Current Medicinal Chemistry - Volume 20, Issue 2, 2013

This review summarizes the progress that has been made recently in the medicinal chemistry of cantharidin, a potent antitumor agent from traditional Chinese medicine. Thousands of analogs have been synthesized on the basis of cantharidin, a part of which shows excellent properties, in particular, norcantharidin and norcantharimide. Despite the enormous efforts made, the intriguing bioactivities, mechanism, indications, and their interplay are still ill-defined. This review provides our up-to-date understanding in connection with the therapeutic use, mechanism, structure-activity relationship (SAR) and interesting properties of cantharidin analogs. Considerable development in the design of cantharidin analogs, in combination with mechanistic studies, has laid a foundation for transforming novel antitumor drugs into the clinic.

Epigenetics is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo covalent modifications of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, including cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification has emerged only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks.

One part of chemical space that is endowed with interesting biological properties is the area of the chalcones. With this review, we provide a comprehensive overview of the numerous in vivo animal studies on the antineoplastic potential of both natural and synthetic members of this flavonoid subclass (covering: up to mid-2011). The thus far identified modes of action of these compounds are also discussed. We hope that this overview may stimulate deeper investigations into the biochemical mechanisms by which chalcones exert their antineoplastic action. As a result, in the foreseeable future, chalcones may prove suitable lead molecules or early drug candidates for the prevention or treatment of various neoplastic diseases.

The design and development of radiolabelled steroid derivatives has been an important area of research due to their wellknown value in breast cancer targeting. The estrogen receptor (ER) and progesterone receptor (PR) are important biomarkers in the diagnosis, prognosis and follow-up of the therapeutic response of breast tumours. Thus, several radioligands based on estrogens and progestins have been proposed for targeted functional ER imaging. The aim of this review is to survey and analyze the developments in this field, which have led to the design of a number of PET steroid-based imaging agents, a few of which seem to be promising as radiopharmaceuticals for detection of ER-positive breast tumours.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRβ) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.

Over the last decades there has been a change in biomedical research with the search for single genes, transcripts, proteins, or metabolites being substituted by the coverage of the entire genome, transcriptome, proteome, and metabolome with the “omics” approaches. The emergence of metabolomics, defined as the comprehensive analysis of all metabolites in a system, is still recent compared to other “omics” fields, but its particular features and the improvement of both analytical techniques and pattern recognition methods has contributed greatly to its increasingly use. The feasibility of metabolomics for biomarker discovery is supported by the assumption that metabolites are important players in biological systems and that diseases cause disruption of biochemical pathways, which are not new concepts. In fact, metabolomics, meaning the parallel assessment of multiple metabolites, has been shown to have benefits in various clinical areas. Compared to classical diagnostic approaches and conventional clinical biomarkers, metabolomics offers potential advantages in sensitivity and specificity. Despite its potential, metabolomics still retains several intrinsic limitations which have a great impact on its widespread implementation - these limitations in biological and experimental measurements. This review will provide an insight to the characteristics, strengths, limitations, and recent advances in metabolomics, always keeping in mind its potential application in clinical/ health areas as a biomarker discovery tool.

A number of prenylated phenols, mainly flavonoids, have been identified as active constituents of medicinal plants. Due to their beneficial effects on human health, this class of compounds has received a great deal of attention, not only from the pharmaceutical industry, but also from other areas of applied sciences, including the food, brewing, and cosmetics industries. The addition of prenyl residues through the activity of isoprenyltransferases, the key biosynthetic enzymes for these plant metabolites, endows flavonoids with a variety of biological activities, mostly due to improved interaction with membranes and proteins. The role of prenylated flavonoids in plants correlates with their activities as antioxidant or anti-infectious agents. In connection with these effects, these compounds have been evaluated for multiple potential uses, e.g. as antibacterial, antiprotozoal, antifungal, anti-inflammatory, antitumor, estrogenic, antidiabetic, or antithrombotic agents, among others. The present review, in principle focused on phenolic derivatives containing a non-cyclized isoprenyl chain, discusses the most relevant pharmacological reports for the period 2005-2012.

Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in biological fluids, vascular endothelium, heart, and kidneys. Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb3, increased concentrations of globotriaosylsphingosine (lyso-Gb3) have recently been reported in urine and plasma of Fabry patients. The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb3 analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb3 molecule minus two hydrogen atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb3 sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb3 analog. None of these analogs was detected in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers.

Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds. The pharmacological potencies of a series of substituted N-[3-(3-methoxyphenyl)propyl] amides towards human melatonin MT1 and MT2 receptors were evaluated by the FLIPR high-throughput screening assay, whilst their subtype-selectivity was subsequently verified with ERK phosphorylation and cAMP assays. Structure-activity relationship analysis of highly potent subtype-selective ligands (MT2 EC50 10-90 pM) revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT2 potency and at the same time decreased MT1 potency. Incorporation of structural moieties conferring the subtype selectivity produced several extremely potent MT2-selective ligands. The most potent subtype-selective ligand, 2q had a substantially higher potency for MT2 receptor than melatonin for elevation of [Ca2+]i and inhibition of forskolin-elevated cAMP. Representative MT2-selective ligands also induced ERK phosphorylation in both recombinant and native cell lines, and no cross-reactivity to 17 other GPCRs could be detected. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes and are viable candidates for drug development.

Schistosomiasis is one of the world's major public health problems, and praziquantel is the only available drug to treat this notable neglected disease. Drug combinations have been considered an important strategy for treatment of infectious diseases, which might enhance therapeutic efficacy and delaying resistance. In this study, we have examined the in vitro activities of the amide piplartine and the antimicrobial peptide dermaseptin 01 administered singly or in combination against Schistosoma mansoni of different ages including 3-hour-old and 7-day-old schistosomula and 49-day-old adult schistosomes as well as on egg output by adult worms. We calculated the median lethal concentrations (LC50) of 7.87 and 17.99 μM on 49-day-old adults, 11.02 and 71.58 μM on 7-day-old schistosomula, and 70.87 and 98.42 μM on 3-hour-old schistosomula for piplartine and dermaseptin, respectively. Most Piplartine/dermaseptin combinations showed synergistic effect, with combination index (CI) values less than 0.9 when S. mansoni adults or schistosomula were simultaneously incubated with both drugs in vitro; synergy between these two compounds was also indicated using isobolograms. Additionally, we observed alterations on the tegumental surface of schistosomula and adult schistosomes by means of laser scanning confocal microscopy. Furthermore, egg laying of surviving worms was considerably more reduced when exposed to the piplartine/dermaseptin combinations than each drug alone, and this inhibition was irreversible. This is the first report on the synergistic effect between piplartine and dermaseptin against S. mansoni and opens the route to further studies (e.g. in vivo) to characterize this combination in greater detail.