drugs.

Research progress on the therapeutic effects of polysaccharides on non-alcoholic fatty liver diseases.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is a leading cause of cirrhosis and hepatocellular carcinoma. Due to its complex pathophysiology, there is currently no approved therapy. Polysaccharide, a kind of natural product, possesses a wide range of pharmacological activities. Numerous preclinical studies have confirmed that polysaccharides could interfere with the occurrence and development of NAFLD at multiple interrelated levels, such as improvement of glucose and lipid metabolism, antioxidation, anti-inflammation, and regulation of gut-liver axis, thus showing great potential as novel anti-NAFLD drugs. In this paper, we reviewed the polysaccharides with anti-NAFLD effect in recent years, and also systematically analyzed their possible pharmacological mechanisms.

Synthesis and application of phosphorylated saccharides in researching carbohydrate-based drugs.

Phosphorylated saccharides are valuable targets in glycochemistry and glycobiology, which play an important role in various physiological and pathological processes. The current research on phosphorylated saccharides primarily focuses on small molecule inhibitors, glycoconjugate vaccines and novel anti-tumour targeted drug carrier materials. It can maximise the pharmacological effects and reduce the toxicity risk caused by nonspecific off-target reactions of drug molecules. However, the number and types of natural phosphorylated saccharides are limited, and the complexity and heterogeneity of their structures after extraction and separation seriously restrict their applications in pharmaceutical development. The increasing demands for the research on these molecules have extensively promoted the development of carbohydrate synthesis. Numerous innovative synthetic methodologies have been reported regarding the continuous expansion of the potential building blocks, catalysts, and phosphorylation reagents. This review summarizes the latest methods for enzymatic and chemical synthesis of phosphorylated saccharides, emphasizing their breakthroughs in yield, reactivity, regioselectivity, and application scope. Additionally, the anti-bacterial, anti-tumour, immunoregulatory and other biological activities of some phosphorylated saccharides and their applications were also reviewed. Their structure-activity relationship and mechanism of action were discussed and the key phosphorylation characteristics, sites and extents responsible for observed biological activities were emphasised. This paper will provide a reference for the application of phosphorylated saccharide in the research of carbohydrate-based drugs in the future.

Anti-inflammatory Effect of a Novel Pectin Polysaccharide From Rubus chingii Hu on Colitis Mice.

Rubus chingii Hu has been used as a functional food for a long time. A novel pectin polysaccharide named RCHP-S from R. chingii Hu was structurally identified and explored its anti-inflammatory effect on colitis mice. RCHP-S was composed of mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, and arabinose. NMR spectroscopy and methylation analysis showed that RCHP-S was mainly composed of HG-type pectin domains but also contains a small amount of RG-I. The anti-inflammatory tests indicated that the mouse macrophage RAW 264.7 cells pretreated with RCHP-S could show a significant inhibitory effect on the mRNA level of iNOS, IL-1ß, IL-6, and TNF-α in vitro. Polysaccharide RCHP-S reduced the enteritis symptoms in dextran sulfate sodium (DSS)-induced colitis mice by inhibiting released inflammatory factors. These results indicated that the R. chingii Hu polysaccharide can be used as food additives for the treatment of intestinal inflammation.

Recent Progress in Transition Metal-Catalyzed Hydrosilane-Mediated C-H Silylation.

Organosilicon compounds are widely used in materials science, medicinal chemistry and synthetic chemistry. Recently, significant progress has been achieved in transition metal-catalyzed dehydrogenative C-H silylation. Particularly, recently developed monohydrosilane and dihydrosilane mediated C-H silylation have emerged as powerful tools in constructing C-Si bonds. Besides, dihydrosilane-mediated enantioselective asymmetric C-H silylation has successfully enabled the construction of central and helical silicon chirality. In addition, chiral organosilicon compounds have exhibited excellent photoelectric material properties and broad application prospects. Furthermore, organosilicon compounds could under a series of functional group transformations to enrich the diversity of silicon chemistry. This review will present a comprehensive picture of the development of transition metal-catalyzed hydrosilane-mediated intramolecular C(sp2 )-H and C(sp3 )-H silylation organized by their reaction types and mechanisms. In addition, dihydrosilane-mediated enantioselective asymmetric C-H silylation to construct central and helical silicon chirality will also be highlighted in the review.

Design, microwave synthesis, and molecular docking studies of catalpol crotonates as potential neuroprotective agent of diabetic encephalopathy.

Catalpol has gained increasing attention for its potential contributions in controlling glycolipid metabolism and diabetic complications, which makes used as a very promising scaffold for seeking new anti-diabetic drug candidates. Acylation derivatives of catalpol crotonate (CCs) were designed as drug ligands of glutathione peroxidase (GSH-Px) based on molecular docking (MD) using Surfex-Docking method. Catalpol hexacrotonate (CC-6) was synthesized using microwave assisted method and characterized by FT-IR, NMR, HPLC and HRMS. The MD results indicate that with the increasing of esterification degree of hydroxyl, the C log P of CCs increased significantly, and the calculated total scores (Total_score) of CCs are all higher than that of catalpol. It shows that CCs maybe served as potential lead compounds for neuroprotective agents. It was found that the maximum Total_score of isomers in one group CCs is often not that the molecule with minimum energy. MD calculations show that there are five hydrogen bonds formed between CC-6 and the surrounding amino acid residues. Molecular dynamics simulation results show that the binding of CC-6 with GSH-Px is stable. CC-6 was screened for SH-SY5Y cells viability by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, the result indicates CC-6 can effectively reverse SZT induced cells apoptosis with dose-dependent manner, which can indirectly show that CC-6 is a potential neuroprotective agent.

Metal-free multicomponent cascade reactions of homopropargylic amines and acyl chlorides as well as potassium thiocyanate and diiodine: an access to thiazine imides.

A novel metal-free multicomponent cascade reaction was developed for the construction of thiazine imides. This four-component cascade reaction had advantages of mild reaction conditions, wide substrate scope and good atom economy. Four new bonds were formed in one pot via a 6-exo-dig iodothiolation cyclization of homopropargylic amines. The corresponding E-configurational thiazine imide products possess an exocyclic vinyliodide functional group.

Cu(OAc)2 /TEMPO Cooperative Promoted Hydroamination Cyclization and Oxidative Dehydrogenation Cascade Reaction of Homopropargylic Amines.

A novel and efficient Cu(OAc)2 -catalyzed hydroamination cyclization and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidative dehydrogenation cascade reaction of homopropargylic amines has been developed. A library of 1,2-disubstituted pyrrole derivatives were obtained in good-to-high yields in one pot with no step-by-step feeding process. This reaction involved TEMPO playing dual roles as both an oxidative dehydrogenation reagent and a ligand. An insight into the reaction mechanism was obtained by using several analytical determination methods.

Regioselective synthesis of 1,3,5-trisubstituted pyrazoles from N-alkylated tosylhydrazones and terminal alkynes.

An efficient synthesis of 1,3,5-trisubstituted pyrazoles from N-alkylated tosylhydrazones and terminal alkynes was developed. The protocol was applied to a wide range of substrates and demonstrated excellent tolerance to a variety of substituents, including both electron-donating and -withdrawing groups. In comparison with the common approaches for substituted pyrazole syntheses, this methodology proceeded with complete regioselectivity, especially, in the cases that R(2) and R(3) are similar substituents.

DABCO-promoted synthesis of pyrazoles from tosylhydrazones and nitroalkenes.

An efficient synthesis of pyrazoles from tosylhydrazones and nitroalkenes was developed. In comparison with the previously reported 1,3-dipolar cycloaddition reaction of diazo compounds with electron-deficient alkenes or alkynes, this methodology proceeded with a sequential Baylis-Hillman/intramolecular cyclization mechanism and a variety of reversed regioselectivity products were prepared in good yields.