Current Medicinal Chemistry - Volume 16, Issue 4, 2009

Stem cells are defined by their unique property to self-renew and starting from one single cell to generate all the different progenies required for tissue regeneration. In adults, stem cells are still present in the majority of tissues and organs where they are responsible for continuous organs and tissues homeostasis. Adult stem cells have been isolated in various tissues and all share common specific characteristics (localization in stem cell niches, drug transporter expression, adhesion, levels of apoptosis inhibitors, DNA methylation, …) involved in high levels of drug resistance of this specific cell subtype. Several studies have identified different populations of cancer cells, within the same tumor, some of them which present properties closely related to normal stem cells and raised the concept of cancer stem cells. Interestingly, the cell surface markers expressed by these particular cancer cells are the same as those expressed by normal stem cells, suggesting that cancer can arise in some cases from the malignant transformation of stem cells. The cancer stem cell (CaSC) model predicts that, even if “conventional” cancer cells can be killed by chemotherapy or radiotherapy, only the destruction of CaSC, considered responsible for relapse, will allow full recovery, thus demonstrating the importance of CaSCtargeting for patient outcome. Therapeutic innovations will emerge from a better understanding of the biology and environment of cancer stem cells. The tumor environment can create a niche favoring the survival and proliferation of CaSC. It also protects CaSC from chemotherapy- induced apoptosis. Clinically, it is crucial to get rid of quiescent and resistant cells and to adapt the therapeutic strategy to cancer stem cells sheltered in niches. Here, we review the major characteristics of cancer stem cells and their behavior in response to chemotherapy; we also highlight the main issues to be considered for efficient and specific cancer stem cell targeting.

Nitric oxide (NO) is a diffusible, short-lived, diatomic free radical ubiquitously produced by mammalian cells. The generation of NO from L-arginine is enzymatically regulated by three different isoforms of NO synthases. The NO signaling pathway involves mainly the activation of soluble guanylyl cyclase to produce cyclic GMP (cGMP) as a second messenger and downstream mediator. In addition, the free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. NO is a pleiotropic biomodulator in several systems, including the cardiovascular, nervous and immune systems. In the hematopoietic system, NO is thought to be an autocrine or paracrine messenger but also an intracellular effector molecule. Megakaryopoiesis and subsequent thrombopoiesis occur through complex biologic steps that involve hematopoietic stem cell commitment to megakaryocytic lineage, megakaryocyte maturation and finally, platelet release. Here, we summarize the current knowledge regarding the role of exogenous and endogenous NO in hematopoietic stem cell biology, megakaryocyte development and platelet biogenesis as well as relevance of plateletderived NO generation on platelet function. Dysregulation of NO synthesis has been observed in several diseases, and the evaluation of a series of pharmacological agents with the ability to modulate the NO/cGMP pathway in platelets will also be discussed.

RNA polymerase (RNAP) currently represents an important target for the development of new antibacterial agents. RNAP is a nucleotidyl transferase enzyme able to generate an RNA copy of a DNA or RNA template chain, controlling initiation and termination of transcription. RNAP is found in nature in all eukaryotes, prokaryotes and archaea, as well as in many viruses. Bacterial RNAP is a large molecule (about 400kDa) and its core structure is composed of four polypeptide subunits: alpha (α) required for assembly of the enzyme, beta (β) involved in chain initiation and elongation, beta' (β') which binds to the DNA template, and omega (ω) which constrains the β' subunit and aids its assembly into RNAP, in the stoichiometry α2ββ'ω. The bacterial enzyme differs both from eukaryotic RNAP, which is composed of different subunits and is present in several variants, and from archaeal or viral RNAP. These differences allow to selectively target the bacterial enzyme with appropriately designed inhibitors, excluding interactions with eukaryotic RNAP, accounting for the deep interest developed around these compounds as selective antibacterial agents. In this review the known natural and synthetic inhibitors of RNAP will be described considering their mechanism of action, biological activity, availability of analogues, Structure Activity Relationship (SAR) information and clinical use when already approved or recently entered into clinical trials.

The term “neuroactive steroid” (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. These steroids positively or negatively modulate the function of members of the ligand-gated ion channel superfamily. Those with positive allosteric actions on the γ-amino butyric acid type A receptor (GABAA receptor) have been shown to be potent anticonvulsants, anxiolytics, and antistress agents and to possess sedative, hypnotic, and anesthetic activities. New types of neuroactive steroids have been widely sought and structural modifications of the naturally occurring metabolites allopregnanolone, pregnanolone and allotetrahydrodeoxycorticosterone, have been examined in the light of the vast family of GABA receptor subtypes within the brain. Here we review the structure-activity relationship (SAR) of neuroactive steroid analogues obtained by modification of the steroid nucleus, including substitutions at the A, B, C, and D rings and the side chain, with emphasis on the different pharmacophores proposed.

Inhibition of carbohydrate processing enzymes is a topic of great interest, as these enzymes are involved in a plethora of key biochemical events, such as digestion, lysosomal catabolism of glycoconjugates and post-translational glycoprotein processing. Among the most potent inhibitors of such enzymes, iminosugars have emerged as versatile tools for medicinal chemists, especially those in quest for new therapeutic agents. Supply of iminosugars from natural sources or by chemical synthesis has provided excellent targets for medical intervention, ranging from antidiabetics and antivirals to inhibitors of genetic disorders. Although a huge body of literature has been reported around iminosugars, most data have focused on D-series iminosugars, whereas relatively little attention has been devoted to the corresponding L-enantiomers, due to their supposed lack of biological activity profile, as well as their scarce availability from natural sources. Notwithstanding, recent insights into the molecular details of enzyme-inhibitor interactions have led to a reassessment of L-iminosugars for pharmaceutical purposes. On one hand, they have been used as tools for intensive SAR (structure-activity-relationship) studies, in order to gain new information on the enzymatic inhibition mechanisms. Likewise, early reports on biological activity of Liminosugars have led to reconsider their therapeutic skills. This review focuses on the most significant discoveries regarding medicinal chemistry of L-iminosugars. The important role L-iminosugars play in unravelling the inhibition mechanisms of specific enzymes is herein recognized; moreover, the high potential of this class of inhibitors as novel drug candidates is under discussion.

Obesity is an increasingly serious socioeconomic and clinical problem. Between 1/4 - 1/3 of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.