Current Medicinal Chemistry - Volume 20, Issue 16, 2013

The tyrosine kinase epidermal growth factor receptor (EGFR) has emerged in recent years as a key and validated target of targeted therapies for solid tumors. It plays a central role in oncology since it is involved in many steps of tumor progression such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Recent advances in targeted therapies have demonstrated that tyrosine kinase inhibitors (TKIs), have provided a marked benefit to subsets of patients whose tumors harbor specific genetic abnormalities. However, resistance phenomenon appears rapidly and patients with EGFR mutations acquire resistance to TKI inhibitors decreasing therefore the median time to disease progression to few months. Several strategies were envisioned to overcome this resistance, such as dual–target inhibitors, multitarget and combined therapy. This review summarizes recent advances in TKIs development with special focus on rational strategies for the design of potent EGFR inhibitors including molecular modeling studies based on crystallographic data. Such advances open the way for new research possibilities in modern medicinal chemistry combined to structure-based drug design.

Despite the great efforts put into their development, the list of clinically approved immunological adjuvants is still very short. Evolution of the knowledge of the immune system has enabled for rational design of novel adjuvants and has led to the conclusion that more than one type of adjuvant will be required. Derivatives of muramyl dipeptide (MDP), the minimal immunomodulatory structure of bacterial cell wall peptidoglycan, have gained considerable attention in the past decades, because of their potent adjuvant effects. Murabutide is a safe derivative of MDP, which interacts with cells of the immune system, both innate and adaptive, and exerts its effect through activation of Nod2. The transcriptional response of murabutide–stimulated macrophages revealed enhanced expression of genes coding for various proteins such as immune mediators and their receptors, transcription factors and kinases, ion channels-transporters and proteins involved in cell metabolic activity, thus reflecting a broad spectrum of biological effects. In addition to its well recognized adjuvant effect, murabutide has also been shown to enhance the host's resistance against microbial infections, nonspecific resistance against tumors and the induction of cytokines and chemokines implicated in enhancing the immune response and hematopoesis. This article provides an insight into the mechanism of action of murabutide and its interactions with the cells of the immune system in vitro and in vivo. On account of its numerous biological effects, murabutide has been the subject of several clinical studies. Many of these have confirmed its potential to synergize with cytokines of therapeutic interest in potentiating the tumoricidal activity of macrophages or targeting chronic viral diseases, as well as reducing the cytokine dosage needed to achieve a therapeutic effect. This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases.

The plethora of biological activities of 1,25(OH)2D3 and its analogs suggests an enormous potential for vitamin D therapy in the treatment of hyperproliferative diseases (cancer, psoriasis), endocrine dysfunction (hyperparathyroidism), immune disorders (autoimmune diseases, transplant rejection), bone disorders (osteoporosis, Paget's bone disease). However, the therapeutic limitation of 1,25(OH)2D3 is its calcemic and phosphatemic activities, since it can cause serious side effects such as hypercalcemia and hyperphosphatemia at super physiological levels. Therefore, numerous efforts have been made to find the new vitamin D analogs, that retain the therapeutically important properties of 1,25(OH)2D3 but with greater selectivity, which allows more effective intervention with fewer toxic side effects. This review will focus on the biological activities of the 2–substituted analogs of 1,25(OH)2D3. They were classified as 2α–, 2β–, 2,2–disubstituted analogs, and those with modifications in both the A–ring at the 2–position and the side chains. Their structure–activity relationships and binding features with the vitamin D receptor (VDR) were discussed.

Metals and their complexes with organic ligands have an important role in biochemical systems such as enzymatic catalysis, metal ion transfer across the cell membranes, treatment of malignancy, rheumatoid arthritis, ulcer and other types of diseases. Special attention is directed to metal complexes with ligands which are important in biological systems, as their incorporation into metallo–organic compounds offers much scope for design of potential metal–based agents that provide new opportunities in the medicinal chemistry. In view of this, derivatives of aminophosphonic acids, owing to their broad spectrum of biological activities and wide range of applications in the medicinal and agrochemical fields, are very attractive metal–ligand agents that might form biomedical important metal complexes. Thus, a number of aminophosphonate complexes of platinum group metals have been found to possess remarkable antitumor activity while complexes of some other transition and rare–earth metals like technetium, rhenium, samarium and gadolinium have been used either as therapeutic and diagnostic radiopharmaceuticals or as magnetic resonance imaging (MRI) contrast agents. In addition, the high phosphonate affinity towards bone and other calcified tissues may be utilized for the drug targeting based on synthesis of metal complexes linked to bioactive carrier systems, affording better modalities of attack to the site of pathology. In this review article, aminophosphonate metal–based compounds with potential biomedical applications are described.

Membrane transporters, including two members: ATP–binding cassette (ABC) transporters and solute carrier (SLC) transporters are proteins that play important roles to facilitate molecules into and out of cells. Consequently, these transporters can be major determinants of the therapeutic efficacy, toxicity and pharmacokinetics of a variety of drugs. Considering the time and expense of bio–experiments taking, research should be driven by evaluation of efficacy and safety. Computational methods arise to be a complementary choice. In this article, we provide an overview of the contribution that computational methods made in transporters field in the past decades. At the beginning, we present a brief introduction about the structure and function of major members of two families in transporters. In the second part, we focus on widely used computational methods in different aspects of transporters research. In the absence of a high–resolution structure of most of transporters, homology modeling is a useful tool to interpret experimental data and potentially guide experimental studies. We summarize reported homology modeling in this review. Researches in computational methods cover major members of transporters and a variety of topics including the classification of substrates and/or inhibitors, prediction of protein–ligand interactions, constitution of binding pocket, phenotype of non–synonymous single–nucleotide polymorphisms, and the conformation analysis that try to explain the mechanism of action. As an example, one of the most important transporters P–gp is elaborated to explain the differences and advantages of various computational models. In the third part, the challenges of developing computational methods to get reliable prediction, as well as the potential future directions in transporter related modeling are discussed.

K203 is an experimental bis–pyridinium mono-aldoxime type cholinesterase reactivator of potential use in organophosphate- organophosphonate poisoning. Pharmacokinetics of K203 were examined in Wistar rats and beagle dogs using ion–pair HPLC. Serum and cerebrospinal fluid concentrations of K203 were determined using ion-pair reversedphase chromatography on octadecyl silica column. HPLC with ultraviolet detection was used for determination of serum concentration of K203 higher than 0.1 μg-mL while its low concentrations in cerebrospinal fluid required electrochemical detection (0.015 through 4 μg-mL range). In rats the serum levels of K203 followed zero order pharmacokinetics from 15 to 120 minutes post administration. Zero order pharmacokinetics was also observed in beagle dogs after low dose (15 μmol-kg) of K203 administration. High dose administration (250 μmol-kg) led to subsequent hindered elimination from both cerebrospinal fluid and serum.

Objective: We found a novel marine drug, SZ–685C, that was isolated from the secondary metabolites of a mangrove endophytic fungus (No. 1403) collected from the South China Sea, which has been reported to inhibit the proliferation of certain tumor cells. However, its anticancer mechanism remains unknown. The aims of this study were to observe the effectiveness of SZ–685C on pituitary adenoma cells and determine the underlying mechanisms of action. Methods: A rat prolactinoma cell line, MMQ, was used in this study. A dose escalation of SZ–685C was performed on this cell line, and cell viability was assessed using an MTT assay. Hoechst 33342, Annexin V–FITC/PI, TUNEL staining and flow cytometry were used to evaluate the extent of apoptosis at each concentration of SZ–685C. The effect of SZ–685C on prolactin expression was also evaluated using RT–PCR and immunoblotting. Quantitative RT–PCR was used to detect the expression of miR–200c in SZ–685C–stimulated MMQ cells and pituitary adenoma tissues. This miRNA was then overexpressed in MMQ cells via transfection of a miR–200c mimic to identify the mechanism underling the anti–tumor effect of SZ–685C. Results: SZ–685C inhibited MMQ cell growth in a dose–dependent manner but showed little toxicity toward rat pituitary cells (RPCs). The IC50s of SZ–685C in MMQ cells and RPCs were 13.2 ± 1.3 mM and 49.1 ± 11.5 mM, respectively, which was statistically significant. Increasing numbers of apoptotic cells were observed in response to escalating concentrations of SZ–685C, and the expression level of prolactin (PRL) was inhibited. Nevertheless, the level of PRL mRNA was unchanged. Additionally, miR–200c was upregulated in MMQ cells compared with RPCs, and downregulation of miR– 200c was observed in SZ–685C–treated MMQ cells. Furthermore, the overexpression of miR–200c weakened the effect of SZ–685C–induced apoptosis of MMQ cells. Conclusions: Our results suggest that SZ–685C induces MMQ cell apoptosis in a miR–200c–dependent manner. Therefore, SZ–685C might be a useful alternative treatment for pituitary adenoma.