Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1.

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy.

Stereoselective Synthesis of ß, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic ß, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Progress in approved drugs from natural product resources.

Natural products (NPs) have consistently played a pivotal role in pharmaceutical research, exerting profound impacts on the treatment of human diseases. A significant proportion of approved molecular entity drugs are either directly derived from NPs or indirectly through modifications of NPs. This review presents an overview of NP drugs recently approved in China, the United States, and other countries, spanning various disease categories, including cancers, cardiovascular and cerebrovascular diseases, central nervous system disorders, and infectious diseases. The article provides a succinct introduction to the origin, activity, development process, approval details, and mechanism of action of these NP drugs.

Regioselective Olefination and Arylation of Arene-Tethered Diols Using the Easily Foldable Directing Groups.

Arene-tethered diols constitute a valuable class of structural motifs of drug and bioactive natural product molecules. In this study, a regioselective protocol for olefination and arylation of arene-tethered 1,2-diols and 1,3-diols has been developed using easily foldable acetal structures for attaching pyridine and nitrile directing groups. The method overcomes the steric hindrance effect of the short-chain diols and affords products in high yield and regioselectivity. This efficient cascaded catalysis has been successfully utilized in the syntheses of natural products such as peucedanol, decursinol, and marmesin.

Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis.

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1-3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy.

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e, encoded KWLX-12e, with good inhibitory activity against PARP1 (IC50 = 6.89 nM) and EZH2 (IC50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC50 = 2.84 µM) and BT-549 cells (IC50 = 0.91 µM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.

Indirubin derivatives as bifunctional molecules inducing DNA damage and targeting PARP for the treatment of cancer.

Based on the facts that significant synergistic effect existed between PARP inhibitors and DNA damage agents and the DNA damage caused by indirubin's derivatives, we herein adopted the strategy to combine the pharmacophores of PARP inhibitors and the unique scaffold of indirubin to design a series of bifunctional molecules inducing DNA damage and targeting PARP. After SAR studies, the most potent compound 12a, encoded as KWWS-12a, exhibited improved inhibitory effect against PARP1 compared with PARP1 inhibitor Olaparib (IC50 = 1.89 nM vs 7.48 nM) and enhanced antiproliferative activities than the combination of Olaparib and indirubin-3'-monoxime towards HCT-116 cells (IC50 = 0.31 µM vs 1.37 µM). In the normal NCM-460 cells, 12a showed low toxicity (IC50 > 60 µM). The mechanism research indicated that 12a could increase the levels of γH2AX concentration dependently, arrest the cell cycle in S phase and induce apoptosis in HCT-116 cells. In vivo experiments showed that 12a displayed more significant antitumor potential than that of the positive controls. Our studies demonstrated that 12a could be a promising candidate for cancer therapy.

Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy.

Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.

Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA.

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC50 = 1.96 µM), MDA-MB-468 (IC50 = 2.81 µM) and BT-549 (IC50 = 2.37 µM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10-20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.

Oxazole-4-carboxamide/butylated hydroxytoluene hybrids with GSK-3ß inhibitory and neuroprotective activities against Alzheimer's disease.

Neuronal cells overexpressing phosphorylated Tau proteins can increase the susceptibility to oxidative stress. Regulation of glycogen synthase-3ß (GSK-3ß) and reduction of Tau protein hyperphosphorylation, along with alleviation of oxidative stress, may be an effective way to prevent or treat Alzheimer's disease (AD). For this purpose, a series of Oxazole-4-carboxamide/butylated hydroxytoluene hybrids were designed and synthesized to achieve multifunctional effects on AD. The biological evaluation showed that the optimized compound KWLZ-9e displayed potential GSK-3ß (IC50 = 0.25 µM) inhibitory activity and neuroprotective capacity. Tau protein inhibition assays showed that KWLZ-9e reduced the expression of GSK-3ß and downstream p-Tau in HEK GSK-3ß 293T cells. Meanwhile, KWLZ-9e could alleviate H2O2-induced ROS damage, mitochondrial membrane potential imbalance, Ca2+ influx and apoptosis. Mechanistic studies suggest that KWLZ-9e activates the Keap1-Nrf2-ARE signaling pathway and enhances the expression of downstream oxidative stress proteins including TrxR1, HO-1, NQO1, GCLM to exert cytoprotective effects. We also confirmed that KWLZ-9e could ameliorate learning and memory impairments in vivo model of AD. The multifunctional properties of KWLZ-9e suggest that it is a promising lead for the treatment of AD.

Effect of Boronizing on the Microstructure and Mechanical Properties of CoCrFeNiMn High-Entropy Alloy.

The CoCrFeNiMn high-entropy alloys were treated by powder-pack boriding to improve their surface hardness and wear resistance. The variation of boriding layer thickness with time and temperature was studied. Then, the frequency factor D0 and diffusion activation energy Q of element B in HEA are calculated to be 9.15 × 10-5 m2/s and 206.93 kJ/mol, respectively. The diffusion behavior of elements in the boronizing process was investigated and shows that the boride layer forms with the metal atoms diffusing outward and the diffusion layer forms with the B atoms diffusing inward by the Pt-labeling method. In addition, the surface microhardness of CoCrFeNiMn HEA was significantly improved to 23.8 ± 1.4 Gpa, and the friction coefficient was reduced from 0.86 to 0.48~0.61.

Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors.

Receptor-interacting protein kinase 1 (RIPK1), a vital protein of the necroptosis pathway, plays a pivotal role in various inflammatory diseases. Sibiriline has been reported to be a potent ATP-competitive RIPK1 inhibitor, but its anti-necroptotic effects are limited. A series of structural analogues of Sibiriline were synthesized and evaluated for their anti-necroptotic activity. Comprehensive structure-activity relationship (SAR) was performed to left azaindole and right substituents of benzene of Sibiriline, respectively. The optimal compound KWCN-41, specifically inhibiting cell necroptosis but not apoptosis, protects cell survival by blocking the necroptotic pathway, which inhibits the phosphorylation of essential proteins of the necroptosis. It also prevented the development of inflammation and reduced the level of inflammatory factors in mice. KWCN-41 is expected to be a lead compound for further studies in inflammatory diseases.

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound 20 exhibited excellent inhibitory activity against HDAC1 (IC50 = 0.12 µM) and EZH2 (IC50 = 0.059 µM), it also showed good antiproliferation activity against MV4-11 (IC50 = 0.17 µM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40 µM). 20 suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological malignancies.

Aryl Halides as Halogenation Reagents in the Bromination and Iodination of Arene-Tethered Diols.

Aromatic halides constitute a valuable class of building blocks that are commonly used in organic synthesis. In this study, we demonstrate usage of aryl bromides and aryl iodides in C-Br or C-I bond formation. Methyl 2-bromobenzoate and 2-nitrophenyl iodides were developed as mild and effective bromination and iodination reagents for functionalization of arene-tethered diols. This efficient cascaded catalysis can be applied to the total syntheses of natural product Mafaicheenamine A and Claulamine A.

Orientation Control for Nickel-Based Single Crystal Superalloys: Grain Selection Method Assisted by Directional Columnar Grains.

The service performance of single crystal blades depends on the crystal orientation. A grain selection method assisted by directional columnar grains is studied to control the crystal orientation of Ni-based single crystal superalloys. The samples were produced by the Bridgman technique at withdrawal rates of 100 µm/s. During directional solidification, the directional columnar grains are partially melted, and a number of stray grains are formed in the transition zone just above the melt-back interface. The grain selected by this method was one that grew epitaxially along the un-melted directional columnar grains. Finally, the mechanism of selection grain and application prospect of this grain selection method assisted by directional columnar grains is discussed.

Discovery of precision targeting EZH2 degraders for triple-negative breast cancer.

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (KD = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC50 = 0.57 µM) and MDA-MB-468 (IC50 = 0.38 µM) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential anticancer molecule for TNBC treatment.

The Microstructure and Corrosion Resistance of Fe-B-W-Mn-Al Alloy in Liquid Zinc.

The microstructure, interfacial characteristics, and corrosion resistance of Fe-W-Mn-Al-B alloys in molten zinc at 520 °C have been investigated using scanning electron microscopy (SEM), X-ray diffractometry (XRD), and electron probe micro-analysis (EPMA). The experimental results indicate that the Fe-B alloy with 11 wt.% W, 7 wt.% Mn, and 4 wt.% Al addition displays a lamellar eutectic microstructure and excellent corrosion resistance to molten zinc. The toughness of M2B-type borides in the hyper-eutectic Fe-4.2B-11W-7Mn-4Al alloy can be more than doubled, reaching 10.5 MPa·m1/2, by adding Mn and Al. The corrosion layer of the Fe-3.5B-11W-7Mn-4Al alloy immersed in molten zinc at 520 °C comprises Fe3AlZnx, δ-FeZn10, ζ-FeZn13, and η-Zn. The lamellar borides provide the mechanical protection for α-(Fe, Mn, Al), and the thermal stability of borides improves as the fracture toughness of the borides increases, which jointly contribute to the improvement of the corrosion resistance to the molten zinc.

Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy.

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 µM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 µM and HDAC6 IC50 = 0.45 µM) and DNA, and had the potential in the treatment of solid tumor.

Parthenolide Derivatives as PKM2 Activators Showing Potential in Colorectal Cancer.

As a vital kinase in the glycolysis system, PKM2 is extensively expressed in colorectal cancer (CRC) to support the energy and biosynthetic needs. In this study, we designed a series of parthenolide (PTL) derivatives through a stepwise structure optimization, and an excellent derivate 29e showed good activity on PKM2 (AC50 = 86.29 nM) and displayed significant antiproliferative activity against HT29 (IC50 = 0.66 µM) and SW480 (IC50 = 0.22 µM) cells. 29e decreased the expression of total PKM2, prevented nucleus translocation of PKM2 dimer, and inhibited PKM2/STAT3 signaling pathway. 29e remarkably increased OCR and decreased the extracellular acidification rate (ECAR). The antiproliferative effect of 29e depended on PKM2, and the Cys424 of PKM2 was the key binding site. Furthermore, 29e significantly suppressed tumor growth in the HT29 xenograft model without obvious toxicity. These outcomes demonstrate that 29e is a promising drug candidate for the treatment of CRC.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease.

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3ß (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3ß with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3ß and Aß mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aß caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.