Targeting ferroptosis in gastric cancer: Strategies and opportunities.

Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.

Atlas of Metastatic Gastric Cancer Links Ferroptosis to Disease Progression and Immunotherapy Response.

BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.

Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance.

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.

Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance.

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.

Vanadate-Mediated Mismatch Configuration over the Reconstructed Nickel-Iron Electrocatalyst for Boosting Alkaline Oxygen Evolution.

During the oxygen evolution reaction (OER), catalyst candidates that can fully trigger self-reconstruction to derive active species with favorable configurations are expected to overcome the sluggish reaction kinetics. Herein, we innovatively propose the introduction of heterogeneous vanadate dopants into nickel-iron alloy precatalysts, where the crystal mismatch structure induces local electron delocalization in the hexagonal close packed alloy phase, thereby facilitating adequate electrochemical reconstruction to form (oxy)hydroxides as the real catalytic species. Simultaneously, the participation of vanadate in the reconstruction also triggers mismatch in the derived (oxy)hydroxides, reinforcing the metal-oxygen covalence, so that lattice oxygen activation is kinetically favorable and facilitates the OER via the lattice oxygen pathway. Optimized reconstructed catalyst r-NiFeVOx-NF exhibits a low overpotential of 220 mV at current densities of 10 mA cm-2 and considerably stable operation. Our study opens up opportunities for achieving robust OER performance through the design and fabrication of the mismatch catalytic configuration.

Synthesis and evaluation of novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors for overcoming MDR in cancer.

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC50 = 0.25 µM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC50 = 4.7 µM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents.

Talaroterpenoids A-F: Six New Seco-Terpenoids from the Marine-Derived Fungus Talaromyces aurantiacus.

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A-C (1-3), and three meroterpenoids containing an orthoester group, talaroterpenoids D-F (6-8), together with five known compounds (4-5 and 9-11), were isolated from the marine-derived fungus Talaromyces aurantiacus. Their chemical structures were elucidated through 1D, 2D NMR, HRESIMS, J-based configuration analysis (JBCA), computational ECD calculations, and single-crystal X-ray diffraction analysis. Compounds 1 and 2 contain an unusual 6,20-γ-lactone-bridged scaffold. Compounds 10 and 11 presented inhibitory effects on NO release in lipopolysaccharide (LPS)-induced BV-2 cells with IC50 values of 11.47 and 11.32 µM, respectively. Talaroterpenoid C (3) showed moderate antifungal activity against A. alternata and P. theae Steyaert.

Research on the Performance of Thermoelectric Self-Powered Systems for Wireless Sensor Based on Industrial Waste Heat.

The issue of energy supply for wireless sensors is becoming increasingly severe with the advancement of the Fourth Industrial Revolution. Thus, this paper proposed a thermoelectric self-powered wireless sensor that can harvest industrial waste heat for self-powered operations. The results show that this self-powered wireless sensor can operate stably under the data transmission cycle of 39.38 s when the heat source temperature is 70 °C. Only 19.57% of electricity generated by a thermoelectric power generation system (TPGS) is available for use. Before this, the power consumption of this wireless sensor had been accurately measured, which is 326 mW in 0.08 s active mode and 5.45 µW in dormant mode. Then, the verified simulation model was established and used to investigate the generation performance of the TPGS under the Dirichlet, Neumann, and Robin boundary conditions. The minimum demand for a heat source is cleared for various data transmission cycles of wireless sensors. Low-temperature industrial waste heat is enough to drive the wireless sensor with a data transmission cycle of 30 s. Subsequently, the economic benefit of the thermoelectric self-powered system was also analyzed. The cost of one thermoelectric self-powered system is EUR 9.1, only 42% of the high-performance battery cost. Finally, the SEPIC converter model was established to conduct MPPT optimization for the TEG module and the output power can increase by up to approximately 47%. This thermoelectric self-powered wireless sensor can accelerate the process of achieving energy independence for wireless sensors and promote the Fourth Industrial Revolution.

Dual inhibition of MYC and SLC39A10 by a novel natural product STAT3 inhibitor derived from Chaetomium globosum suppresses tumor growth and metastasis in gastric cancer.

Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (Kd= 3.29 µM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 µΜ. XYA-2 at 1 µΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.

Design and synthesis of proteolysis-targeting chimeras (PROTACs) as degraders of glutathione peroxidase 4.

Ferroptosis is a new type of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) has been considered as an effective cancer treatment strategy, but only few GPX4 inhibitors have been reported to date. Targeted protein degradation is receiving increasing attention in the discovery and development of therapeutic modality, particularly proteolysis targeting chimeras (PROTACs). Herein, we reported the design, synthesis, and evaluation of different types of GPX4-targeting PROTACs using ML162 derivatives and ligands for CRBN/VHL E3 ligases. Among them, CRBN-based PROTAC GDC-11 showed a relatively balanced biological profile in GPX4 degradation (degradation rate of 33% at 10 µM), cytotoxicity (IC50 = 11.69 µM), and lipid peroxides accumulation (2-foldincreaserelatedtoDMSO), suggesting a typical characteristic of ferroptosis. In silico docking and quantum chemistry theoretical calculations provided a plausible explanation for the moderate degrading effect of these synthesized PROTACs. Overall, this work lays the foundation for subsequent studies of GPX4-targeting PROTACs, and further design and synthesis of GPX4-targeting degrader are currently in progress in our group, which will be reported in due course.

Synthesis and biological evaluation of esculetin derivatives as potential anti-HBV agents.

Previous in vivo and in vitro studies revealed that esculetin (Fig. 1) has anti-hepatitis B virus (anti-HBV) activity as well as a protective effect on liver damage caused by duck hepatitis B virus. We designed and synthesized a series of esculetin derivatives, introduced side chains containing various amino groups into site 7 of the parent structure, and synthesized C-4 and C-8 substituted derivatives with the goal of investigating their anti-HBV activities. In vitro anti-HBV activity was performed against HepG2.2.15 cells by using Enzyme-Linked Immunosorbent Assay(ELISA) kit and cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay with lamivudine as the positive control. The results demonstrated that several compounds showed moderate anti-HBV activity, while the introduction of morpholine groups could significantly inhibit the expression of hepatitis B e antigen (HBeAg) and the introduction of the 2-methylimidazole group could significantly inhibit the expression of Hepatitis B surface antigen (HBsAg). Among all tested compounds, compound 4a demonstrated the best anti-HBeAg activity (IC50 = 15.8 ± 4.2 µM), while compound 6d demonstrated the best anti-HBsAg activity (IC50 = 21.4 ± 2.8 µM). Compounds 6b and 6c showed moderate anti-HBV activity and HBsAg inhibition. Compounds 4b showed moderate anti-HBV activity and an inhibitory effect on HBeAg. In addition, compounds 4a, 4c, 4d, 6b, 6c and 6d showed improved metabolic stability. This study provides useful guidance for the discovery of anti-HBV drugs, which merits further investigation.

Targeting KRAS mutant cancers: from druggable therapy to drug resistance.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

Targeting E2 ubiquitin-conjugating enzyme UbcH5c by small molecule inhibitor suppresses pancreatic cancer growth and metastasis.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. METHODS: Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. RESULTS: UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. CONCLUSIONS: These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.

Inhibiting STAT3 signaling pathway by natural products for cancer prevention and therapy: In vitro and in vivo activity and mechanisms of action.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in signal transmission from the plasma membrane to the nucleus, regulating the expression of genes involved in essential cell functions and controlling the processes of cell cycle progression and apoptosis. Thus, STAT3 has been elucidated as a promising target for developing anticancer drugs. Many natural products have been reported to inhibit the STAT3 signaling pathway during the past two decades and have exhibited significant anticancer activities in vitro and in vivo. However, there is no FDA-approved STAT3 inhibitor yet. The major mechanisms of these natural product inhibitors of the STAT3 signaling pathway include targeting the upstream regulators of STAT3, directly binding to the STAT3 SH2 domain and inhibiting its activation, inhibiting STAT3 phosphorylation and/or dimerization, and others. In the present review, we have systematically discussed the development of these natural product inhibitors of STAT3 signaling pathway as well as their in vitro and in vivo anticancer activity and mechanisms of action. Outlooks and perspectives on the associated challenges are provided as well.

S3I-201 derivative incorporating naphthoquinone unit as effective STAT3 inhibitors: Design, synthesis and anti-gastric cancer evaluation.

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of many human cancers and has been widely recognized as a promising target for cancer therapy. A variety of small-molecule inhibitors have been developed for targeting STAT3, and some of them are now undergoing clinical trials. S3I-201, a known STAT3 inhibitor, may block STAT3 function in cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complex formation. Using S3I-201 as a starting point for drug development, we synthesized a series of new STAT3 inhibitors 9a-x in this study by introducing naphthoquinone unit, a privileged fragment in STAT3 inhibitors. Most of the compounds exhibited strong anti-proliferation activity of gastric cancer cells (MGC803, MKN28, MNK1, and AGS). The representative compound 9n (SIL-14) could effectively inhibit the colony formation and migration of gastric cancer cells MGC803, arrest the cell cycle and induce MGC803 cell apoptosis at low micromolar concentrations in vitro. In addition, SIL-14 can also inhibit the phosphorylation of STAT3 protein and significantly decrease the expression of total STAT3, suggesting that it may exert anticancer effects by blocking the STAT3 signaling pathway. These results support that SIL-14 may be a promising STAT3 inhibitor for the further development of potential anti-gastric cancer candidates.

Characterization of a bioactive meroterpenoid isolated from the marine-derived fungus Talaromyces sp.

A new meroterpenoid, taladrimanin A (1), was isolated from a marine-derived fungus Talaromyces sp. HM6-1-1, together with eleven biogenetically related compounds (2-12). A plausible biosynthetic pathway for the meroterpenoids (1-4) was proposed. The planar structure of 1 was assigned by HRESIMS and NMR. Its relative configuration was established by quantum chemical NMR calculation of two possible isomers and analyzed by DP4 + method. Finally, X-ray diffraction unambiguously confirmed the relative configuration and revealed the absolute configuration of compound 1. 2-12 were assigned by comparing their NMR data with those reported in the literature. 1 was the first drimane-type meroterpenoid with a C10 polyketide unit bearing an 8R-configuration. In the bioactive assay, 1 exhibited antitumor activity against gastric cancer cells MGC803 and MKN28; it also inhibited the colony formation and induced apoptosis in MGC803 cells both in a concentration-dependent manner. Additionally, 1 displayed selective antibacterial activity against Staphylococcus aureus 6538P, and low activities towards strains of Vibrio parahaemolyticus and Escherichia coli in this study. KEY POINTS: • Twelve compounds were obtained from Talaromyces sp., including four meroterpenoids, one of which was new. • The new compound taladrimanin A (1) inhibits the growth of gastric cancer cells MGC803 and MKN28 as well as the pathogenic bacteria Staphylococcus aureus 6538P. • The biosynthetic pathway of the meroterpenoids was proposed.

Discovery of benzochalcone derivative as a potential antigastric cancer agent targeting signal transducer and activator of transcription 3 (STAT3).

Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.

p-MEK expression predicts prognosis of patients with adenocarcinoma of esophagogastric junction (AEG) and plays a role in anti-AEG efficacy of Huaier.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

Copper(I)-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides with bicyclic alkenes.

A variety of tetrahydroquinoline-fused bicycles bearing multiple stereocenters are prepared in good yields with high diastereoselectivity through Cu2O-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides (ao-QMs) with bicyclic alkenes. Mechanistic studies reveal that the Cu(i) catalyst not only promotes the formation of ao-QMs through a radical process by single electron transfer but also accelerates [4 + 2] cycloaddition. The reaction was easily performed on gram scale and the obtained tetrahydroquinoline-fused bicycles can be converted to diverse tetrahydroquinoline scaffolds.

Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update.

The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.