Current Medicinal Chemistry - Volume 20, Issue 11, 2013

Problems associated with the administration of anticancer drugs, such as limited solubility, poor biodistribution, lack of selectivity, and healthy tissue damage, can be overcome by the implementation of drug delivery systems. A wide range of materials, including liposomes, microspheres, polymers and recently, carbon nanotubes (CNTs), have been investigated for delivering anticancer drugs on the purpose of reducing the number of necessary administrations, providing more localized and better use of the active agents, and increasing patient compliance. Carbon nanotubes (CNTs) have attracted particular attention as carriers of biologically relevant molecules due to their unique physical, chemical and physiological properties. The exact relationship between the physical-chemical properties of carbon nanotubes, their cellto- cell interactions, reactivity, and biological/systemic consequences are relevant issues and it is important to know such inter-relationships beforehand to employ the benefits of these nanomaterials without the hazardous consequences. The purpose of this review is to present highlight of recent developments in the application of carbon nanotubes as cargoes for anticancer drugs and in the diagnosis of cancer diseases.

While increasing expertise in molecular biology and proteomics is markedly speeding up the target elucidation process, various strategies have been proposed that improve the chances of identifying active molecules. Among them, the Fragment Based Drug Design (FBDD) is surely worth noting. The FBDD entails the screening of a small number of low molecular weight compounds in the hopes of finding even low affine but high ligand efficient fragments that have high probability to became drug candidates. Since 1996, when the first paper on FBDD was reported, the potentialities of this strategy became progressively more apparent as testified by the growing number of publications. Many drug discovery projects started with the identification of fragments which after the optimization gave many molecules close to the approval and one marketed drug Vemurafenib, approved in 2011. A preamble that highlights the advantages of dealing with simple and “very small” molecules over conventional drug-like compounds will be herein given prior to discussing the canonical FBDD stages, from fragment library design, to the different screening methods concluding with the various optimization strategies, in an attempt to illustrate the whole FBDD workflow while discussing the most recent and successful applications. While this review is a tribute to the success achieved by the researchers in this field, it is particularly addressed to scientists who want to become aware of the versatility and potentiality of FBDD.

Alterations in serotonergic activity have been observed in many pathological conditions, including neuropsychiatric diseases, irritable bowel syndrome, and hypertension. The serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT) in the brain clears 5-HT from extracellular spaces, modulating the strength and duration of serotonergic signaling. Outside the central nervous system, it is also present in platelets, where it takes up 5-HT from plasma, keeping levels very low (i.e., ˜1 nM). Importantly, it is generally accepted that SERT protein expressed in platelets is identical to the one found in neurons, displaying similar structural and functional properties in both tissues. At the present time, it is technically difficult to measure SERT binding and function in vivo since imaging methods are limited by a number of factors, especially the cost and the selectivity of the available radioligands. One of the most frequently used molecular imaging techniques to study SERT is positron emission tomography (PET). Although an impressive number of PET radioligands have been synthesized and validated, there is still a lack of suitable ligands for a large part of the 5-HT system. Interest in determining both the molecular characteristics and the regulation of SERT has been enormous over the last decade, but the difficulty in obtaining human tissues and the ethical limitations in human experiments have turned researchers to look for alternative models. This review summarizes recent clinical and preclinical data relevant to the use of blood platelets as a peripheral marker for the central 5-HT system, and outlines future directions in this field.

The standards of medical care in diabetes recommend that statin therapy is added to lifestyle therapy for diabetic patients with overt cardiovascular disease (LDL cholesterol goal <70 mg/dl), or without cardiovascular disease who are over the age of 40 years and who have one or more other cardiovascular disease risk factors (LDL cholesterol goal <100 mg/dl). In order to reach strict LDL targets, high doses of statins may be required. However, the frequency of statinassociated adverse effects and statin intolerance in clinical practice is high (up to 10-15% of statin users) especially at muscle level. The review overviews: 1) the known or hypothesised mechanisms through which causal and contributing factors are associated with adverse effects in diabetic people, and 2) the rationale of strategies for managing statin intolerant patients.

In mammals several members of the Transient Receptor Potential channel family (TRPs), expressed mainly in the sensory neurons and skin keratinocytes, are implicated in relevant physiological functions, including thermosensation, nociception and vision. Since the TRPV1-4, TRPA1 and TRPM8 channels from this family play a pivotal role in both the detection and possibly modulation of painful stimuli, they are regarded as a very promising target of novel analgesic drugs. A few agents acting at TRPs, such as capsaicin or menthol, have a long history of their application as analgesics, whereas others (e.g. SB705498, JTS653, JNJ17203212, AP18, A967079, Chembridge-5861528 or PBMC) are currently being evaluated both in animals and in humans. In this review we discuss pain physiology, as well as the pharmacological properties of the TRPs involved in pain detection as potential critical peripheral analgesic targets. We present one of the most relevant strategies in the search for novel analgesic drugs, namely the TRP channels and their ligands, both agonists and antagonists as potential novel therapeutics for inflammatory and neuropathic pain syndromes. The safety profile of these agents, in particular their impact on thermosensation, is also discussed below.

Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitors that can play a major role in tumour development and chronic inflammation. The importance of the suppressive function of MDSCs was first suggested by studies involving cancer patients and cancer-bearing mice. In addition, recent studies have demonstrated that MDSCs can also be involved in many other pathological conditions. MDSCs have unique ways of abrogating an immune response in addition to those utilised by other immune-suppressive cell types, for example via the induction of arginase-1 and consequent upregulation in reactive oxygen species (ROS) production. Due to their heterogeneity, they further can express a variety of lineage markers, which overlap with other myeloid cell types such as Gr1, CD11b, MHCIIlo, Ly6C and Ly6G, making it difficult to identify them by surface phenotype alone. The disparity between mouse and human MDSCs further complicates the identification of these elusive cell populations. In this review, we will summarise the recent updates on the methods for eliciting and studying different MDSC subsets, including newly proposed surface phenotypes, as well as insights into how their function is being characterised in both mice and humans. In addition, exciting new discoveries suggesting their involvement across a number of different pathological settings, such as sepsis, autoimmunity and Leishmaniasis, will be discussed.

The synthesis of polysubstituted imidazopyridines and imidazopyrazines through the orthogonal union of Groebke-Blackburn and Ugi reactions is described. These motifs were produced efficiently in a tandem operation without intermediate isolation. The synthesized scaffolds were biologically evaluated and found to posses potent anticancer and antibacterial activities. Importantly, some of these motifs (e.g. compound 5) were found to possess specific anti-breast cancer activity against MCF7 cell line and others (e.g. compound 15) possess specific effects against melanoma cancer cell line (M8). Interestingly, the introduction of imidazobenzothiazole framework produced compounds with potent anticancer activities (e.g. compounds 29 and 33) in vitro. Interestingly, many of synthesized compounds displayed potent and broad spectrum antibacterial activity against hospital-resistant clinical isolates namely, Escherichia coli, Klebsiella pneuomoniae, Staph. epidermidis, Ps. aeruginosa and Proteus vulgaris. Furthermore, many of the synthesized motifs were found to effective against Gram positive methicillin-sensitive Staphylococcus aureus (MMSA; ATCC 25923), and methicillin-resistant Staphylococcus aureus (MRSA; ATCC 35591). These findings, however, form the foundation for further investigation in our continuing efforts to develop selective anticancer and antibacterial agents.