Current Medicinal Chemistry - Volume 16, Issue 32, 2009

The prevalence of chronic renal disease is increasing dramatically in industrialized nations. Recent surveys in Europe and the US show that about 10% of the total population are affected. Patients with end stage disease, necessitating dialysis or transplantation, are only the tip of the iceberg. Even with treatment these subjects suffer from a massive reduction in quality and quantity of life despite consuming a large proportion of healthcare expenditures. As quite effective treatment strategies are available to prevent progression there is a pressing clinical need for early detection, differential diagnosis and assessment of the individual prognosis of renal disease. The current gold standard is the measurement of serum creatinine; despite the fact this method has some major limitations. These can be partially overcome by the use of newer markers like Cystatin C. However, a major problem using this approach is the fact that serum creatinine and Cystatin C are markers of renal excretory function only and hence no differential diagnosis can be derived from them. Furthermore a single measurement is not sufficient to estimate the prognosis of an individual patient, especially in the early stages of the disease, making tailored treatment difficult. In this review we will summarize our current knowledge about the markers in use today and also provide information on new, potentially superior markers, which would enable a much more complete non-invasive assessment of a growing patient population.

CRH and Urocortins 1, 2 and 3 comprise the, so far identified, members of the CRH family of peptides in humans. Their actions are mediated through two distinct receptors, CRHR1 and CRHR2, encoded by different genes. CRHlike peptides and their receptors have been identified in reproductive tissues, such as the ovary, uterus as well as fetal and placental membranes. The participation of the “CRH family” of peptides and receptors in the physiology of these organs is currently under intense investigation. During the estrus cycle, endometrial CRH acts as a fine tuner of stromal cells decidualization. CRH is produced by embryonic trophoblast and maternal decidual cells and plays important roles in implantation. CRH also participates in the control of trophoblast invasion. Furthermore, placental CRH and Urocortin are involved in the mechanisms controlling maintenance of pregnancy and the onset of labor. The level of participation of urocortins 2 and 3 in these phenomena is currently under investigation. This review will focus on existing data on the expression and regulation of the CRH family of peptides and their receptors in the female reproductive system, as well as in their potential biologic role(s) in human reproductive functions.

Coumarins are of many different structures. They constitute an important class of pharmacological agents possessing a range of different physiological activities including anti-cancer, anti-oxidant, anti-inflammation, anti-HIV, anticoagulant, anti-bacterial, analgesic and comparative immune-modulation. Recently, coumarins have attracted intense research interest. Of great interest is the possibility that this class of molecules could be a source of drugs for the therapy of several diseases. These include recent insights into inhibiting cell proliferation by interfering with mitotic spindle microtubule function, decrease Matrix Metalloproteinase (MMP) activity, block the cell cycle in the S or G2/M phases to interfere with processes of cell division, suppress O2 - generation in leukocytes, inhibit different protein kinases, modulate the signalings, induce carcinogen-detoxifying enzymes glutathione Stransferases (GSTs) and/or NAD(P)H quinine oxidoreductase (NQO1), suppress the phosphorylation of Akt/PKB as a mechanism inhibiting inflammation, progress in structure modification to increase in anti-fungal action, to broaden against bacteria spectrum, to enhance inhibiting activities of nitric oxide synthase (NOS) and cyclooxygenase (COX), to strengthen anti-oxidant activity and to exhibit a much higher cytotoxicity against human umbilical vein endothelial cell (HUVEC). With fewer non-hemorrhagic side effects than the indanedione derivatives, they can be applied as an oral anticoagulant commonly for preventing venous thromboembolism following orthopedic surgery, recurrent myocardial infarction and the treatment of systemic embolism in atrial fibrillation, together with the significant advances in the basis of drug action. It is therefore useful to build up some correlations with the data available in order to better explore the molecular and cellular mechanism of coumarin action in the treatment of diseases. This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.

Nuclear Factor-Kappa B (NF-κB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF- κB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-κB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasomedependent degradation of its inhibitory protein (IκB), resulting in free NF-κB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-κB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-κB. In this article, we present a critical review of the pharmacological agents that have been studied as inhibitors of NF-κB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of κB DNA recognition and binding. Beginning with a general overview of NF-κB pathway and several possibilities of chemical interventions, the significance of redoxregulation in NF-κB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-κB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-κB-inhibitors.

Pharmacological suppression of cyclooxygenase (COX)-1 and -2-mediated prostanoid biosynthesis by non steroidal anti-inflammatory drugs (NSAIDs) is used in the therapy of inflammation, fever, and pain. However, long-term application of these drugs is associated with severe side effects, mainly gastrointestinal injury and renal irritations, apparently due to impaired biosynthesis of physiologically relevant prostanoids. Although COX-2 selective drugs (coxibs) show reduced gastrointestinal complications, recent clinical trials indicated a significantly increased cardiovascular risk. In order to minimize these side-effects, selective suppression of microsomal prostaglandin E2 synthase (mPGES)-1 derived prostaglandin (PG)E2 formation has been considered as alternative to general inhibition of prostanoid biosynthesis. mPGES-1 is functionally coupled to COX-2 being responsible for excessive PGE2 generation connected to pathologies and current knowledge suggests key roles of mPGES-1 in inflammation, pain, fever, atherosclerosis, and tumorigenesis. However, mPGES-1 as promising therapeutic target was questioned because blockade of mPGES-1 allows redirection of the substrate PGH2 to other PG synthases, and the consequences are still elusive. This review summarizes current knowledge about synthetic and natural mPGES-1 inhibitors focusing on structural and mechanistic investigations. Further, the therapeutic efficiency and safety is critically discussed on the basis of cellular and animal studies in which mPGES-1 activity was pharmacologically or genetically (knockout, knockdown) modulated.

Quantitative Structure-Activity Relationships (QSAR) are based on the hypothesis that changes in molecular structure reflect proportional changes in the observed response or biological activity. In order to successfully conduct QSAR studies certain conditions have to be met that are not frequently reported in the literature. This suggests that some authors are not aware of the principle flaws, occasional shortcomings, and circumstantial downsides of QSAR methods. The present paper focuses on prerequisites to set up correct models and on limitations of model applications. Their implications are systematically described and illustrated as pitfalls that have strong implications in QSAR, and possible solutions are suggested. The paper is focused on small scale 2D- and 3D-QSAR studies for lead optimization. The work is enriched with comprehensive comments and non-mathematical explanations for the computer practitioner in Medicinal Chemistry.

Cisplatin is one of the chemotherapeutic agents used the most for testicular, ovarian and several other cancers. In order to overcome cisplatin resistance, other platinum (Pt) compounds have been developed and, in the last ten years, Pt-derivatives with reporting activity have also been synthesized. The first generation of reporting Pt-compounds was based on linking a fluorescent molecule (e.g. cyanine) to cisplatin, but more recent studies have focused on strategies to synthesize intrinsically fluorescent derivatives. Accordingly, bile acid Pt-compounds have shown fluorescence intensity that is stable at room temperature for a long time; this fluorescence is maintained after binding to oligonucleotides or DNA. Because of this, the binding mode of these compounds to DNA can be easily analyzed both by flow injection and fluorescence techniques, showing that although these compounds target the nuclei, they form adducts with the DNA that are different from those due to cisplatin. In line with this, these bile acid derivatives have shown increased cytotoxicity and ability to overcome resistance as compared to cisplatin in several cell lines. Moreover, in contrast to cisplatin, the activity of these compounds does not seem to be restricted to cycling cells but they also seem to kill resting cells. This review summarizes the information available on reporting Pt-compounds and focuses on these novel, intrinsically fluorescent bile acid Pt derivatives, their biochemical characteristics and biological activity.

p53 and its related genes, p73 and p63, are members of the p53 gene family. While p53 is the most frequently mutated gene in human tumors, p73 and p63 are rarely mutated or lost in cancers. Although p53-deficient cancer cells are often less responsive to chemotherapy, they are not completely drug resistant, suggesting that other apoptotic pathways are at work. Interestingly, several studies have shown that p73, and more recently p63, are involved in cellular response to cancer therapy, while others have indicated that p63 and p73 are required for p53-induced apoptosis, delineating functional interplay between p53 family members. The latest reports in this field have established that Nutlin-3, a selective inhibitor of p53-MDM2 interaction, disrupts p73-MDM2 and enhances p73 function in p53-null cells, and that a p53- derived peptide that targets iASPP—a common negative regulator of p53 family members—can trigger cell death via a p73-dependant mechanism. It has also been shown that a small-molecule RETRA suppressed mutant p53-bearing cancers cells through a p73-dependant salvage pathway. Finally, there is increasing evidence that cleaved fragments of p53, p63 and p73 are involved in apoptosis and it remains to be determined whether or not pro-forms of the p53 family play an apoptotic role mediated by cleavage. This review will highlight research into drugs and mechanisms that activate p63 and p73, since these proteins are not mutated in cancers and as such are potential candidates for replacing p53 in p53-deficient cells. It will therefore focus on recent findings in the search for pathways and molecules capable of modulating p53 family protein activities and restoring response to cancer therapy, particularly in tumors bearing p53 mutations.