Current Medicinal Chemistry - Volume 21, Issue 35, 2014

The effectiveness of anticancer therapies relies on the ability of these substances to selectively eliminate the malignant cells with little or no toxicity to normal cells. The isolation in most human tumors of a rare subpopulation of cancer stem cells (CSCs) associated with chemo resistance leads to the “stem cell theory” (SCT). The SCT proposed that eliminating this fraction will eventually cure cancer but experimental data supporting this classical view are controversial and now being gradually replaced by other models. These novel models of cancer biology predict that to cure cancer only drugs or combination of drugs that eliminate all (CSCs and non-CSCs) cancer cells at once (“pankiller drugs”) will be effective. The search for “pankiller drugs” will require tests to assess (i) the elimination of all cancer cells in in vitro systems (ii) the ability to eradicate the tumors and prevent tumor relapse in in vivo systems. However, at present, most drugs are being tested in assays that can only provide a picture of the short term activity of anticancer compounds. This in part explains why only a small fraction of the drugs that enter clinical trials are actually approved for clinical use. This article will provide a concise review of the systems, assays and endpoint parameters routinely used to screen for potential anticancer drugs and propose, based in the current knowledge of cancer biology, a more rationale anticancer drug screening program.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder affecting women in reproductive age. Although the etiology of PCOS remains unclear, it is believed to result from genetic, environmental and behavioral interactions. Women with PCOS have higher lifetime risk for cardiovascular disease (CVR) than healthy women at the same age and tend to display insulin resistance (IR). IR has traditionally been defined as a decreased ability of insulin to mediate the metabolic actions on glucose uptake, glucose production, and/or lipolysis. This results in a requirement for increased amounts of insulin to achieve a given metabolic action. Metabolic syndrome (MS) includes hyperinsulinemia, dyslipidemia, increased CVR and hyperleptinemia and metabolic disorders such as hypertension, IR, gestational diabetes, type 2 diabetes mellitus, systemic inflammation and endothelial dysfunction. The prevalence of MS in women is around 50 %. In addition, it has been recently suggested that women with MS show increased circulating androgens. The present review discusses the main alterations and features of PCOS and MS and the most important treatments.

Inhibition of DPP-IV enzyme has taken centre stage as a validated drug target for type 2 diabetes therapy and as a result of research efforts done towards developing effective DPP-IV inhibitors, the first clinical candidate of this class came in focus in 1998. Thus, from 1998 to 2013, these 16-years have witnessed heightened research activities in the discovery and development of clinically relevant inhibitors of DPP-IV as antidiabetic agents. The effective DPP-IV inhibitors have played a key role in this endeavour and as result there are eight approved gliptins in the clinical usage while others are in different stages of clinical trials. A wide variety of DPP-IV inhibitors were synthesized and evaluated; and were classified into several categories based on their core structural features. In this article, classification of all the clinically relevant DPP-IV inhibitors based on selectivity, clinical efficacy and safety profiles is reviewed in terms of generations. This review also encompasses clinical phase wise discussion, developmental progress, chemistry and binding modes of all clinical DPP-IV inhibitors. In addition, major challenges facing the future design and development of safe clinical DPP-IV inhibitor are also briefly mentioned.

In the last decades, the cannabinoid system (comprising synthetic and endogenous cannabinoid agonists and antagonists, their receptors and degrading enzymes) has been shown to induce potent immunomodulatory activities in atherogenesis and acute ischemic complications. Different from the other cannabinoid receptors in which controversial results are reported, the selective activation of the cannabinoid receptor type 2 (CB2) has been shown to play antiinflammatory and protective actions within atherosclerotic vessels and downstream ischemic peripheral organs. CB2 is a transmembrane receptor that triggers protective intracellular pathways in cardiac, immune and vascular cells in both human and animal models of atherosclerosis. Considering basic research data, medications activating CB2 function in the circulation or peripheral target organs might be a promising approach against atherogenesis. This review updates evidence from preclinical studies on different CB2-triggered pathways in atherosclerosis and acute ischemic events.

Photodynamic therapy (PDT) is a novel medical technique involving three key components: light, a photosensitizer molecule and molecular oxygen, which are essential to achieve the therapeutic effect. There has been great interest in the use of PDT in the treatment of many cancers and skin disorders. Upon irradiation with light of a specific wavelength, the photosensitizer undergoes several reactions resulting in the production of reactive oxygen species (ROS). ROS may react with different biomolecules, causing defects in many cellular structures and biochemical pathways. PDT-mediated tumor destruction in vivo involves cellular mechanisms with photodamage of mitochondria, lysosomes, nuclei, and cell membranes that activate apoptotic, necrotic and autophagic signals, leading to cell death. PDT is capable of changing the tumor microenvironment, thereby diminishing the supply of oxygen, which explains the antiangiogenic effect of PDT. Finally, inflammatory and immune responses play a crucial role in the long-lasting consequences of PDT treatment. This review is focused on the biochemical effects exerted by photodynamic treatment on cell death signaling pathways, destruction of the vasculature, and the activation of the immune system.

Tuberculosis continues to be a deadly infectious disease, mainly due to the existence of persistent bacterial populations that survive drug treatment and obstruct complete eradication of infection. The enzymes GlgE and GlgB, which are involved in the glycan pathway, have recently been identified as promising drug targets for combating persistent bacillus strains. In the glycan pathway, enzymes GlgE, GlgA, and Tre-xyz produce linear α-glucans, which are then converted to essential branched α-glucan by GlgB. This α-glucan is a vital cell-wall and storage polysaccharide, critical for Mtb virulence and persistence. We highlight recent insights into the significance of both GlgE and GlgB in the glycan pathway and also discuss drug strategies for tuberculosis such as polypharmcological targeting of GlgB and GlgE. Small molecule-based modulation of GlgB and GlgE to boost the design and development of novel and improved drugs for more selective and efficient targeting of tuberculosis are also discussed.

Intravascular substances invade extracellular spaces in the brain via endothelial cells in the sites without bloodbrain barrier (BBB) and move not only in the cerebrospinal fluid (CSF) but also in the interstitial fluid (ISF) of brain parenchyma adjacent to non-BBB sites. It is likely that CSF drains directly into the blood via arachnoid villi and granulations and also to lymph nodes via subarachnoid spaces in the brain and nasal lymphatics, whereas ISF drains to cervical lymph nodes through pathways along vascular wall of capillaries and arteries. As the supposed pathways of fluids seem to be critical for the maintenance of normal brain function, it is reasonable to suspect that an obstacle to the passage of fluids through these pathways likely induces some kinds of brain dysfunction such as Alzheimer’s disease. According to assumed pathways for the elimination of amyloid-β (Aβ) from the brain, Aβ peptides produced mainly in neurons are degraded by peptidases, flow out of the brain parenchyma into the blood through efflux transporters located in cerebral vessels, drain through perivascular pathways into the cervical lymph nodes, or are taken up by some kinds of cells in the brain. As for the perivascular pathways, ISF including Aβ peptides diffuses in the extracellular spaces of the brain parenchyma, enters basement membranes of capillaries, passes into the tunica media of arteries, and drains out of the brain. In this review, these pathways for the clearance of fluids including Aβ from the brain into the blood are briefly reviewed and the relationship between dysfunction of these pathways and brain diseases is discussed.