Iron Catalysis in Organic Synthesis

Bull. Chem. Soc. Jpn. への投稿のすすめ

The development of mild and general methods for C–S bond formation has received significant attention because the C–S bond is indispensable in many important biological and pharmaceutical compounds. Early examples for the synthesis of C–S bonds are generally limited to the condensation reaction between a metal thiolate and an organic halide. Recent chemical approaches for C–S bond formation, based upon direct C–H bond functionalization and decarboxylative reactions, not only provide new insights into the mechanistic understanding of C–S coupling reactions but also allow the synthesis of sulfur-containing compounds from more effective synthetic routes with high atom economy. This review intends to explore recent advances in C–S bond formation via C–H functionalization and decarboxylation, and the growing opportunities they present to the construction of complex chemical scaffolds for applications encompassing natural product synthesis, synthetic methodology development, and functional materials as well as nanotechnology.

Recent advances in C–S bond formation via C–H bond functionalization and decarboxylation

The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

https://www.mdpi.com/2073-4409/8/9/1015/pdf

Long Non-Coding RNA in the Pathogenesis of Cancers.

An auxiliary-assisted, copper catalyzed or promoted sulfenylation of benzoic acid derivative β-C–H bonds and benzylamine derivative γ-C–H bonds has been developed. The method employs disulfide reagents, copper(II) acetate, and DMSO solvent at 90–130 °C. Application of this methodology to the direct trifluoromethylsulfenylation of C–H bonds was demonstrated.

Copper-Promoted Sulfenylation of sp2 C–H Bonds

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy

Peptide-based cancer therapy: Opportunity and challenge

A Lewis acid (AgI, NiII, or FeII) catalyzed, CuII-mediated thiolation reaction between heteroarenes and thiols was achieved with good yield under base-free conditions. DMSO could serve as an effective methylthiolation reagent for the synthesis of heterocyclic methyl thioethers.

Lewis Acid-Catalyzed, Copper(II)-Mediated Synthesis of Heteroaryl Thioethers under Base-Free Conditions

Liver cancer has a tendency to develop asymptomatically in patients, so most patients are diagnosed at a later stage. Accumulating evidence implicates that liver tumour-initiating cells (TICs) as being responsible for liver cancer initiation and recurrence. However, the molecular mechanism of liver TIC self-renewal is poorly understood. Here we discover that a long noncoding RNA (lncRNA) termed LncSox4 is highly expressed in hepatocellular carcinoma (HCC) tissues and in liver TICs. We find that LncSox4 is required for liver TIC self-renewal and tumour initiation. LncSox4 interacts with and recruits Stat3 to the Sox4 promoter to initiate the expression of Sox4, which is highly expressed in liver TICs and required for liver TIC self-renewal. The expression level of Sox4 correlates with HCC development, clinical severity and prognosis of patients. Altogether, we find that LncSox4 is highly expressed in liver TICs and is required for their self-renewal.

LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression.

TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro, the tumor growth in mice was considerably inhibited. TIGIT knockout led to the increase of IFN-γ secretion by NK and CD8+ T cells. Further, in BABL/c nude mice, CD8+ T cells depleting mice and NK cells depleting nude mice, the promotion of tumor growth was significantly diminished, suggesting that both NK cells and CD8+ T cells were involved in the tumor promoting process mediated by intrinsic TIGIT. In addition, blocking TIGIT/PVR interaction by the antibody or recombinant PVR protein could elicit anti-tumor effects by facilitating the tumor infiltration and restoring the function of CD8+ T cells, and the antibody-mediate TIGIT blockade could inhibit MC38 tumor growth through blocking TIGIT expressed on tumor cells. We therefore propose a novel TIGIT/PVR interaction mode that tumor intrinsic TIGIT delivers inhibitory signals to CD8+ T cells and NK cells by engaging with PVR.

/pdf/intrinsic-expression-of-immune-checkpoint-molecule-tigit-eujtq00bdu.pdf

Yanfeng Gao

Papers

Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy

Peptide-based cancer therapy: Opportunity and challenge

Lewis Acid-Catalyzed, Copper(II)-Mediated Synthesis of Heteroaryl Thioethers under Base-Free Conditions

LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression.

Intrinsic Expression of Immune Checkpoint Molecule TIGIT Could Help Tumor Growth in vivo by Suppressing the Function of NK and CD8+ T Cells.