Current Medicinal Chemistry - Volume 26, Issue 12, 2019

Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. Methods: In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.

Background: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient’s body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. Methods: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. Conclusion: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.

The term cancer represents a set of more than 100 diseases that are caused due to an uncontrolled growth of cells; and their subsequent spread to the other tissues and organs of the body by a phenomenon, called ‘metastasis’. According to the estimates provided by the World Health Organization (WHO), cancer is expected to account for about 10 million deaths per year by 2020 and 21 million cancer cases, which may lead to 13 million deaths by 2030, making cancer as the cause of highest mortality in contrast to other diseases. The search for potential therapeutics against cancer, which can reduce the side-effects that occur due to the difficulty of recognition between cancerous and normal cells, has ever been increased. In this view, nanotechnology, especially metallic nanoparticles (MNPs), comes to aid in the development of novel therapeutic agents, which may be synthesized or modified with the most diverse functional chemical groups; this property makes the metallic nanoparticles suitable for conjugation with already known drugs or prospective drug candidates. The biocompatibility, relatively simple synthesis, size flexibility and easy chemical modification of its surface, all make the metallic nanoparticles highly advantageous for opportune diagnosis and therapy of cancer. The present article analyzes and reports the anti-tumor activities of 78 papers of various metallic nanoparticles, particularly the ones containing copper, gold, iron, silver and titanium in their composition.

In recent years inorganic materials are largely present in products intended for health care. Literature gives many examples of inorganic materials used in many healthcare products, mainly in pharmaceutical field. Silver, zinc oxide, titanium oxide, iron oxide, gold, mesoporous silica, hydrotalcite-like compound and nanoclays are the most common inorganic materials used in nanosized form for different applications in the health field. Generally, these materials are employed to realize formulations for systemic use, often with the aim to perform a specific targeting to the pathological site. The nanometric dimensions are often preferred to obtain the cellular internalization when the target is localized in the intracellular space. Some materials are frequently used in topical formulations as rheological agents, adsorbents, mattifying agents, physical sunscreen (e.g. zinc oxide, titanium dioxide), and others. Recent studies highlighted that the use of nanosized inorganic materials can represent a risk for health. The very small dimension (nanometric) until a few years ago represented a fundamental requirement; however, it is currently held responsible for the inorganic material toxicity. This aspect is very important to be considered as actually numerous inorganic materials can be found in many products available in the market, often dedicated to infants and children. These materials are used without taking into account their dimensional properties with increased risk for the user/patient. This review deals with a deep analysis of current researches documenting the toxicity of nanometric inorganic materials especially those largely used in products available in the market.

Background: Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance. Methods: In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes. Results: These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed. Conclusion: The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.

High-resolution nuclear magnetic resonance (NMR) spectroscopy is a universal analytical tool. It can provide detailed information on chemical shifts, J coupling constants, multiplet patterns, and relative peak areas. It plays an important role in the fields of chemistry, biology, medicine, and pharmacy. A highly homogeneous magnetic field is a prerequisite for excellent spectral resolution. However, in some cases, such as in vivo and ex vivo biological tissues, the magnetic field inhomogeneity due to magnetic susceptibility variation in samples is unavoidable and hard to eliminate by conventional methods. The techniques based on intermolecular multiple quantum coherences and conventional single quantum coherence can remove the influence of the field inhomogeneity effects and be applied to obtain highresolution NMR spectra of biological tissues, including in vivo animal and human tissues. Broadband 1H homo-decoupled NMR spectroscopy displays J coupled resonances as collapsed singlets, resulting in highly resolved spectra. It can be used to acquire high-resolution spectra of some pharmaceuticals. The J-difference edited spectra can be used to detect J coupled metabolites, such as γ-aminobutyric acid, the detection of which is interfered by intense neighboring peaks. High-resolution 1H NMR spectroscopy has been widely utilized for the identification and characterization of biological fluids, constituting an important tool in drug discovery, drug development, and disease diagnosis.

Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of rapamycin (mTOR) and activate AMP-kinase (AMPK) have beneficial effects in promoting differentiation and blocking proliferation of AML. Most of these drugs are already in use for other purposes; rapalogs as immunosuppressants, biguanides as oral antidiabetics, and 5-amino-4-imidazolecarboxamide ribonucleoside (AICAr, acadesine) as an exercise mimetic. Although most of these pharmacological modulators have been widely used for decades, their mechanism of action is only partially understood. In this review, we summarize the role of AMPK and mTOR in hematological malignancies and discuss the possible role of pharmacological modulators in proliferation and differentiation of leukemia cells.