Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction.

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure-activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1.

Synthesis and Anti-Proliferation Activity Evaluation of Novel 2-Chloroquinazoline as Potential EGFR-TK Inhibitors.

A novel series of 2-chloroquinazoline derivatives had been synthesized and their anti-proliferation activities against the four EGFR high-expressing cells A549, NCI-H1975, AGS and HepG2 cell lines were evaluated. The preliminary SAR study of the scaffold of new compounds showed that the compounds with a chlorine substituent on R3 had a better anti-proliferation activity than those substituted by hydrogen atom or vinyl group. Among them, 2-chloro-N-[2-chloro-4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]acetamide (10b) had the best activity, and the corresponding IC50 were 3.68, 10.06, 1.73 and 2.04 µM, respectively. And compound 10b had better or equivalent activity against four cell lines than Gefitinib. The activity of the compound 10b on the EGFR enzyme was subsequently tested. The Wound Healing of A549, AGS and HepG2 cells by this compound showed that the compound can inhibit the migration of cancer cells. Finally, the action channel of the compound 10b was supported by western blotting experiments. It provides useful information for the design of EGFR-TK inhibitors.

Summary and future of medicine for hereditary angioedema.

Hereditary angioedema (HAE) is a rare autosomal genetic disease for which there are currently nine FDA-approved drugs. This review summarizes drug treatments for HAE based on four therapeutic pathways: inhibiting the contact system, inhibiting bradykinin binding to B2 receptors, supplying missing C1 inhibitors, and inhibiting plasminogen conversion. The review generalizes the clinical use, pharmacological effects and mechanisms of HAE drugs, and it also discusses possible development directions and targets to enhance understanding of HAE and help researchers.

Targeted small molecule therapy and inhibitors for lymphoma.

Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure-activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.

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Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Targeting TYK2 for Fighting Diseases: Recent Advance of TYK2 Inhibitors.

TYK2 (tyrosine-protein kinase 2) is a non-receptor protein kinase belonging to the JAK family and is closely associated with various diseases, such as psoriasis, inflammatory bowel disease, systemic lupus erythematosus. TYK2 activates the downstream proteins STAT1-5 by participating in the signal transduction of immune factors such as IL-12, IL-23, and IL-10, resulting in immune expression. The activity of the inhibitor TYK2 can effectively block the transduction of excessive immune signals and treat diseases. TYK2 inhibitors are divided into two types of inhibitors according to the different binding sites. One is a TYK2 inhibitor that binds to JH2 and inhibits its activity through an allosteric mechanism. The representative inhibitor is BMS-986165, developed by Bristol-Myers Squibb. The other class binds to the JH1 adenosine triphosphate (ATP) site and prevents the catalytic activity of the kinase by blocking ATP and downstream phosphorylation. This paper mainly introduces the protein structure, signaling pathway, synthesis, structure-activity relationship and clinical research of TYK2 inhibitors.

Synthesis, structure analysis, antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives.

3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC50 values were 0.575 and 2.08 µM, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r(2) values were 0.978 and 0.988, respectively, the predicted R(2) values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.

Clinical Application and Synthesis Methods of Deuterated Drugs.

Many drugs have adverse absorption, distribution, metabolism, and excretory (ADME) properties that prevent their widespread use or limit their use in some indications. In addition to preparation techniques and prodrug strategies, deuterium modification is a viable method for improving ADME properties. Deuterated drugs have attracted increasing attention from the pharmaceutical industry in recent years. To date, two deuterated drugs have been approved by the FDA. In 2017, austedo was approved by the FDA as a new drug for Huntington's disease in the United States, the first deuterium drug to be marketed worldwide. Recently (June 9, 2021), donafinil has been listed in China; this result has caused major pharmaceutical companies and the pharmaceutical industry to pay attention to deuterium technology again. In addition, BMS-986165, RT001, ALK-001, HC-1119, AVP-786 and other drugs are in phase III clinical studies, and some solid deuterium compounds have entered phase I and II clinical trials. The deuterium strategy has been widely used in pharmaceutical research and has become a hot spot in pharmaceutical research in recent years. In this paper, the research and development of deuterated drugs are reviewed, and the influence of deuterium modification on drugs, the advantages of deuterium strategies and the synthesis strategies of deuterated drugs are mainly introduced. Hoping to provide references for clinical application, the discovery of new deuterium chemical entities and research and development of new deuterated drugs.

Research Progress in Competitive Purine Antagonists.

Purine, one of the nucleotides, is an important substance for the metabolism and regulation of the body. Purine plays a key role not only in the composition of coenzymes but also in the supply of energy. Since purine was artificially synthesized, it has always been an important scaffold for respiratory diseases, cardiovascular diseases, and anti- tumor and anti-viral drugs. In addition to being widely used as competitive antagonists in the treatment of diseases, purines can be used in combination with other drugs and as precursors to benefit human life. Unfortunately, few new discoveries have been made in recent years. In this article, purine drugs in the market have been classified according to their different targets. In addition, their mechanism of action and structure-activity relationship have also been introduced. This paper provides details of the signaling pathways through which purine drugs can bind to the respective receptors on the surface of cells and cause consequent reactions within the cell, which finally affect the targeted diseases. The various receptors and biological reactions involved in the signaling for respective disease targets within the cells are discussed in detail.

A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C).

K-Ras is a frequently mutated oncogene in human malignancies, and the development of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant, which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent years, significant progress has been made in developing small molecule covalent inhibitors targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target. With the successful launch of sotorasib and adagrasib, the development of small molecule inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.

Research Progress in Pharmacological Mechanisms, Structure-Activity Relationship and Synthesis of Sartans.

The sartans are a new class of antihypertensive drugs as angiotensin II receptor blockers which possess plenty of advantages in treating hypertension and related pathologies. This review describes the clinical treatment, side effects, and potential therapeutic effects of sartans from 1995 to date. The synthesis, structural-activity and molecular docking with Angiotensin Type 1 receptor of imidazole derivatives, benzimidazole derivatives and other compounds are also described. With a clear Structure-Activity Relationship and abundant pharmacological effects, some types of novel Angiotensin Type 1 receptor antagonists are emerging gradually for further research in the meantime.

Protein Lysine Methyltransferases Inhibitors.

Protein lysine methylation is a significant protein post-translational modification (PTMs) and has a key function in epigenetic regulation. Protein lysine methyltransferase (PKMTs) mainly catalyzes the lysine methylation of various core histones and a few non-histone proteins. It has been observed that aberrant activity of PKMTs has been found in many cancers and other diseases, and some PKMT inhibitors have been discovered and progressed to clinical trials. This field developed rapidly and has aroused great interest. In this paper, we reviewed the biochemical and biological activities of PKMTs and their association with various cancers. Selective small-molecule inhibitors, including their chemical structure, structure-activity relationship, and in vitro/vivo studies, are also described to provide ideas for the discovery of highly potent, selective PKMT inhibitors.

A precise method to monitor hydroxyl radical in natural waters based on a fluoride-containing fluorescence probe.

In natural waters, hydroxyl radical (OH) can initiate many free radical-induced reactions, oxidizing various inorganic and organic compounds through electron transfer reactions, dehydrogenation reactions, addition reactions, and self-quenching reactions. However, due to its extremely low concentration and short lifetime in natural waters, studies on the quantitative measurement of OH levels are insufficient. In this work, we developed the first quinolinium-based fluorescence probe containing fluoride substituted donor that could detect hydroxyl radicals in the water system. This probe exhibits excellent selectivity towards OH with a large Stokes shift (114 nm) and 23-fold enhancement in fluorescence. Additionally, this probe has been proven to be low toxicity and applied to detect OH in living cells, zebrafish, and natural water samples with good recovery (over 92 %).

3,6-Dimethyl-N,N-bis-(1-phenyl-eth-yl)-1,4-dihydro-1,2,4,5-tetra-zine-1,4-dicarboxamide.

In the title mol-ecule, C(22)H(26)N(6)O(2), the central tetra-zine ring exhibits a boat conformation, and the two phenyl rings form a dihedral angle of 88.39 (6)°. In the crystal, weak N-H⋯O and C-H⋯O hydrogen bonds link mol-ecules into layers parallel to the ab plane.

N,N'-Bis(2,6-diisopropyl-phen-yl)-3,6-di-methyl-1,2,4,5-tetra-zine-1,4-dicarboxamide.

In the title mol-ecule, C(30)H(42)N(6)O(2), the amide-substituted N atoms of the tetra-zine ring deviate from the approximate plane of the four other atoms in the ring by 0.457 (3) and 0.463 (3) Å, forming a boat conformation. The two benzene rings form a dihedral angle of 47.69 (9)°. Intra-molecular N-H⋯N and weak C-H⋯O hydrogen bonds are observed.

3-(2-Chloro-3,3,3-trifluoro-prop-1-en-1-yl)-2,2-dimethyl-N-[3-(trifluoro-meth-yl)phen-yl]cyclo-propane-carboxamide.

In the title mol-ecule, C(16)H(14)ClF(6)NO, the cyclo-propane ring forms a dihedral angle of 70.82 (18)° with the benzene ring. The torsion angles about the ethyl-ene and amide bonds are -2.2 (5) (Cl-C-C-C) and 0.8 (5)° (O-C-N-C). A supra-molecular chain propagated by glide symmetry along [001] and mediated by N-H⋯O hydrogen bonds is observed in the crystal packing.

1-{[3-(2-Chloro-3,3,3-trifluoro-prop-1-en-yl)-2,2-dimethyl-cyclo-propan-1-yl]carbon-yl}-3-(methyl-sulfon-yl)imidazolidin-2-one.

In the title mol-ecule, C(13)H(16)ClF(3)N(2)O(4)S, the imidazolidine ring is approximately planar, the largest deviation from this plane being 0.025 (3) Å. The cyclo-propane ring forms a dihedral angle of 64.1 (2)° with the imidazolidine ring. In the crystal, C-H⋯O hydrogen bonds are observed.

N(1),N(4),3,6-Tetra-methyl-1,2,4,5-tetra-zine-1,4-dicarboxamide.

The asymmetric unit of the title compound, C(8)H(14)N(6)O(2), contains two independent mol-ecules. In one mol-ecule, the amide-substituted N atoms of the tetra-zine ring deviate from the plane [maximum deviation = 0.028 (1) Å] through the four other atoms in the ring by 0.350 (2) and 0.344 (2) Å, forming a boat conformation, and the mean planes of the two carboxamide groups form dihedral angles of 10.46 (13) and 20.41 (12)° with the four approximtely planar atoms in the tetra-zine ring. In the other mol-ecule, the amide-substituted N atoms of the tetra-zine ring deviate from the plane [maximum deviation = 0.033 (1) Å] through the four other atoms in the ring by 0.324 (2) and 0.307 (2) Å, forming a boat conformation, and the mean planes of the two carboxamide groups form dihedral angles of 14.66 (11) and 17.08 (10)° with the four approximately planar atoms of the tetra-zine ring. In the crystal, N-H⋯O hydrogen bonds connect mol-ecules to form a two-dimensional network parallel to (1-1-1). Intra-molecular N-H⋯N hydrogen bonds are observed.

3,6-Bis(4-chloro-phen-yl)-N,N-bis-(1-phenyl-eth-yl)-1,2,4,5-tetra-zine-1,4-di-carboxamide.

In the title mol-ecule, C(32)H(28)Cl(2)N(6)O(2), the amide-substituted N atoms of the tetra-zine ring deviate from the approximate plane of the four other atoms in the ring by 0.468 (3) and 0.484 (3) Å, forming a boat conformation. The dihedral angle between the two phenyl rings is 67.0 (1)° and that between the two chloro-substituted benzene rings is 73.8 (1)°. Two intra-molecular N-H⋯N hydrogen bonds are observed.