Current Medicinal Chemistry - Volume 18, Issue 32, 2011

Genito-urinary malignancies (prostate, bladder, renal and testicular cancers) rank high among human tumors with an incidence that varies with age and organ involvement. Prostate cancer is the most commonly detected male cancer followed by bladder and kidney cancers, less frequent in women. Testicular cancer, although rare, is the most frequent cancer in males under 35. The majority of oncogenic and tumor suppressor signaling pathways involved with urogenital cancers converge on sets of transcription factors that ultimately control gene expression resulting in tumor formation and metastatic progression. The activity of these transcription factors is modulated by multiple mechanisms spanning from transcriptional regulation, deregulation of the splicing, maturation, export and location of mRNAs, protein synthesis and post-translational modifications. The recent involvement of the epigenitic mechanisms in the generation and the evolution of cancer has produced a great deal of interest. This is related to the possibility that revealing these mechanisms able to regulate the cell memory program (the gene systems polycomb, trithorax and HOX) may generate important biological and therapeutic achievements. The HOX gene network is the only physically and functionally identifiable transcription factor network located in the human genome controlling crucial cellular processes. Here we describe the implication of the HOX genes in the urogenital embryonic development and cancers. We further highlight the mechanisms uncovered along these processes and involving the HOX genes. Finally, we foresee the specific targeting of HOX genes and in general the cell memory gene program in the therapeutic setting of urogenital malignancies due to their upstream location in these stepwise cell processes and their early deregulation in cancer evolution.

About one hundred and fifty of the several thousands of drugs on the market are known to have active metabolites. Medicinal chemistry of the parent drugs as well as that of the metabolites are very important both in medical practice and drug research. The efficacy of a drug will depend on a number of properties including, pharmacokinetic behavior, absorption, tissue distribution, pharmacological potency, toxicity and tissue-specificity. The production and release of active metabolites are important because active drug metabolites may influence the clinical outcome of a drug by increasing the gross level of pharmacologically active compounds (drug + active metabolite) and/or essentially increasing the duration of drug effect, when t1/2 of active metabolite is much longer than that of the parent drug. Furthermore, certain drug metabolizing enzymes can either be inhibited or induced by other drugs and a variety of food and environmental factors. A careful control of the clinical effects of any drug with active metabolites is important especially in the treatment of the elderly population where the administration of several drugs is not unusual. This review provides a detailed description of the medicinal chemistry of drugs yielding active metabolites after undergoing transformation via aliphatic and aromatic oxidations, epoxidation and S-oxidation. Their respective pharmacologically active metabolites, metabolizing enzymes and changes in lipophilicity are also summarized. The most recent analytical methods used for the reliable quantification of both the parent drugs and their metabolites are also included.

Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

Since the subtypes of α1-adrenergic receptor have been thoroughly determined, to date medicinal chemists raise their deliberation on how to conceive selective α1-adrenergic receptor antagonist with the minimal side effects. It needs to be well recognized that natural products can exist as a significant source of drug leads, thus portraying a consequential capacity in drug design and development. The current review article would like to present a comprehensive survey on natural products, mainly including alkaloids and flavonoids, which exhibit α1-adrenergic receptor antagonistic activities.

We describe the alterations of classical neurotransmitters and neuropeptides in generalized epilepsy. A neuronal network in this disease is developed. Gamma aminobutyric acid (GABA) hypoactivity induces dopamine hyperactivity because dopaminergic neurons are affected by the inhibitory influence of the GABAergic system through GABAA receptors. Glutamate hyperactivity is exerted via presynaptic N-methyl-D-aspartate (NMDA) receptors, which strongly inhibit serotoninergic neurons, and via postsynaptic ionotropic glutaminergic receptors, which can induce epileptic seizures. A collection of specific subreceptors of classical neurotransmitters and neuropeptides involved in epileptogenesis is reported. The question arises whether agonists/antagonists of neuropeptides (neuropeptide Y, galanin…) could have additional antiepileptic properties. The effect of conventional and newer antiepileptic drugs interfering with these subreceptors is discussed on the basis of the neuronal network suggested. From these data, it is concluded that new antiepileptic drugs interfering with other specific subreceptors (GABAB antagonists, metabotropic glutaminergic receptors subtype 5 (mGlu5R) antagonists, mGlu2/3R agonists, 5-serotonin (5-HT7) agonists) could further stabilize the neuronal network in generalized epilepsy.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H3 receptor antagonism, cannabinoid CB1 receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

The richly structured neuroendocrine control of the heart in health and disease requires, in addition to the autonomic nervous outflow, the essential contribute of various and often interacting humoral peptides (e.g. natriuretic peptides, Chromogranin-A-derived fragments, etc). In many cases, these molecules also influence the activity of other organ systems, including the gastrointestinal apparatus, in which they control mucosal function as well as motility and secretion. Interestingly, by acting centrally, some of these peptides also regulate satiety and appetite, thus forming an interesting link between cardiac and gastrointestinal function, and the feeding pattern. Prolonged inhibition and/or activation of these peptide pathways frequently results in severe and long-lasting dysfunctions, including cardiovascular diseases associated to alimentary disorders (e.g. obesity). Notably, their multifarious actions and mutual interactions make them excellent candidates for long-term resetting of both cardiac, gastrointestinal and nutrition homeostasis. Here we will provide only few examples taken from the quickly evolving scenario, with the purpose to provide indications concerning the complex circuits generated by multilevel signalling peptides, which contributes to orchestrate the association between cardiovascular, gastrointestinal and alimentary functions. This will highlight not only the complexity of the cardiovascular and GI regulatory networks, but also aspects of integration between feeding stimulating peptides and the other neuroendocrine systems affecting the heart and the GI tract.

Fatty livers are more prone to damage caused by ischemia/reperfusion (I/R). Impaired microcirculation, Kupffer cell dysfunction, increased adhesion of leukocytes, impaired mitochondrial function and ATP depletion are probable causes for fatty liver susceptibility. Therefore, hepatic steatosis is a major risk factor for liver surgery and success of transplantation of fatty donor organs. The mechanisms involved in I/R injury are complex and there is no general consensus regarding the sources of ROS generation, nitric oxide (NO) action, the role of tumor necrosis factor-α (TNF-α), and transcription factors, such as nuclear factor kappa B (NFκB). Impairment of mitochondrial function is one of the most important alterations that occur in I/R injury, resulting in the alteration of energy metabolism. Ischemic preconditioning (IPC) and post conditioning (IPost) are adaptive mechanisms against I/R insults that induce intracellular protective responses associated with the preservation of mitochondrial function. There are several pharmacological drugs and natural derivatives presenting metabolic and/or antioxidant effects that can directly or indirectly protect the liver against I/R injury. While the precise targets and mechanisms are still not totally understood, the mitochondrion presents itself as a major player on mediating these protective events. As so, compounds that are able to improve mitochondrial function and hepatic energetic balance might prove viable candidates when developing new pharmacological approaches that can minimize injury to steatotic livers subjected to I/R events.

Aptamers are single-stranded oligonucleotides (ssDNA or RNA) selected from combinatorial libraries by an in vitro process and possess a specific three-dimensional structure depending on its sequence. These molecules are able to recognize and, eventually, alter the activity of their targets by binding directly in a similar way to antibodies. Over the last years, aptamer technology has been used in a wide range of diagnostic and therapeutic applications and, concretely, several strategies are currently being explored using aptamers against Plasmodium and trypanosomatid proteins associated with parasitic diseases which affect hundreds of millions people. One approach tries to block the interaction between the parasite and the host using aptamers targeting host-cell matrix receptors. A second strategy consists in attack the parasite intracellularly targeting heme group or interfering in the intracellular RNA transport. In another strategy, aptamers targeting invariant polypeptides could be used as a specific drug delivery system into the parasite. Finally, aptamers addressed to re-direct the immune response of the infected host are being studied. Other potential use of the aptamers is as biorecognition element in diagnostic systems for parasitic diseases. In this paper, we briefly review how aptamers against Plasmodium and trypanosomatids are discovered, with a focus on recent advances that improve the aptamers properties as a real tool for parasite fighting.

APN is an important zinc dependent metallo-exopeptidase, which can degrade the extracellular matrix, and plays an important role in tumor invasion, metastasis and angiogenesis. it has been considered as a suitable target for anti-cancer drug design. Recently, research of structure-based APN inhibitors is becoming an interesting field, and many APN inhibitors have been reported. Here we review a series of APN inhibitors and the recent progress in this field.