Current Medicinal Chemistry - Volume 23, Issue 13, 2016

For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

Metals are known for playing essential roles in human physiology. Copper and zinc are trace elements closely dependent on one another and are involved in cell proliferation, growth, gene expression, apoptosis and other processes. Their homeostasis is crucial and tightly controlled by a resourceful system of transporters and transport proteins which deliver copper and zinc ions to their target sites. Abnormal zinc and copper homeostasis can be seen in a number of malignancies and also in head and neck cancer. Imbalance in this homeostasis is observed as an elevation or decrease of copper and zinc ions in serum or tissue levels in patients with cancer. In head and neck cancer these altered levels stand out from those of other malignancies which makes them an object of interest and therefore zinc and copper ions might be a good target for further research of head and neck cancer development and progression. This review aims to summarize the physiological roles of copper and zinc, its binding and transport mechanisms, and based on those, its role in head and neck cancer. To provide stronger evidence, dysregulation of levels is analysed by a meta-analytical approach.

The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. A mutation of JAK2 (V617F in specific) that results in constitutive activation of the enzyme is found in patients with myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. The genetic, biological, and physiological evidence available to date has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of MPNs as well as solid tumors, hepatitis C virus (HCV) infection, Alzheimer’s disease, and Parkinson’s disease. Important features essential for JAK2 inhibitors are potent enzymatic inhibition and a high degree of selectivity among other isoforms of JAK. The extent of the potency and selectivity of JAK2 inhibitors is dependent upon receptor-ligand interactions and structural difference between isoenzymes. Thus, detailed knowledge regarding structural characteristics and the binding mode between JAK2 and its inhibitors is necessary. Accordingly, we compiled in this review a comprehensive summary of the three dimensional (3D) structural features of reported JAK2-ligand complexes and the structureactivity relationship (SAR) of JAK2 inhibitors, with particular focus on potent JAK2 inhibition and specificity.

Background/Objectives: The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on plasma concentrations of adiponectin, a fat-derived hormone with anti-atherogenic and anti-inflammatory properties, is uncertain. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to investigate this association in humans. Methods: RCTs investigating the impact of DPP-4 inhibitors on plasma adiponectin concentrations were identified after searching PubMed-Medline, SCOPUS, and Google Scholar databases (up to February 2015). As quantitative data synthesis methods, the random-effects model and the generic inverse variance method were applied. Standard methods of meta-regression, sensitivity analysis, and publication bias assessments were performed. Results: Eight RCTs with nine treatment-arms were included. Meta-analysis did not suggest a significant pooled effect of DDP-4 inhibitors on adiponectin values (weighed-mean-difference [WMD]: 0.19 μg/mL, 95%CI: -0.50, 0.88). However, a significant elevation of plasma adiponectin concentrations was observed in the subset of trials with vildagliptin (WMD: 0.55 μg/mL, 95%CI: 0.13, 0.98, p=0.010) but not sitagliptin (WMD: -0.06 μg/mL, 95%CI: -1.13, 1.00, p=0.907). There was a significant elevation of plasma adiponectin levels in the subset of trials comparing DPP-4 inhibitors versus placebo or no treatment (WMD: 0.74 μg/mL, 95%CI: 0.36, 1.12, p <0.001) but not in the subset using hypoglycemic drugs as comparators), or using other hypoglycemic drugs (WMD: -0.18 μg/mL, 95%CI: -0.99, 0.62, p=0.654). No significant effect was found for treatment duration, confirmed by meta-regression analyses. Conclusion: DPP-4 inhibitors cause a significant increase in plasma adiponectin concentrations and this effect is greater with vildagliptin than sitagliptin.

ATP binding cassette (ABC) transporters are involved in drug absorption, distribution and elimination. They also mediate multidrug resistance in cancer cells. Isoflavones, such as genistein (GNT), belong to a class of naturally-occurring compounds found at high concentrations in commonly consumed soya based-foods and dietary supplements. GNT and its metabolites interact with ABC transporters as substrates, inhibitors and/or modulators of their expression. This review compiles information about regulation of ABC transporters by GNT with special emphasis on the three major groups of ABC transporters involved in excretion of endo- and xenobiotics as follows: Pglycoprotein (MDR1, ABCB1), a group of multidrug resistance associated proteins (MRPs, ABCC subfamily) and ABCG2 (BCRP), an ABC half-transporter. The impact of these regulations on potential GNT-drug interactions is further considered.