Current Medicinal Chemistry - Volume 25, Issue 6, 2018

Background: Steroids play an important role in life because they can regulate a variety of biological processes and have been widely used in medicine namely as antiinflammatory, anabolic, contraceptives and anticancer drugs. In recent years, there has been an increasing interest in the introduction of the oxime group in a large variety of molecules in order to increase their biological effects. This review highlights steroidal oximes with anticancer properties and their potential mechanisms of action, as well as data on their relative potencies reported in literature in the last few years. Methods: To prepare this review, an extensive literature search was performed on three databases, PubMed, ISI Web of Knowledge and Science Direct, to generate a critical but comprehensive overview of the potential antitumor activities of steroidal oximes. The main keywords used for the search consisted of combinations of the following terms or their synonyms: steroidal oximes, anticancer activity and enzymatic inhibitory activity. The abstracts and full texts were evaluated for their clarity and scientific merit and to further help on the selection of other articles. Results: Over the last decades the introduction of oxime groups in the steroid scaffold is originating molecules with relevant antitumor activities, as well as steroid sulfatase, aromatase, 17α-hydroxylase-17,20-lyase, 5α-reductase and 17β-hydroxysteroid dehydrogenase type 1 inhibitory activities. As relevant examples, pregnenolone 20-oximes showed high activity as 17α-hydroxylase-17,20-lyase and 5α-reductase inhibitors and the introduction of an oxime group at C-6 in androstane series also led to relevant results as aromatase inhibitors. Interestingly, the introduction of this functional group frequently improves the bioactivity when compared with non-oxime analogous compounds, which can be due to extra interactions with biological targets. In addition, it has been observed that varying the position of the hydroximino group on the parent skeleton leads to remarkable changes in the antitumor activity. Conclusion: The recent advances in synthesis and in vitro bioactivity studies of steroidal oximes contributed to understand the potential interest of the introduction of this functional group in the steroidal nucleus in the development of anticancer molecules. Moreover, the cytotoxic/enzyme inhibitory activity usually depends on the position of the oxime group in different steroid scaffolds. However, despite the promising results, it is necessary to perform more in vitro and in vivo assays not only to better explore the mechanisms of action but also to confirm the potential effectiveness and safety of this interesting family of compounds in clinical practice.

Background: Long-term immunosuppressive therapy, as provided to solid organ transplant recipients, inevitably results in a significant inhibition of immune defenses; this leads to frequent skin infections and malignancies, which represent an important cause of morbidity and mortality for transplanted patients. The incidence and risk of skin carcinomas are elevated in solid organ transplant recipients in comparison with the general population, with a 10-fold increased risk for basal cell carcinoma and a 50-100-fold for squamous cell carcinoma. The schedule of immunosuppressive drugs influences the type and timing of skin malignancies, but a crucial role is also played by endogenous and exogenous risk factors. Methods & Results: Here, we will review the state-of-the-art in chemoprevention of epidermal carcinomas in order to provide useful information for clinicians involved in the management of transplant recipients. One-hundred and forteen paper, published on peerreviewed journals, has been included. Conclusion: Chemoprevention would be key in controlling skin carcinogenesis in high-risk patients.

Background: Gastric cancer is a malignancy with high mortality rate worldwide. Poor clinical symptoms, unfavorable prognosis and absence of proper diagnostic techniques for early detection cause death in many patients. Presence of new sensitive and specific biomarkers for early detection and progression of GC could lead to reduction in the mortality rate. In addition to intracellular miRNAs, circulating miRNAs reflect the state of cancer progression and might be potential biomarkers for rapid detection and also therapy in GC. Objective: After giving a brief explanation about circulating miRNAs and their various types, we then reviewed comprehensively the last studies which investigated circulating miRNAs as diagnostic/prognostic biomarkers in GC. Methods: Research and review articles in PubMed and Scopus databases were summarized. Keywords mainly used were in related to circulating miRNAs and their diagnostic and prognostic value in gastric cancer. Among the numerous circulating miRNAs a comparison was made based on their repeatability, specificity and sensitivity. Results: Comparisons indicated high diagnostic value of circulating miRNAs in comparison with other detection methods based on their high sensitivity and specificity. There was also a relation between altered expression level of large number of circulating miRNAs and clinicopathological factors and also response to therapy in GC. Conclusion: Several advantages of circulating miRNAs as detection biomarker have led to extensive studies and significant advances. Altered expression pattern of circulating miRNAs have correlation with pathological status of GC tissues and their exclusive features make them ideal early diagnostic, prognostic and predictive biomarkers for GC.

Background: The metal ions dyshomeostasis is increasingly recognized to play a crucial role in the development of aging-related neurodegenerative diseases. Metal trafficking in the brain is related to proteins regulating both uptake and efflux of metals in neurons. Different pathways may occur, depending on specific binding features of metallo-protein complexes. In particular, copper, zinc and iron are recognized to influence the biochemistry of proteins involved in neurodegeneration (for instance Aβ and α-synuclein), as well as those playing a crucial role in neuronal development and efficiency (neurotrophins). Nowadays the application of peptide-based drugs is widespread for different pathologies, but the short lifetime in vivo due to proteolysis and other shortcomings still limit their use. Methods: A structured search was performed about the state of the art on: i) peptidomimetic approaches used to obtain peptides mimicking the metal binding activities of proteins involved in neurons survival, ii) peptide-based nanostructures, as promising biomaterials in tissue engineering and substrates for neurites outgrowth and synapses formation. Results: Recent developments on metal-binding peptides and peptide nanostructures for therapeutic application in neurodegenerative diseases are reviewed, showing as metal ions interaction may affect structural and biological properties of different proteins involved in neurodegenerative diseases. Conclusion: This review provides a survey on peptides able to mimic some biofunctional activities of the whole protein, e.g., the binding features to metal ions, thus highlighting their promising potentialities as new, more effective, therapeutics. The integration of such peptides into multifunctional nanoplatforms can be a smart route for the development of biomaterials scaffolds and nanomedicine applications.

Background: Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively. Objective: This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction. Results: BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF). Conclusion: The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring.