Current Medicinal Chemistry (v.22, #6)

Meet the Editorial Board: by Mariangela Biava (669-669).

Alcohol Addiction: A Molecular Biology Perspective by Giampiero Ferraguti, Esterina Pascale, Marco Lucarelli (670-684).
Alcohol misuse represents worldwide an important risk factor for death and disability. Excessive alcohol consumption is widely diffused in different ethnicities and alcohol use is part of the lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represents an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease.

Dis-organizing Centrosomal Clusters: Specific Cancer Therapy for a Generic Spread? by D. Bhakta-Guha, M.E.M. Saeed, H.J. Greten, T. Efferth (685-694).
Cancer is a leading cause of mortality and the annual incidence of new cancer cases is rising worldwide. Due to the frequent development of resistance and the side effects of established anti-cancer drugs, the quest for new drugs with improved therapeutic features goes on. In contrast to cytotoxic chemotherapy of the past, the concept of targeted chemotherapy attempts to increase specificity of therapy by attacking tumor-related mechanisms. A novel emerging treatment concept represents the inhibition of centrosomal clustering. The centrosome regulates mitotic spindle formation assuring uniform separation of chromosomes to daughter cells. Many tumors contain supernumerary centrosomes, which contribute to aneuploidy induction via multipolar mitotic spindle formation. As spindle multipolarity leads to cell death, tumor cells developed centrosomal clustering mechanism to prevent multipolar spindle formation by coalescence of multiple centrosomes into two functional spindle poles. Inhibition of centrosome clustering represents a novel strategy for drug development and leads to the formation of multipolar spindles and subsequent cell death. In the present review, we report advances in understanding the biology of centrosomal clustering as well as enlist compounds capable of inducing the formation of multipolar spindles such as indolquinolizines, integrin-linked kinase inhibitors (QLT-0267), noscapinoids (EM011), phthalamide derivatives (TC11), griseofulvin, phenanthridines (PJ-34), CCC1-01, CW069 GF-15, colcemid, nocodazole, paclitaxel, and vinblastine. We also present in silico result of compounds that bind to γ-tubulin under the ambit of centrosomal clustering inhibition. We observed maximum binding efficacy in GF-15, CW069, paclitaxel and larotaxel with GF-15 exhibiting least energy of -8.4 Kcal/mol and 0.7 μM Pki value.

Multi-Kinase Inhibitors by Laura Garuti, Marinella Roberti, Giovanni Bottegoni (695-712).
The limitations of many mono-kinase inhibitors can be overcome by agents with multi-target action. An important advantage of targeting more than one kinase, is an increase in potency, due to the synergistic effect. Moreover, this approach can reduce the possibility of developing drug resistance. Several multitarget agents have been designed as single kinase inhibitors and found to be multi-target inhibitors because of the structural homology among the ATP-binding site of kinases. In other cases, these inhibitors have been obtained by optimization of potent individual inhibitors or by combination of selective ligands. Also some irreversible inhibitors act on different kinases and covalently modify the cysteine residues located near the ATP-binding pocket. In this review the most recent examples of multi-kinase inhibitors are reported, focusing on chemical structures, structure-activity relationship (SAR) and biological activity. These inhibitors, suitably substituted, could be used in designing other multitarget agents. Virtual molecular docking would suggest potential targets of molecules, moreover combining pharmacophore combination and screening methods could probably help in the discovery of more potent multikinase inhibitors.

The purinergic receptor P2X7 is highly expressed in immune peripheral and central cells suggesting its important role in numerous diseases characterized by inflammatory processes like cancer, or neurodegenerative pathologies in relation with modulation of the immune system. Thereby, antagonization of this receptor may be a hopeful therapeutic strategy to treat a large range of diseases. Indeed, selective P2X7 antagonists display beneficial anti-inflammatory, analgesic, and in some cases, anticancer properties. This article will review the involvement of P2X7 in the immune system, the update of P2X7 antagonists series since 2009 and their promising therapeutic potential for the treatment of several immune- related diseases.

Benzothiazoles - Scaffold of Interest for CNS Targeted Drugs by Lukas Hroch, Laura Aitken, Ondrej Benek, Martin Dolezal, Kamil Kuca, Frank Gunn-Moore, Kamil Musilek (730-747).
Benzothiazole compounds represent heterocyclic systems comprising a benzene ring fused with a thiazole ring containing nitrogen and sulphur in its structure. Besides the presence of a benzothiazole core in naturally occurring molecules, synthesized compounds containing a benzothiazole moiety in their structure proved to be a significant class of potential therapeutics, as they exhibit biological effects such as antitumor, antibacterial, antitubercular, antiviral, anthelmintic, antidiabetic and many others. Apart from the aforementioned peripheral or microbial active sites, benzothiazole analogues are also biologically active compounds in the central nervous system, where some approved drugs containing a benzothiazole moiety have already been identified and are used in the treatment of various neurological disorders. New benzothiazole molecules are currently under development and are being evaluated for several uses including diagnostics and as therapeutic drug candidates for the treatment of epilepsy and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis amongst others.

Role of microRNAs in Osteoblasts Differentiation and Bone Disorders by Yasir Arfat, Wei-Zhong Xiao, Munazza Ahmad, Fan Zhao, Di-Jie Li, Yu-Long Sun, Lifang Hu, Chen Zhihao, Ge Zhang, Salman Iftikhar, Peng Shang, Tuan-Ming Yang, Ai-Rong Qian (748-758).
Advanced studies of single stranded endogenous ~22 nt microRNAs (miRNAs) have demonstrated their diverse biological functions including control of cell differentiation, cell cycle and pathological conditions. Recent studies suggest the potential application of miRNAs in stem cell engineering. miRNAs play a vital role as post-transcriptional regulators of gene expression which controls osteoblasts-mediated bone formation and osteoclasts related bone remodeling. Transcriptional and post-transcriptional mechanisms regulate the differentiation of osteoblasts and osteogenesis. The differentiation of osteoblasts is a key step in the development of skeletal muscles and it is involved in triggering the signaling pathways. Signaling pathways like TGFβ, BMP and Wnt are regulated by miRNAs which in turn, are shown to be associated with bone dynamics and bone disorders. This recap highlights the role of miRNAs in osteoblasts differentiation and emphasizes their potential therapeutic role in metabolic bone disorders.

Microglial Activation as a Compelling Target for Treating Acute Traumatic Brain Injury by Chung-Ching Chio, Mao-Tsun Lin, Ching-Ping Chang (759-770).
Microglia and several inflammatory cytokines and neurotrophic growth factors are involved in traumatic brain injury (TBI). Tumor necrosis factor-alpha (TNF-α) can be released by microglia, astrocytes, and neurons. TNF-α has been reported to be both proneurogenic and antineurogenic, depending upon the model, method, and cell-derived region. There are two subtypes of microglia: M1 and M2. The former (or M1 subtype of non-phagocytic microglia) is able to secrete higher levels of TNF-α but lower levels of interleukin (IL)-10 (IL-10), an anti-inflammatory cytokine. Both the proinflammatory and the pro-apoptotic function can also be promoted by activation of tumor necrosis factor-receptor 1 (TNF-R1). In contrast, M2 activation produces lower levels of TNF-α but higher levels of IL-10. Pro-growth and survival pathways can be promoted by the activation of TNFR2. During the acute stage of TBI, both M1 subtype of microglia and TNF-R1 are activated to cause higher levels of TNF-α but lower levels of IL-10, which lead to suppressed neurogenesis, neuronal loss and organ dysfunction (so-called microglial activation I). In contrast, activation of both M2 subtype of microglia and TNF-R2 is able to promote neurogenesis and tissue recovery (so-called microglial activation II). The severity of TBI depends upon the net effects between microglial activation I and microglial activation II. Indeed, by using rodent models of TBI, therapeutic evaluation studies reveal that several agents or strategies attenuate contused brain volume and neurological deficits by inhibiting microglial activation I but inducing microglial activation II. For example, etanercept therapy might attenuate contused brain volume and neurological deficits by inactivating the M1 subtype and TNF-R1 to reduce the microglial activation I response, but it might promote neurogenesis and functional recovery by activating the M2 subtype and TNF-R2. Therefore, based on microglial responses I and II, we conclude that future studies should focus on multiple therapeutic agents and strategies for optimal TBI therapy.

GABAA Receptor Subtype-Selectivity of Novel Bicuculline Derivatives by Joachim Ramerstorfer, Verena Foppa, Hanna Thiery, Philippe Hermange, Simon Janody, Michael L. Berger, Robert H. Dodd, Werner Sieghart (771-780).
GABAA receptors are the major inhibitory neurotransmitter receptors in the central nervous system and are targets of clinically important drugs modulating GABA induced ion flux by interacting with distinct allosteric binding sites. ROD 185 is a previously investigated structural analogue of the GABA site antagonist bicuculline, and a positive allosteric modulator acting via the benzodiazepine binding site. Here, we investigated 13 newly synthesized structural analogues of ROD 185 for their interaction with rat GABAA receptors. Using [3H]flunitrazepam binding assays, we identified four compounds exhibiting a higher affinity for the benzodiazepine binding site than ROD 185. Two electrode voltage clamp electrophysiology at recombinant GABAA receptors indicated that most of these compounds positively modulated GABA-induced currents at these receptors. Additionally, these experiments revealed that this compound class not only interacts with the benzodiazepine binding site at αβγ receptors but also with a novel, so far unidentified binding site present in αβ receptors. Compounds with a high affinity for the benzodiazepine binding site stimulated GABA-induced currents stronger at αβγ than at αβ receptors and preferred α3β3γ2 receptors. Compounds showing equal or smaller effects at αβγ compared to αβ receptors differentially interacted with various αβ or αβγ receptor subtypes. Surprisingly, five of these compounds interacting with αβ receptors showed a strong stimulation at α6β3γ2 receptors. The absence of any direct effects at GABAA receptors, as well as their potential selectivity for receptor subtypes not being addressed by benzodiazepines, make this compound class to a starting point for the development of drugs with a possible clinical importance.