Current Medicinal Chemistry (v.22, #15)

Meet Our Editorial Board Member: by Ramon Eritja (1775-1775).

Insights into Ecto-5'-Nucleotidase as a New Target for Cancer Therapy: A Medicinal Chemistry Study by Patricia Frasson Corbelini, Fabricio Figueiro, Gustavo Machado das Neves, Saulo Andrade, Daniel Fabio Kawano, Ana Maria Oliveira Battastini, Vera Lucia Eifler-Lima (1776-1792).
Ecto-5'-nucleotidase (ecto-5'-NT, 5'-NT, eN, CD73) is a membrane ectoenzyme that is primarily responsible for the extracellular production of adenosine from AMP. Ecto-5'-NT is overexpressed in various types of cancer cells, leading to elevated concentrations of adenosine in the tumour microenvironment. Adenosine has also been found to be important in cancer pathogenesis, showing strong immunosuppressive effects over antitumour T cells and macrophages and promoting neovascularization and cell adherence. These actions support tumour growth and development. It has been suggested that the inhibition of ecto-5'-NT results in lower extracellular concentrations of adenosine within the tumour microenvironment, which would directly affect cancer cells and render malignant cells more susceptible to host defence systems. Such mechanisms are proposed to represent promising new targets for cancer therapy. The aim of this review is to explore the biochemical and structural features of ecto-5'-NT, including a brief analysis of its active site by molecular modelling, as a means of evaluating whether the inhibition of this enzyme does indeed represent a feasible strategy for treating cancer. Known inhibitors and possible prototypes that could be used to target ecto-5'-NT during cancer therapy are also discussed.

Fluorescent tagged glucose probes offer an attractive alternative to traditional, radioactive based methods for measuring glucose flux in biological systems. Thus, it could be envisaged that these probes would be widely used. However, this is not the case and, since their development in the mid-1980s, fluorescent tagged glucose bioprobes are relatively underutilized in biological research compared to radioactive methods, with only a small number (<10) publications per year using these probes. However, within the past five years there has been a surge in research activity. By the year 2012, numerous novel probes were developed and the number of research publications dramatically increased. This was especially relevant for drug discovery applications related to cancer, neurology and diabetes research. In this review article, we discuss the research impact of these bioprobes and assess which probes have been most successfully applied to drug discovery applications. Significantly, we also discuss latest research that shows the potential of these probes to be used for drug discovery in animal models and their application to in vivo-based drug validation. Overall, we hope that this review will raise awareness of the research opportunities that these probes offer to the drug discovery research community.

Iron Oxide Nanoparticles: An Insight into their Biomedical Applications by Diana Couto, Marisa Freitas, Felix Carvalho, Eduarda Fernandes (1808-1828).
Iron oxide nanoparticles (IONs) are among the most common types of nanoparticles (NPs) used in biomedical applications. IONs can be presented in different forms [e.g. magnetite (Fe3O4), hematite (α-Fe2O3) and maghemite (γ- Fe2O3)], and are usually coated with substances and/or polymers according to the purpose for which they are intended to be used. In recent years, IONs use has been increasing exponentially in many fields of biomedicine, namely in magnetic resonance imaging, cell sorting, tissue repair, induction of hyperthermia and drug delivery, among others. This review aims to provide an update on the different IONs and the substances and/or polymers that can be used to coat the IONs core as well as their applications and biological properties, namely their biodistribution in the human body and their cellular internalization pathways.

Necrosis is an in vivo chaotic event distinguished by uncontrolled disintegration of the cell membrane leading to cytolysis, inflammation and tissue destruction followed by a healing or regenerating process. Targeting necrosis may offer potential diagnostic, therapeutic and/or theragnostic applications in translational medicine. This article reviews the current concept of necrosis including definition, etiology and pathophysiology. The evolution and development of a wide diversity of necrosis targeting agents and their potential applications in preclinical and clinical settings are also elaborated and discussed.

A Review on GABA/Glutamate Pathway for Therapeutic Intervention of ASD and ADHD by Priyanka Purkayastha, Aruna Malapati, Perumal Yogeeswari, Dharmarajan Sriram (1850-1859).
Balance between excitatory glutamate and inhibitory GABA neurotransmitter is essential and critical for proper development and functioning of brain. GABAergic (gamma aminobutyric acid) and glutamatergic interneurons maintain excitability, integrity and synaptic plasticity. Several evidences implicated relative loss of inhibitory GABA with corresponding glutamate mediated hyperexcitation in the development of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). ASD is the common neurological disorder with an estimated relative occurrence of 0.5-1% of universal population. Several studies have demonstrated the imbalance of excitatory/inhibitory neurotransmitters resulting from neurodevelopmental impairments in glutamatergic and GABAergic system, which might resemble common pathological mechanism for developmental disorders. This review focuses on the necessity for developing GABA enhancing and glutamate suppressing drug candidates, and illustrates the role of GABAergic and glutamatergic system in cognition and memory impairment involved in neurodevelopmental disorders, with emphasis on ASD and ADHD. The review also highlights the emerging drugs for neurodevelopmental disorders.

The Changing Face of Hepatitis C: Recent Advances on HCV Inhibitors Targeting NS5A by Diwakar Rai, Liu Wang, Xuemei Jiang, Peng Zhan, Haiyong Jia, Erik De Clercq, Xinyong Liu (1860-1879).
Current treatment for HCV infections consists of approved direct acting antivirals (DAAs), viz. the protease inhibitors (boceprevir, telaprevir, and simeprevir), NS5B polymerase inhibitors (sofosbuvir) and NS5A inhibitor (ledipasvir) in combination with pegylated interferon α and ribavirin). These treatments have made a great improvement in the treatment of chronic HCV infections in recent years, but their adverse side effects, emergence of resistant mutants, high cost, and increased pill burden have limited their clinical use. Recently, with the increasing knowledge in understanding the HCV life cycle, more targets have been recognized. NS5A protein plays a critical role in assembly of infectious HCV particles and offering potential for HCV therapies. Therefore, discovery and development of novel DAAs targeting NS5A with novel mechanisms of action, are of great necessity to improve the quality of existing HCV treatments. In the present review, we discuss recent advances with NS5A inhibitors with potent anti-HCV activity, and the potential for the development of HCV NS5A inhibitors to combat HCV infections.

Using Strictosidine Synthase to Prepare Novel Alkaloids by Huajian Zhu, Petra Kercmar, Fangrui Wu, Chitra Rajendran, Lianli Sun, Meitian Wang, Joachim Stockigt (1880-1888).
The Pictet-Spenglerase strictosidine synthase (STR) has been characterized as the central enzyme in the biosynthesis of around 2000 monoterpenoid indole alkaloids in plants. In the light of a high therapeutic value and huge scaffold diversity these alkaloids represent, STR as an enzyme has attracted great attentions in recent years, intending to be utilized in the formation of new interesting alkaloids with unusual substitution pattern or even with novel scaffolds. For outlining the application potential that STR possesses, together with insight into the reaction mechanism catalyzed by STR, strategies and methods for exploring the applicability of STR have been updated in this article by taking R. serpentina STR (RS-STR) and C. roseus. STR (CR-STR) as representative models, followed by introducing the latest released complex structures of RS-STR with new substrates. Examples provided here, including substrate scaffold tailoring, X-ray crystal complex structure comparison, protein engineering and biosynthetic pathway reprogramming, pave the way to finally construct novel alkaloids libraries by chemo-enzymatic approaches.