Current Medicinal Chemistry - Volume 29, Issue 11, 2022

Novel therapeutic strategies are needed to address depression, a major neurological disorder affecting hundreds of millions of people worldwide. Cannabinoids and their synthetic derivatives have demonstrated numerous neurological activities and may have the potential to be developed into new treatments for depression. This review highlights cannabinoid (CB) receptors, monoamine oxidase (MAO), N-methyl-D-aspartate (NMDA) receptor, gammaaminobutyric acid (GABA) receptor, and cholecystokinin (CCK) receptor as key molecular targets of cannabinoids that are associated with depression. The anti-depressant activity of cannabinoids and their binding modes with cannabinoid receptors are discussed, providing insights into rational design and discovery of new cannabinoids or cannabimimetic agents with improved druggable properties.

Background: T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling. Methods: This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types and the rationale for TIM-3-targeted cancer immunotherapy. Results: TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models. Conclusion: TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.

The complexity of the tumor microenvironment and the diversity of tumors seriously affect the therapeutic effect, the focus, therefore, has gradually been shifted from monotherapy to combination therapy in clinical research in order to improve the curative effect. The synergistic enhancement interactions among multiple monotherapies majorly contribute to the birth of the multi-mode cooperative therapy, whose effect of the treatment is clearly stronger than that of any single therapy. In addition, the accurate diagnosis of the tumour location is also crucial to the treatment. Bismuth-based nanomaterials (NMs) hold great properties as promising theranostic platforms based on their many unique features that include low toxicity, excellent photothermal conversion efficiency as well as the high ability of X-ray computed tomography imaging and photoacoustic imaging. In this review, we will introduce briefly the main features of the tumor microenvironment first and its effect on the mechanism of nanomedicine actions and present the recent advances of bismuth-based NMs for diagnosis and photothermal therapy-based combined therapies using bismuth-based NMs are presented, which may provide a new way for overcoming drug resistance and hypoxia. In the end, further challenges and outlooks regarding this promising field are discussed accompanied with some design tips for bismuth- based NMs, hoping to provide researchers some inspiration to design safe and effective nanotherapeutic agents for clinical treatments of cancers.

Kinases are pivotal regulators in tumorigenesis and metastasis by modulating the expression of oncogenes and the transcription of antioncogenes directly or indirectly. Correspondingly, multifarious 3-substituted indolin-2-one derivatives as selective kinase inhibitors for cancer therapy exhibited a low nanomolar activity with prominent efficacy, superior response rate and admirable tolerability. Particularly, certain 3-substituted indolin- 2-one derivatives have met the requirements for clinical trials or the pharmaceutical market. Herein, we focus on the traits of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy, overview recent progress of 3-substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy, analyze the selectivity for tyrosine kinases inhibitors and serine/threonine kinases inhibitors from the molecular aspects based on the molecular docking studies, summarize the structure-activity relationships (SARs) as selective kinase inhibitors and provide our perspectives for the development of 3- substituted indolin-2-one derivatives as kinase inhibitors for cancer therapy.

Diabetes mellitus (DM) and DM-induced vascular complications are significant global healthcare problems, causing a decrease in patient quality of life. The main reason for the disability and mortality of patients is rapidly progressing micro-and macroangiopathies. Currently, free radical oxidation is recognized as one of the main mechanisms in the development of DM and associated complications. Under normal physiological conditions, the level of free radicals and antioxidant defense capabilities is balanced. However, imbalance occurs between the antioxidant defense system and pro-oxidants during chronic hyperglycemia and may invoke the formation of excess free radicals, leading to activation of lipid peroxidation and accumulation of highly toxic products of free radical oxidation. This is accompanied by varying degrees of insulin deficiency and insulin resistance in DM patients. Simultaneously with the activation of free radical generation, a decrease in the activity of antioxidant defense factors (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, vitamins C and E) and an acceleration of diabetic complications are seen. Therefore, we hypothesize that antioxidants may play a positive role in the treatment of DM patients to prevent DM-induced vascular complications. However, this has not been sufficiently studied. In this review, we discuss recent insights into the potential underlying mechanisms of oxidative stress-induced diabetic complications and the implications of antioxidants in mitigation of DM-induced vascular complications.

Background: Tuberculosis is a chronic respiratory disease caused by Mycobacterium tuberculosis. The common treatment regimens of tuberculosis are lengthy with adverse side effects, low patient compliance, and antimicrobial resistance. Drug delivery systems (DDSs) can overcome these limitations. Objective: This review aims to summarize the latest DDSs for the treatment of tuberculosis. In the first section, the main pharmacokinetic and pharmacodynamic challenges posed by the innate properties of the drugs are put forth. The second section elaborates on the use of DDS to overcome the disadvantages of the current treatment of tuberculosis. Conclusion: We reviewed research articles published in the last 10 years. DDSs can improve the physicochemical properties of anti-tuberculosis drugs, improving solubility, stability, and bioavailability, with better control of drug release and can target alveolar macrophages. However, more pre-clinical studies and robust bio-relevant analyses are needed for DDSs to become a feasible option to treat patients and attract investors.

Tanshinone IIA, a major bioactive constituent of Danshen, a Chinese herbal medicine, has gained extensive exploration owing to its unique structural features and multiple promising biological activities. This review focuses on the pharmacology, total synthesis, and structural modifications of tanshinone IIA. We hope this review will contribute to a better understanding of the progress in the field and provide constructive suggestions for further study of tanshinone IIA.

Cannabis is the most widely trafficked and abused illicit drug due to its calming psychoactive properties. It has been increasingly recognized as having potential health benefits and relatively less adverse health effects as compared to other illicit drugs; however, growing evidence clearly indicates that cannabis is associated with considerable adverse cardiovascular events. Recent studies have linked cannabis use to myocardial infarction (MI); yet, very little is known about the underlying mechanisms. A MI is a cardiovascular disease characterized by a mismatch in the oxygen supply and demand of the heart, resulting in ischemia and subsequent necrosis of the myocardium. Since cannabis is increasingly being considered a risk factor for MI, there is a growing need for better appreciating its potential health benefits and consequences. Here, we discuss the cellular mechanisms of cannabis that lead to an increased risk of MI. We provide a thorough and critical analysis of cannabinoids’ actions, which include modulation of adipocyte biology, regional fat distribution, and atherosclerosis, as well as precipitation of hemodynamic stressors relevant in the setting of a MI. By critically dissecting the modulation of signaling pathways in multiple cell types, this paper highlights the mechanisms through which cannabis may trigger life-threatening cardiovascular events. This then provides a framework for future pharmacological studies which can identify targets or develop drugs that modulate cannabis’ effects on the cardiovascular system as well as other organ systems. Cannabis’ impact on the autonomic outflow, vascular smooth muscle cells, myocardium, cortisol levels and other hemodynamic changes are also mechanistically reviewed.