Mini Reviews in Medicinal Chemistry - Volume 13, Issue 5, 2013

Present-day is developing in many fields. Many pathological processes are better understood, including carcinogenesis. Consequently, the failure of pharmacotherapy aimed at cancerous diseases is becoming explainable. At the same time, new anticancer drugs continue to be introduced. Anthracycline antibiotics are a well-known and widely used group of anticancer drugs. However, in addition to their efficiency they demonstrate severe side effects compounded by the appearance of resistant cells. Therefore, the search for new anthracycline derivatives with improved pharmacodynamic properties and fewer adverse effects is in progress, delivering promising results.

Progesterone (P4) participates in the regulation of several physiological and pathological processes in mammals through the interaction with its intracellular receptors (PR), which are ligand-dependent transcription factors. Many human cancers depend on P4 for growth and metastasis, especially cancers of reproductive tissues. In women, administration of combined estrogen and progestin hormone replacement therapy for postmenopausal symptoms increases the risk of breast cancer relative to women taking estrogens alone. P4 exerts its actions through various mechanisms classified as classical and non-classical. PR has dual functions as a nuclear transcription factor and as a modulator of cell signaling pathways. Many PR target genes do not contain canonical progesterone response elements (PRE) in their promoter regions and may thus be regulated by PR tethering to other transcription factors and/or rapid signaling, independent of direct PR DNA binding. We review the mechanisms involved in P4 effects on genes implicated in control of cell cycle, proliferation, angiogenesis and metastasis, such as cyclin D1 and epidermal growth factor receptor (EGFR) whose promoters lack PRE sequences, and vascular endothelial growth factor (VEGF) which gene contains PRE in its promoter region. The understanding of the molecular mechanisms involved in the regulation of cyclin D1, EGFR and VEGF expression by P4 will be helpful for the development of new cancer therapies.

Cancer is the second leading cause of death around the world. Cancer may be induced by viral infection (EBV, HBV and HPV), bacterial infection (Helicobacter pylori), carcinogen, ultraviolet (UV) radiation exposure, and genetic mutation. Tumor can be suppressed by traditional surgery, radiotherapy, and/or chemotherapy with devastating side effects and very poor quality of postoperative life. The therapeutic index has been further promoted by the newly developed nanomedicine. However, the disseminated tumor cells can result in micrometastases. So the cancer can just be supresssed but not cured by these ways. Fortunately, the developments of immunology have successfully improved many disciplines with special effort on oncology. Various immune cells including B cells, T-lymphocytes (TL), natural killer (NK) cells, dendritic cells (DCs), macrophages, and polymorphonuclear leukocytes are recruited to the tumor. These immune cells can recognize, eliminate, and protect the body from viral, bacterial infections, and the transformed cells (pre-cancer cell) extension. The modification of host immune system, and/or the utilization of components of the immune system for cancer treatment are called immunotherapy. The immunotherapy is not only to target and kill tumor cells in a specific manner, but also to alert the immune system to eradicate the disseminated tumor cells present in the blood circulation and micro-metastases in remote organs. Herein, the development of immunology, cancer immunotherapy, tumor immunoescape was introduced firstly. Then the correlations between host, the tumor and the nano particulates were proposed. And how to improve the cancer immunotherapy by finely nanocarrier’s engineering (nanoimmunotherapy) was systematically illustrated with special focus on the unique pathology of tumor microenviroments and properties of immuno cells.

Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF- 1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date.

The design, development and use of small molecule fluorescent ligands to directly or indirectly study receptors, enzymes and other targets in the central nervous system (CNS) have in the recent years become an intense area of investigation, especially for use in quantitative, sensitive and direct binding assays to study target proteins, both intra- and extra-cellularly and as prodromal diagnostic tools. The rapid development of ultra sensitive fluorescent spectroscopic approaches, such as fluorescence correlation spectroscopy, flow cytometry, confocal laser scanning microscopy, fluorescence polarization and multi-photon fluorescence microscopy, is opening new scenarios for the use of small molecule fluorescent ligands in the study of CNS pharmacology. In combination with effective and efficient labeling protocols, these techniques offer enormous possibilities at both micro- and nanometer level to develop parallel multifaceted tools in pharmacological and related sciences. This review covers small molecule fluorescent ligands that have been applied to study proteins and other targets in the CNS through visualization by means of fluorescent imaging technologies.

Epilepsy which is a diverse set of complex neurological disorders comprised of seizures affecting more than 50 million people worldwide among which 90 % are from developing countries. The aim of current antiepileptic therapy is to control the seizures with minimal side effects and improve the patients' quality of life. Near by about 20 medications are approved by Food and Drug Administration among which only five to six are widely used for the treatment of epileptic seizures. Ezogabine (D-23129) is a recently approved antiepileptic drug approved by USFDA for adjunctive therapy of partial onset seizures. It was developed by Valeant Pharmaceuticals and Glaxosmithkline in 2011 for the management of partial onset seizures. The drug has shown unique mechanism of action among other antiepileptic drugs by facilitating potassium channel current in nerve growth factor differentiated PC12 cells. It also promotes membrane repolarisation and thus opposes rapid repetitive discharges. The drug is quickly absorbed and reaches maximum plasma concentration between 0.5 hour and 2 hours after a single oral dose also showing a moderately high bioavailability, volume of distribution and a terminal half life of 8 to 11 hours. It is metabolized via glucuronidation and acetylation. The various adverse effects found with the drug were related to central nervous system and appeared to be dose related like drowsiness, dizziness, vertigo and confusion etc. All these parameters make it superior from other available drugs for the management of epileptic seizures. The present review describes the development; medicinal chemistry; mechanism of action, pharmacokinetics and pharmacodynamics of Ezogabine. Further the review put forwards the indispensible role of this drug for antiepileptic treatment.

Peroxisome Proliferator Activated Receptors gamma (PPARγ) are a class of ligand activated transcription factors with a prominent role in the regulation of metabolic processes. The present work aims towards examining the functional and structural features that facilitate the binding of small molecules based on Thiazolidinedione pharmacophore to PPARs. The intent of this article is to review all the reported thiazolidinediones and associated groups of PPARγ ligands.

1-Monosubstituted 1,2,3-triazoles have widespread applications in diverse fields, and their preparation has attracted increasing attention. This review mainly covers the modern advances in the synthesis of these heterocycles based on different methods including the substitution of 1H-1,2,3-triazole and cycloaddition reactions involving moieties, such as acetylene, substituted acetylene, and vinyl compounds, among others.

Idiosyncratic adverse drug reactions (IADRs) cause a broad range of clinically severe conditions of which drug induced liver injury (DILI) in particular is one of the most frequent causes of safety-related drug withdrawals. The underlying cause is almost invariably formation of reactive metabolites (RM) which by attacking macromolecules induce organ injuries. Attempts are being made in the pharmaceutical industry to lower the risk of selecting unfit compounds as clinical candidates. Approaches vary but do not seem to be overly successful at the initial design/synthesis stage. We review here the most frequent categories of mechanisms for RM formation and propose that many cases of RMs encountered within early ADME screening can be foreseen by applying chemical and metabolic knowledge. We also mention a web tool, SpotRM, which can be used for efficient look-up and learning about drugs that have recognized IADRs likely caused by RM formation.

The development of leishmanicidal quinolines and their in vitro (promastigote and amastigote) and, where applicable, in vivo activities are reviewed. This survey provides a direct comparison of bioactivity across different species (e.g. L. donovani, L. amazonensis, L. chagasi, L infantum), and in different animal models (e.g. L. donovani Balb/c mice and L. donovani infected hamsters). The progress of selected quinolines through pre-clinical development and phase I/II trials, and the lead quinoline drugs sitamaquinine and Imiquimod, are discussed in conjunction with delivery systems and combination therapies.

The γ-aminobutyric acid (GABA) A receptor is composed of a variety of subunits and combinations and shows a characteristic distribution in the CNS. To date, 20 subunits of the GABA A receptor have been cloned: α1–6, β1–4, γ1–3, δ, π, ε, Θ, and ρ1–3. Oocyte of Xenopus laevis is one of the most frequently used heterologous expression systems, which are used to design and analyze specific combinations of GABA A receptor subunits. In oocytes, a certain GABA A receptor function is studied only by comparing the amplitude of the response to GABA and other drugs by physiological and pharmacological methods. According to the studies on Xenopus laevis oocytes, the α1β2γ2S receptor combination is mostly used. The α1-containing receptors mediate sedative and anticonvulsant acts. The results of studies on oocytes show that PKA, NKCC1, P2X3 receptors, and GABA A receptor-associated protein, etc., are existing systems that show different reactivity to the GABA A receptors. The GABA A receptor subunits contain distinct binding sites for BZDs, neurosteroids, general anesthetics, etc., which are responsible for the numerous functions of the GABA A receptor. A variety of other drugs, such as topiramate, TG41, (+)- and (-)-borneol, apigenin, and 6-methylflavone could also have modulatory effects on the GABA A receptors. Some of the different models and hypotheses on GABA A receptor structure and function have been achieved by using the two-electrode voltage clamp method in oocytes.

Hepatitis B virus (HBV) infection is a serious health problem worldwide, and the current treatment methods including vaccines, immunomodulators, interferons and nucleoside analogs are far from satisfactory. For the search of new anti-HBV agents, much investigation has revealed a large number of small-molecule compounds with various skeletons and promising anti-HBV activities. Although some reviews on anti-HBV progress have been published, they are mainly concentrated on the results reported in journal articles. This review provides an overview of the structural features and anti-HBV properties of the small-molecule anti-HBV inhibitors claimed in recent patents (from 2001 to 2010). These small-molecules can be structurally classified as two main types, nucleoside analogs (cyclic and acyclic nucleosides) and non-nucleosides (natural and synthesized compounds), which are declared with the activity inhibiting the secretion of HBsAg and HBeAg and HBV DNA replication in vitro, as well as anti-DHBV DNA in vivo. Especially, the nonnucleosides with diverse skeletons and novel mechanism offer prolific candidates for anti-HBV drug discovery, which are preferred to be used as adjuvant therapy for HBV infection. This paper will provide valuable information for understanding the current anti-HBV investigation and developing new anti-HBV agents.

Using a standard two-stage fermentation technique, the fungus Beauveria bassiana (ATCC 7159) was found to convert the eudesmanolide vulgarin (1) to 1α,4α-dihydroxy-5αH,6,11βH-eudesman-6,12-olide (2). The use of the yeast Hansenula anomala ATCC 20170 instead, produced the less polar 4α-hydroxy-1-oxo-5αH,6,11βH-eudesman-6,12-olide (3), in addition to the more polar 3α,4α-dihydroxy-1-oxo-5αH,6,11βH-eudesman-6,12-olide (4). These metabolites were characterized on the basis of their spectral data and the identity of 4 was further confirmed by chemical synthesis.