Current Medicinal Chemistry - Volume 24, Issue 32, 2017

Background: The first reports of the natural enediyne anticancer antibiotics date back to the late 1980s; since then, a great deal of interest has been devoted to the chemistry, biology and potential medical applications of this family of compounds. The biological activity of enediynes is linked to the presence of a highly unsaturated hex-1-ene-1,5-diyne system. The thermally induced transformation of this unit into a benzene σ-σ diradical (the Bergman cycloaromatization) is the key step of the antitumor properties of such compounds: 1,4-diaryl radicals are able to abstract H-atoms from the deoxyribose backbone of DNA, thus leading to DNA strand cleavage and ultimately cell death. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using focused and high quality papers. Research efforts addressed at understanding and mimicking the various processes involved in the targeting, activation and DNA cleavage associated with these products are described. The potential of a great number of non natural enediynes in the treatment of many infectious diseases, apart their role in anticancer drugs, such as antibacterial activity, protein degradation activity, has been reported Results: Due to the interesting mode of action of this class of compounds, the unique molecular architecture of enediynes has been exploited towards the synthesis of many non natural compounds in order to study and enhance their biological properties. Seventy-six papers were included in this review. It is divided in paragraphs that include: Carbo- oxygen-nitrogen- and sulfur- enediynes, polymers and macrocycles. The synthetic approaches to the different classes of compounds are discussed in detail together with the biological implications of the synthesized compounds Conclusion: The review summarizes the most recent advances in the synthesis and reactivity of non natural enediynes by focusing the attention particularly to the biological properties of the most interesting members of the family of carbo- and hetero- enediynes. The findings of this review confirm the importance of non natural enediynes as potential drugs in the treatment of cancer and many infectious diseases.

Background: The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target. Methods: We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines. Results: Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer. Conclusions: Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.

Background: Depression is a debilitating disease that is affecting a growing number of patients, both physically and mentally. In addition to mood changes, depression results in cognitive impairment. Although depression studies have been going on for decades, the underlying mechanism still remains unclear. MicroRNAs (miRNAs), a type of small non-coding RNAs, predominantly control the expression of their target mRNAs to exert their functions. Some evidences have revealed the importance of miRNAs in the mechanism of depression,however, these studies are still in their infancy. Alterations in brain regions, synaptic plasticity, hypothalamic-pituitary-adrenal (HPA) axis, changes in the levels of serotonin and glucocorticoids, together with stress response have been proven to be involved in depression. These alterations can influence cognition, learning and memory, with recent evidences demonstrating the involvement of miRNAs in several aspects of stress response, neural plasticity and neurogenesis as well as pathogenesis of depression. Objective: In light of these theories of depression, this review was aimed at elucidating the role of miRNAs in the underlying mechanisms of depression resulting in cognitive, learning and memory impairments. Method/Results: Both PubMed and Scopus databases were employed in scouring for research reports pertaining to this area of study. A total of 180 articles were obtained from these two databases. Conclusion: With the probing of classical theories of depression as well as the connection between miRNAs and depression, more studies,nevertheless, are needed to ascertain the full mechanism of depression along with its resultant cognitive, learning and memory impediments.

Background: The design of multifunctional agents represents one of the most active research field in medicinal chemistry. In particular, tacrine, a well known Acetylcholinesterase inhibitor, is one of the most used starting point to develop multifunctional ligands and hundreds of papers report about these new agents. This is the third review of a series concerning tacrinebased multifunctional ligands; in particular, in the present, we will summarize and discuss the most intriguing examples of tacrine-based multifunctional agents published since 2013 until 2016. Methods: We analyzed the bibliographic databases for peer-reviewed publications concerning tacrine-based multifunctional agents possessing biological actions that go beyond the simple “cholinergic” blockage. These papers have been subdivided according to their biological activities. Since this is the third review of a series, we took into considerations only the papers appeared since 2013 until 2016. Results: In this review, we have analyzed more than 33 papers. All the reported compounds retain good inhibitory activity towards acetyl- and butyryl-cholinesterase. The other biological activities concern mostly inhibition of a) β-amyloid aggregation, b) β-secretase, c) monoamino oxidases, modulation of Τ and ROS and metal chelation. Conclusion: The analysis of the current literature reported in this review confirm the importance of tacrine as scaffold to develop multifunctional agents potentially usefull to contrast Alzheimer's disease. Furthermore, the compounds herein reported showed very intriguing biological activities that could be used as starting point to develop new compounds even more interesting and, hopefully, clinically usefull to contrast Alzheimer's Disease.

Background: There is growing evidence of the involvement of the kynurenine metabolic pathway and the enhancement of kynurenic acid production in the neuroprotective effects of the ketogenic diet. Objective: Here, we review evidence implicating kynurenic acid in the efficacy of ketogenic diet in eye diseases associated with neurodegeneration. Findings: Ketogenic diet and ketone bodies that are elevated during exposure to the ketogenic diet each have a neuroprotective effect on retinal ganglion cells in a rat model of Nmethyl- D-aspartate induced neuronal damage. Chronic exposure to ketogenic diet also increases kynurenic acid concentrations in discrete rat brain structures. A non-selective glutamate receptor agonist, glutamate, also decreases the production of kynurenic acid in bovine retinal slices; this effect is attenuated by acetoacetate and β-hydroxybutyrate, two of three ketone bodies overproduced during ketogenic diet. Perspective: Whether ketogenic diet induced enhancement of kynurenic acid production would translate into a clinically significant improvement in certain eye diseases like glaucoma and retinal neurodegenerations awaits further experimental and clinical verification.