Photoinduced Decarboxylative Thioacylation of N-Hydroxyphthalimide Esters with Tetraalkylthiuram Disulfides.

Dithiocarbamate is a key structural sequence in pharmaceuticals and agrochemicals, and its synthesis is crucial in organic chemistry. Although significant progress has been made in related synthesis research, developing a practical and universal synthesis method remains fascinating. Herein, we report a new visible-light-induced decarboxylation coupling reaction between N-hydroxyphthalimide esters and tetraalkylthiuram disulfides, which uses Ir(ppy)3 as a photocatalyst to promote the generation of corresponding decarboxylation thioacylation product-dithiocarbamates in high yields. This redox-neutral protocol uses inexpensive and readily available starting material under mild reaction conditions, exhibiting broad substrate scope and wide functional group compatibility. This method can be further used for post modification of complex natural products and bioactive drugs.

Discovery of novel 2-oximino-2-indolylacetamide derivatives as potent anticancer agents capable of inducing cell autophagy and ferroptosis.

A series of 2-oximino-2-indolylacetamide derivatives were designed, synthesized and evaluated for their antitumour effects. Among them, 4d exhibited the most potent antiproliferative effect in vitro on the tested human cancer cells. Additionally, 4d significantly induced cell apoptosis, caused mitochondrial dysfunction, promoted Bax, cleaved-PARP and p53 expression and inhibited Bcl-2 expression in 5-8F cells. Moreover, 4d remarkably promoted autophagosome formation, leading to cell apoptosis. Further investigation indicated that 4d could trigger cell death through cell ferroptosis, including increased ROS generation and lipid peroxidation and decreased glutathione peroxidase 4 (GPx4) expression and glutathione (GSH) levels. More importantly, 4d induced 5-8F cell death by activating ROS/MAPK and inhibiting the AKT/mTOR and STAT3 signalling pathways. Interestingly, 4d significantly suppressed tumour growth in a 5-8F cell xenograft model without obvious toxicity to mice. Overall, these results demonstrate that 4d may be a potential compound for cancer therapy.

New alkaloids and their in vitro antitumor activity of Corydalis balansae.

The chemical investigation on Corydalis balansae resulted in the isolation of three previous undescribed compounds (1, 10, and 11) and 17 known compounds. Compound 1 and 2 were obtained as two lignanamide dimers, and compound 11 had a spiro [benzofuranone-benzazepine] skeleton, which was found in Corydalis for the first time. The structures of new compound were determined by the detailed analysis of 1D/2D NMR, UV, and IR data. Absolute configurations of compounds 10 and 11 were defined by their crystal X-ray diffraction data and calculations of electronic circular dichroism (ECD). The CCK-8 method was used to assay the inhibition effect of all the compounds on the growth of Hela, MGC-803, A549, and HepG2 cancer cells. Compound 2, 13, and 14 showed moderate inhibitory activity against the tested cell lines. Compound 2 exhibited potential antitumor activity against MGC-803 cells with an IC50 value of 20.8 µM, while the positive control etoposide was 17.3 µM. Furthermore, results from the cellular-mechanism investigation indicated that compound 2 could induce S-phase cell-cycle arrest and MGC-803 cells apoptosis, which was triggered by the up-regulation of PARP1, caspase-3 and -9, Bax, and down-regulation of Bcl-2. The 2-induced strong apoptosis indicated that compound 2 had good potential as an antitumor lead compound.

Pentagalloylglucose suppresses the growth and migration of human nasopharyngeal cancer cells via the GSK3ß/ß-catenin pathway in vitro and in vivo.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of malignant squamous cell tumour originating from the nasopharynx epithelium. Pentagalloylglucose (PGG) is a natural polyphenolic compound that exerts anticancer effects in many types of tumours. However, the role and underlying mechanism of PGG in NPC cells have not been fully defined. PURPOSE: This study aimed to investigate the anticancer activity of PGG as well as the potential mechanism in NPC cells. METHODS: The effects of PGG on the proliferation, apoptosis and cell cycle distribution of CNE1 and CNE2 cells were assessed by MTT and flow cytometry assays. Cell migration was evaluated using wound healing and transwell assays. The expression of microtubule-associated protein 1 light chain 3 beta (LC3B) was observed by immunofluorescence staining. Western blotting was used to explore the levels of related proteins and signalling pathway components. Furthermore, the effects of PGG on NPC cell growth were analysed in a xenograft mouse model in vivo using cisplatin as a positive control. RESULTS: PGG dose-dependently inhibited the proliferation of CNE1 and CNE2 cells. PGG regulated the cell cycle by altering p53, cyclin D1, CDK2, and cyclin E1 protein levels. PGG induced apoptosis and autophagy in NPC cells and elevated the Bax/Bcl-2 ratio and the protein levels of LC3B. Moreover, PGG decreased NPC cell migration by increasing E-cadherin and decreasing N-cadherin, vimentin and CD44 protein levels. Mechanistically, PGG treatment downregulated p-mTOR and ß-catenin expression but upregulated p-p38 MAPK and p-GSK3ß expression. In addition, PGG significantly inhibited NPC cell tumour growth and lung metastasis in vivo. CONCLUSION: PGG may suppress cell proliferation, induce apoptosis and autophagy, and decrease the metastatic capacity of NPC cells through the p38 MAPK/mTOR and Wnt/ß-catenin pathways. The present study provides evidence for PGG as a potential therapy for NPC.

Lysine enhances the effect of amphotericin B against Candida albicans in vitro.

Amphotericin B (AmB) is a polyene antibiotic produced by Streptomyces nodosus and has been used for >50 years in the treatment of acute systemic fungal infections. In the present study, we demonstrated that lysine, an essential amino acid, could enhance the effect of AmB against Candida albicans in vitro, although lysine itself did not exert a fungicidal effect. In addition, the combination of AmB with lysine could provide an enhanced action against Candida parapsilosis and Cryptococcus neoformans compared with AmB alone. Lysine could also enhance the antifungal effect of caspofungin or nystatin. An enhanced effect of the combination of lysine with AmB was observed for the prevention of biofilm and hypha formation. Furthermore, our results demonstrated that lysine-mediated oxidative damage, such as the generation of endogenous reactive oxygen species, may be the mechanism underlying the enhancing effect of lysine on AmB. Our results also showed that CaMCA1 gene plays an important role in increasing the sensitivity of C. albicans cells upon AmB treatment. Using AmB together with lysine may be a promising strategy for the therapy of disseminated candidiasis.

The structure and retrotransposition mechanism of LTR-retrotransposons in the asexual yeast Candida albicans.

Retrotransposons constitute a major part of the genome in a number of eukaryotes. Long-terminal repeat (LTR) retrotransposons are one type of the retrotransposons. Candida albicans have 34 distinct LTR-retrotransposon families. They respectively belong to the Ty1/copia and Ty3/gypsy groups which have been extensively studied in the model yeast Saccharomyces cerevisiae. LTR-retrotransposons carry two LTRs flanking a long internal protein-coding domain, open reading frames. LTR-retrotransposons use RNA as intermediate to synthesize double-stranded DNA copies. In this article, we describe the structure feature, retrotransposition mechanism and the influence on organism diversity of LTR retrotransposons in C. albicans. We also discuss the relationship between pathogenicity and LTR retrotransposons in C. albicans.

Structural features and mechanism of translocation of non-LTR retrotransposons in Candida albicans.

A number of abundant mobile genetic elements called retrotransposons reverse transcribe RNA to generate DNA for insertion into eukaryotic genomes. Non-long-terminal repeat (non-LTR) retrotransposons represent a major class of retrotransposons, and transposons that move by target-primed reverse transcription lack LTRs characteristic of retroviruses and retroviral-like transposons. Yeast model systems in Candida albicans and Saccharomyces cerevisiae have been developed for the study of non-LTR retrotransposons. Non-LTR retrotransposons are divided into LINEs (long interspersed nuclear elements), SINEs (short interspersed nuclear elements), and SVA (SINE, VNTR, and Alu). LINE-1 elements have been described in fungi, and several families called Zorro elements have been detected from C. albicans. They are all members of L1 clades. Through a mechanism named target-primed reverse transcription (TPRT), LINEs translocate the new copy into the target site to initiate DNA synthesis primed by the 3' OH of the broken strand. In this article, we describe some advances in the research on structural features and origin of non-LTR retrotransposons in C. albicans, and discuss mechanisms underlying their reverse transcription and integration of the donor copy into the target site.