Current Medicinal Chemistry - Volume 25, Issue 27, 2018

Background: The approval of Taxol® in 1993 marked the great entrance of terpenoids in the anti-cancer area and this drug is still highly important in the treatment of refractory ovarian, breast and other cancers. Over decades, other prominent natural terpenoids have become indispensable for the modern pharmacotherapy of breast cancer. However, given the rapid evolution of drug resistance, effective treatments for advanced breast cancers requiring cytotoxic chemotherapy represent a major unmet clinical need. Therefore, innovative agents effective in long-term chemotherapy are urgently needed. Objective: This review examines recent advances/research about natural terpenoids, and their mechanisms against female breast cancer over the period covering January 1st, 2012 to December 31st, 2016. Results: Carcinogenesis constitutes a multistep process wherein each stage is characterized by distinct phenotypic changes. Numerous chemicals recorded in this review have been shown to significantly inhibit proliferation, migration, apoptosis resistance, tumor angiogenesis or metastasis in different breast cancer cells/tumours in vitro and in vivo. Targeting simultaneously several or all these aspects/steps of cancer progression could be an advantage. In line with this, phytochemicals such as thymoquinone (8), costunolide (46), tanshinone IIA (132), triptolide (136), cucurbitacin B (179), celastrol (226) and lycopene (238) had caught our attention. Conclusion: These compounds appear to be promising to overcome breast cancer treatment failure. However, despite the interesting activities, additional preclinical investigations are needed in further breast cancer cell/tumor models in vitro and in vivo.

The 5-HT1A receptor is a pharmacologically well characterized serotonin receptor subtype and it has long been investigated because of its involvement in several physiopathological mechanisms and treatment of neurological diseases like ansia and depression. Serotonin (5-HT) also shows many non-neural functions such as essential hypertension, embryogenesis, follicle maturation and behavior. Moreover, it exerts a growth factor function on different types of non-tumoral cells, and it was also found to be related to oncogenes. In fact, growth-stimulatory activity of serotonin in different human tumor cells has been reported. Recently, new chemical molecules binding the 5-HT1A receptor have been described as novel therapeutic entities useful in neuroprotection, cognitive impairment, Parkinson's Disease, pain treatment, malignant carcinoid syndrome and cancer. It was widely demonstrated that 5-HT1A receptor is involved in the carcinogenesis and consequently in many human tumor types, such as prostate, bladder, small cell lung, colonrectal and cholangiocarcinoma. Furthermore, depending on the tumor type, 5-HT1A receptor antagonists were shown to be capable of blocking the 5HT-induced increase in tumor growth. In this review, we have focused our attention on each tumor type where the 5-HT1A receptor is involved, investigating the role of this molecular target and the different classes of compounds that have shown the capability to modulate it. The analyzed aspects could represent a hint for the medical chemists to develop novel molecules as selective 5-HT1A agents are useful in further elucidating the role of this therapeutic target.

Flavonoids are phytochemicals present in almost all terrestrial plants and, as a consequence, in plant-based foods, and thus consumed by humans through diet. Recent evidences suggest that several flavonoids have positive effects against dementia and Alzheimer's disease, reversing age-related declines in neurocognitive performances. In this review, we provide a general classification of natural and synthetic flavonoids, a description of their physico-chemical properties, in particular their redox properties and stability, and an extensive overview about their biological activities and structure-activity relationship in the field of neurodegenerative diseases. In addition, a section will be dedicated to the synthetic strategies for the preparation of bioactive derivatives. This information will be essential for the design and development of new drugs that can improve brain functions.

UDP-glucuronosyltransferases (UGTs) are important phase II metabolic enzymes responsible for approximately 40-70% of endo and xenobiotic reactions. It catalyzes the transfer of glucuronic acid to lipophilic substrates, converting them into hydrophilic compounds that are excreted. There are 22 active human UGTs that belong to 4 families. This review focuses on human UGTs, highlighting the most current issues in order to connect all information available and allowing a discussion on the challenges already solved and those in which we need to move forward. Although, several UGTs studies have been conducted, the most recent ones addressing drug-drug interactions and polymorphism issues, there are still bottlenecks to overcome. Tridimensional structure is difficult to obtain due to overexpression, purification, and crystallization problems as well as the action mechanism - since overlapping of substrate specificities renders impasses on the identification of which isoform is responsible for a particular drug metabolic pathway. For this reason, bioinformatic tools are gaining more space, since it is a faster and less expensive reliable methodology that complements in vitro and in vivo researches. Combinations of quantum and molecular methods have become increasingly common, leading to the incorporation of enzyme features comprising their structure, dynamics and chemical reactions. Breakthroughs related to the enzyme, not only enable the discovery of new drugs essential for the treatment of various diseases, but also provide an improved action of the existing drugs.

Background: Kidney disease is a serious problem that adversely affects human health, but critical knowledge is lacking on how to effectively treat established chronic kidney disease. Mounting evidence from animal and clinical studies has suggested that Vitamin D Receptor (VDR) activation has beneficial effects on various renal diseases. Methods: A structured search of published research literature regarding VDR structure and function, VDR in various renal diseases (e.g., IgA nephropathy, idiopathic nephrotic syndrome, renal cell carcinoma, diabetic nephropathy, lupus nephritis) and therapies targeting VDR was performed for several databases. Result: Included in this study are the results from 177 published research articles. Evidence from these papers indicates that VDR activation is involved in the protection against renal injury in kidney diseases by a variety of mechanisms, including suppression of RAS activation, anti-inflammation, inhibiting renal fibrogenesis, restoring mitochondrial function, suppression of autoimmunity and renal cell apoptosis. Conclusion: VDR offers an attractive druggable target for renal diseases. Increasing our understanding of VDR in the kidney is a fertile area of research and may provide effective weapons in the fight against kidney diseases.

Background: In the 1990s, the beta interferons and glatiramer acetate were introduced for treating relapsing-remitting multiple sclerosis. These medications have a demonstrated record of efficacy and safety, although they require frequent administration via injection and are only partially effective. The optimization of treatment in patients who do not respond adequately to this first-line therapy is essential for attaining the best long-term outcomes. Switching to the recently approved emergent therapies is a strategy to consider for treatment of patients with a suboptimal response. Objective: This review summarizes the mechanisms of action, clinical benefits, and safety profiles of current multiple sclerosis disease-modifying therapies, including highly efficacious monoclonal antibodies or convenient oral therapies, and with a special focus on the pegylated interferon beta 1a formulation. Methods: We reviewed the recent literature and human clinical trials on multiple sclerosis therapies by bibliographic search in PubMed and clinicaltrials.gov. Results and Conclusion: Although the first-line interferon beta exhibits a favorable benefit-torisk profile, treatment compliance is compromised potentially due to its known adverse events and frequent injectable administration. Less frequent dosing and improved pharmacological properties have been achieved by reaction of interferon beta with chemically activated polyethylene glycol. Provided that none of the available therapies show better effectiveness for all outcomes and their safety in clinical practice is of a fundamental concern, the pegylated form of interferon beta seems to keep its place as a competitive therapeutic option.