Current Medicinal Chemistry (v.21, #35)

The effectiveness of anticancer therapies relies on the ability of these substances to selectively eliminate themalignant cells with little or no toxicity to normal cells. The isolation in most human tumors of a rare subpopulation ofcancer stem cells (CSCs) associated with chemo resistance leads to the “stem cell theory” (SCT). The SCT proposed thateliminating this fraction will eventually cure cancer but experimental data supporting this classical view are controversialand now being gradually replaced by other models. These novel models of cancer biology predict that to cure cancer onlydrugs 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 drugsare being tested in assays that can only provide a picture of the short term activity of anticancer compounds. This in partexplains why only a small fraction of the drugs that enter clinical trials are actually approved for clinical use. This articlewill provide a concise review of the systems, assays and endpoint parameters routinely used to screen for potential anticancerdrugs and propose, based in the current knowledge of cancer biology, a more rationale anticancer drug screeningprogram.

Association Between Polycystic Ovary Syndrome and Metabolic Syndrome by Leandro Martin Velez, Alicia Beatriz Motta (3999-4012).
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder affecting women inreproductive age. Although the etiology of PCOS remains unclear, it is believed to result from genetic, environmental andbehavioral interactions. Women with PCOS have higher lifetime risk for cardiovascular disease (CVR) than healthywomen at the same age and tend to display insulin resistance (IR). IR has traditionally been defined as a decreased abilityof insulin to mediate the metabolic actions on glucose uptake, glucose production, and/or lipolysis. This results in a requirementfor increased amounts of insulin to achieve a given metabolic action.;Metabolic syndrome (MS) includes hyperinsulinemia, dyslipidemia, increased CVR and hyperleptinemia and metabolicdisorders such as hypertension, IR, gestational diabetes, type 2 diabetes mellitus, systemic inflammation and endothelialdysfunction. The prevalence of MS in women is around 50 %. In addition, it has been recently suggested that women withMS show increased circulating androgens. The present review discusses the main alterations and features of PCOS andMS and the most important treatments.

Inhibition of DPP-IV enzyme has taken centre stage as a validated drug target for type 2 diabetes therapy andas a result of research efforts done towards developing effective DPP-IV inhibitors, the first clinical candidate of this classcame in focus in 1998. Thus, from 1998 to 2013, these 16-years have witnessed heightened research activities in the discoveryand development of clinically relevant inhibitors of DPP-IV as antidiabetic agents. The effective DPP-IV inhibitorshave played a key role in this endeavour and as result there are eight approved gliptins in the clinical usage while othersare in different stages of clinical trials. A wide variety of DPP-IV inhibitors were synthesized and evaluated; and wereclassified into several categories based on their core structural features. In this article, classification of all the clinicallyrelevant 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 allclinical DPP-IV inhibitors. In addition, major challenges facing the future design and development of safe clinical DPP-IVinhibitor are also briefly mentioned.

Cannabinoid Receptor Type 2 Activation in Atherosclerosis and Acute Cardiovascular Diseases by Federico Carbone, Francois Mach, Nicolas Vuilleumier, Fabrizio Montecucco (4046-4058).
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 inatherogenesis and acute ischemic complications. Different from the other cannabinoid receptors in which controversial resultsare reported, the selective activation of the cannabinoid receptor type 2 (CB2) has been shown to play antiinflammatoryand protective actions within atherosclerotic vessels and downstream ischemic peripheral organs. CB2 is atransmembrane receptor that triggers protective intracellular pathways in cardiac, immune and vascular cells in both humanand animal models of atherosclerosis. Considering basic research data, medications activating CB2 function in thecirculation or peripheral target organs might be a promising approach against atherogenesis. This review updates evidencefrom preclinical studies on different CB2-triggered pathways in atherosclerosis and acute ischemic events.

Cellular Changes, Molecular Pathways and the Immune System Following Photodynamic Treatment by P. Skupin-Mrugalska, L. Sobotta, M. Kucinska, M. Murias, J. Mielcarek, N. Duzgunes (4059-4073).
Photodynamic therapy (PDT) is a novel medical technique involving three key components: light, a photosensitizermolecule and molecular oxygen, which are essential to achieve the therapeutic effect. There has been great interest inthe 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 mayreact with different biomolecules, causing defects in many cellular structures and biochemical pathways. PDT-mediatedtumor destruction in vivo involves cellular mechanisms with photodamage of mitochondria, lysosomes, nuclei, and cellmembranes that activate apoptotic, necrotic and autophagic signals, leading to cell death. PDT is capable of changing thetumor 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 reviewis focused on the biochemical effects exerted by photodynamic treatment on cell death signaling pathways, destructionof the vasculature, and the activation of the immune system.

α-Glucan Pathway as a Novel Mtb Drug Target: Structural Insights and Cues for Polypharmcological Targeting of GlgB and GlgE by Pushpa Agrawal, Pawan Gupta, Kunchithapadam Swaminathan, Raman Parkesh (4074-4084).
Tuberculosis continues to be a deadly infectious disease, mainly due to the existence of persistent bacterialpopulations 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 persistentbacillus strains. In the glycan pathway, enzymes GlgE, GlgA, and Tre-xyz produce linear α-glucans, which are thenconverted to essential branched α-glucan by GlgB. This α-glucan is a vital cell-wall and storage polysaccharide, criticalfor Mtb virulence and persistence. We highlight recent insights into the significance of both GlgE and GlgB in the glycanpathway and also discuss drug strategies for tuberculosis such as polypharmcological targeting of GlgB and GlgE. Smallmolecule-based modulation of GlgB and GlgE to boost the design and development of novel and improved drugs for moreselective and efficient targeting of tuberculosis are also discussed.

Clearance of Beta-Amyloid in the Brain by Masaki Ueno, Yoichi Chiba, Koichi Matsumoto, Toshitaka Nakagawa, Hiroshi Miyanaka (4085-4090).
Intravascular substances invade extracellular spaces in the brain via endothelial cells in the sites without bloodbrainbarrier (BBB) and move not only in the cerebrospinal fluid (CSF) but also in the interstitial fluid (ISF) of brain parenchymaadjacent to non-BBB sites. It is likely that CSF drains directly into the blood via arachnoid villi and granulationsand also to lymph nodes via subarachnoid spaces in the brain and nasal lymphatics, whereas ISF drains to cervicallymph nodes through pathways along vascular wall of capillaries and arteries. As the supposed pathways of fluids seem tobe critical for the maintenance of normal brain function, it is reasonable to suspect that an obstacle to the passage of fluidsthrough these pathways likely induces some kinds of brain dysfunction such as Alzheimer's disease. According to assumedpathways for the elimination of amyloid-β (Aβ) from the brain, Aβ peptides produced mainly in neurons are degradedby 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 thebrain. 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. Inthis review, these pathways for the clearance of fluids including Aβ from the brain into the blood are briefly reviewed andthe relationship between dysfunction of these pathways and brain diseases is discussed.