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Journal: Current medicinal chemistry


The bio-reversible protection of nucleoside diphosphates is summarized. The design, the hydrolysis behavior, and the antiviral activity of these prodrugs of NDPs are described. In contrast to earlier attempts, the DiPPro-approach [-(bis (acyloxybenzyl) nucleoside diphosphates)] successfully led to the delivery of the nucleoside diphosphates. It was proven [by hydrolysis studies in aqueous PBS buffer (pH 7.3), 20 % human plasma in PBS, RPMI-1640 culture medium, and CEM cell extracts] that the stability towards hydrolysis was dependent on the acyl moieties in the bis (acyloxybenzyl) unit as well as on the nucleoside analogue. Contrary to a high chemical and plasma stability, the compounds showed a very low half-life in CEM cell extracts, and efficiently released the nucleoside analogues diphosphates, e.g. of AZT, d4T and BVDU. Two types of cycloSal-NDP prodrugs were also initially studied but proved to be not useful as nucleoside diphosphate prodrugs. Finally the obtained results led to the development of non-symmetric nucleoside diphosphate prodrugs that selectively deliver the nucleoside diphosphate in cell extracts.

Concepts: Antiretroviral drug, PH, Adenosine triphosphate, Instability, Chemistry, Antivirals, Buffer solution, Pyrophosphate


The current treatment regimens for uncomplicated malaria comprise an artemisinin in combination with another drug (ACT). However, the recent emergence of resistance to ACTs in South East Asia dramatically emphasizes the need for new artemisinins. The current artemisinins have been in use since the late 1970s and have relatively poor thermal, chemical and metabolic stabilities - all are metabolized or hydrolyzed in vivo to dihydroartemisinin (DHA) that itself undergoes facile decomposition in vivo. The current artemisinins possess neurotoxicity as demonstrated in animal models, an issue that mandates increased vigilance in view of trends to use of protracted treatment regimens involving sequential administration of different ACTs against the resistant disease. As artemisinins induce the most rapid reduction in parasitaemia of any drug, common sense dictates that any new artemisinin derivative, selected on the bases of more robust chemical and thermal stability, metabolic stability with respect to the generation of DHA in vivo, and relatively benign neurotoxicity should be used in any new ACT whose components are rationally chosen in order to counter resistant malaria and inhibit transmission. 11-Aza¬artemisinin and its N-substituted derivatives attract because of overall ease of preparation from artemisinin. Some derivatives also possess notable thermal stabilities and although metabolic pathways of the derivatives are as yet unknown, none can provide DHA. The azaartemisinins synthesized over the past 20 years are critically discussed on the basis of their synthetic accessibility and biological activities with the view to assessing suitability to serve as new artemisinin derivatives for treatment of malaria.

Concepts: Metabolic pathway, Enzyme, Metabolism, Artesunate, Southeast Asia, Adenosine triphosphate, Artemisinin, Malaria


Although photodynamic therapy (PDT) was discovered over a hundred years ago by its ability to destroy microorganisms, it has been developed mainly as a cancer therapy. In recent years, due to the inexorable rise in multi-antibiotic resistant strains of pathogens, PDT is being considered as a versatile antimicrobial approach to which microbial cells will not be able to develop resistance. The goal of this review is to survey the different classes of chemical compounds that have been tested as antimicrobial photosensitizers. Some of these compounds have been known for many years, while others have been rationally designed based on recently discovered structural principles. Tetrapyrrole-based compounds (some of which are approved as cancer therapies) that efficiently generate singlet oxygen are more efficient and broad-spectrum when they bear cationic charges, As the macrocycle structure moves from porphyrins to chlorins to phthalocyanines to bacteriochlorins the long wavelength absorption moves to the near-infrared where tissue penetration is better. Four main types of natural products have been tested: curcumin, riboflavin, hypericin and psoralens. Phenothiazinium dyes, such as methylene blue and toluidine blue, have been tested, and some are clinically approved. A variety of non-phenothiazinium dyes with xanthene, triarylmethane and indocyanine structures have also been tested. New ring structures based on BODIPY, squaraine and fullerene cages can also mediate antimicrobial PDT. Finally the process of photocatalysis using titanium dioxide can also have medical uses. Designing new antimicrobial photosensitizers is likely to keep chemists engaged for a long time to come.

Concepts: Antibiotic resistance, Microbiology, Bacteria, Photodynamic therapy, Methylene blue, Oxide, Oxygen, Singlet oxygen


Histamine and histamine receptors are well known for their immunomodulatory role in inflammation. In this review we describe the role of histamine and histamine H4 receptor on human eosinophils. In the first part of article we provide short summary of histamine and histamine receptors role in physiology and histamine related therapeutics used in clinics. We briefly describe the human histamine receptor H4 and its ligands, as well as human eosinophils. In the second part of the review we provide detailed description of known histamine effects on eosinophils including: intracellular calcium concentration flux, actin polymerization, cellular shape change, up regulation of adhesion proteins and cellular chemotaxis. We provide proofs that these effects are mainly connected with the activation of histamine H4 receptor. When examining experimental data we discuss the controversial results and limitations of the studies performed on isolated eosinophils. In conclusion we believe that studies on histamine H4 receptor on human eosinophils can provide interesting new biomarkers that can be used in clinical studies of histamine receptors. That in future might result in development of new strategies in treatment of chronic inflammatory conditions like asthma or allergy, in which eosinophils are involved.

Concepts: Histamine H4 receptor, Asthma, Inflammation, Protein, Cell biology, G protein coupled receptors, Immune system, Signal transduction


Sigma-2 receptor is a widely distributed protein, which can modulate cell proliferation and involved in the pathogenesis of tumor. Photo affinity labelling techniques testified that its molecular size is about 18 kDa. Recent studies indicated that sigma-2 receptor modulates the cytosolic Ca2+ concentration, dopaminergic transmission, and cocaine-induced addiction behavior. Some sigma-2 receptor ligands (ditolylguanidine, afobazole, etc) display the neuroprotective effect. Although sigma-2 receptor hasn’t been cloned, tens of sigma-2 receptor ligands, which demonstrate high affinity and selectivity, have been identified in the past decade. In this review, we mainly focus onthese series of selective sigma-2 receptor ligands, their neuropsychological effects, and molecular probe for tracing sigma-2 receptors in central nervous system.

Concepts: Brain, Receptor, Sigma receptor, Central nervous system, Psychology, Nervous system, Cell signaling, Signal transduction


The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention and the challenges in targeting validation and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Concepts: Leukemia, Immune system, Metastasis, Radiation therapy, Breast cancer, Oncology, Chemotherapy, Cancer


This review covers the compounds isolated from marine sponges with neuroprotective activities during the period between 1999 and 2014 based on their chemical structures, collections sites, sponge taxonomy and neuroprotective effects. These compounds were isolated from marine sponges collected from 18 countries, most of them in Indonesia, followed by Japan. A total of 90 compounds were reported to exhibit a range of neuroprotective efficacy. These compounds were shown to modulate the synthesis or activity of some neurotransmitters such as acetylcholinesterase and glutamate, enhancement of serotonin, reducing oxidative stress, inhibition of kinases and proteases, and enhancement of neurite growth. None of them have progressed into any marine pharmaceutical development pipeline, sustained researches will be required to enhance the potential of utilizing these compounds in the future prevention and therapeutic treatment of neurodegenerative diseases.

Concepts: Amino acid, Medicine, Neuroscience, Neurology, Sponge, Nervous system, Photosynthesis, Enzyme


Gaultheria, a genus belonging to the Ericaceae family, is typically a shrub that produces berries, and closely resembles the blueberry genus Vaccinium. Gaultheria species are used worldwide especially as food and medicine in China. Certain Gaultheria species are biologically active, as antioxidants, anti-inflammatories, and cytotoxic agents. Through literatures searches and field surveys, the results of ethnobotanical uses, especially in China, as well as in vitro and in vivo studies are reviewed critically. This review examines the chemistry and bioactivity of this under-studied plant genus, and thus lays the groundwork for its future development for human health.

Concepts: Genus, Anthropology, Cranberry, Botany, Species, In vivo, Vaccinium, Ericaceae


Natural phenolics are secondary plant metabolites, which can be divided into several categories with the common structural feature of phenolic hydroxyl. The biological activity of phenolics is often modified and enhanced by prenylation by prenyl and geranyl; higher terpenoid chains are rare. The type of prenyl connection and modification affects their biological activity.

Concepts: Phenols, Alcohol, Prenylation


New-generation antidepressants (NGAs) are the latest additions to the clinician’s arsenal in the fight against depression. After the introduction of selective serotonin reuptake inhibitors (SSRIs), a plethora of other groups followed, identified by their main mechanisms of activity: serotonin and norepinephrine reuptake inhibitors (SNRI); serotonin modulators and stimulators (SMS); serotonin antagonists and reuptake inhibitors (SARI); noradrenergic and selective serotonergic antidepressants (NaSSA); norepinephrine reuptake inhibitors (NeRI); serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRI) or triple reuptake inhibitors (TRI); and melatonin and serotonin agonists (MaSA). Although SSRIs are still the most widely used and well known NGAs, the other groups are increasingly being used in the current therapeutic settings obtaining comparable clinical results, and with tolerability and safety profiles that can often provide significant advantages over those of SSRIs.

Concepts: Bupropion, Norepinephrine, Dopamine, Reuptake inhibitor, Tricyclic antidepressant, Antidepressant, Serotonin, Selective serotonin reuptake inhibitor