Current Bioactive Compounds - Volume 6, Issue 1, 2010

Organophosphates (OPs) are still one of major classes of chemicals used in pesticide control worldwide. Through their widespread application, large human populations are continuously exposed to OPs. While this particularly holds for developing countries of the third world where a number of pesticide preparations banned in the West are still in use surprisingly high incidence of individuals with detectable levels of OP residuals in their blood was recently detected in some of worlds most developed countries. The continuous danger of massive OP exposure on the other hand comes from stockpiles of nerve gas warfare, soman, sarin, cyclosarin, tabun and VX, some of which originally developed as pesticides, proved to be overly toxic for that purpose. Irrespective of the intent of administration, exposure to high OP doses leads to states of acute OP intoxication. Therapy involving treatment with combination of atropine and nucleophylic oximes directed towards reactivation of OP inhibited acetylcholinesterase has been commonly used for about fifty years now. The efficiency of oximes in this treatment varies as diversity of OP structures modify acetylcholinesterase active center geometry in a compound specific manner differentially amenable to reactivation. The collection of articles gathered in this issue of CBC addresses specific therapeutic procedures in OP intoxication as well as molecular properties of variety of oximes, in an attempt to devise more efficient treatment of OP intoxication.

Prophylaxis against nerve agent intoxication is based on various approaches: Keeping AChE, key enzyme for toxic action of OP/nerve agents intact (protection of cholinesterases) is a basic requirement for effective prophylaxis. Detoxification realised by administration of the enzymes splitting the OP or evaluating specific enzymes (cholinesterases) is another possibility (scavenger effect). The antidotes currently used for the treatment of OP poisoning including reactivators are to be tested as prophylactics. This principle can be considered as a “treatment in advance”. Moreover, they are uneffective when administered alone; their effect is potentiated when they are administered with anticholinergics. Transdermal administration of reactivator HI-6 was used and prophylactic antidote TRANSANT was developed and introduced into the Czech Army. At present, PYRIDOSTIGMINE seems to be common prophylactic antidote; prophylactics PANPAL (tablets with pyridostigmine, trihexyphenidyle and benactyzine), TRANSANT (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. TRANSANT is only one prophylactics evaluating reactivator. When administered simultaneously with PANPAL, prophylactic efficacy is increased and represents the best prophylaxis at present.

The phosphorylation of the serine hydroxyl group in the active site of acetylcholinesterase (AChE) inactivates this essential enzyme in neurotransmission. Oximes are reactivators of AChE phosphorylated by organophosphorus compounds (OP) including insecticides and nerve agents. The effectiveness of oxime-assisted reactivation is primarily attributed to the nucleophilic displacement rate of organophosphate, but efficiency varies with the structure of the bound organophosphate, the structure of the oxime as well as rates of several other cholinesterase's reactions. Besides reactivating cholinesterases, oximes also reversibly inhibit cholinesterases and protect them from phosphorylation by OP. In this paper, we bring an overview of in vitro native and tabun-inhibited AChE and butyrylcholinesterase interactions with oximes together with conformational analysis of the oximes to relate molecular properties to their reactivation potency.

In the past decades a vast number of oximes have been synthesised in order to identify effective compounds for the reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE). Up to now, oxime efficacy has been tested primarily in animal experiments. However, the accretive evidence of substantial species differences regarding kinetic properties of human and animal AChE led to an increasing number of in vitro kinetic studies quantifying the reactivating potency of oximes. These data were shown to provide a basis for the selection of effective oximes and for defining adequate oxime doses in human OP poisoning. This review will discuss experimental and theoretical models for the in vitro assessment of oxime efficacy and will give an overview of the present status in the evaluation of oximes as antidotes against OP poisoning.

Diabetes mellitus is a devastating disease and the World Health Organization (WHO) expects that the number of diabetic patients will increase to 300 million by the year 2025. A variety of peptides, known as protein transduction domains (PTDs) or cell-penetrating peptides (CPPs), have been recently characterized for their ability to translocate into live cells. Some studies have shown that this technology is useful for the treatment of diabetes. In islet isolation and transplantation, cell-permeable peptides deliver anti-apoptotic molecules such as inhibitors of the c-Jun NH2-terminal kinases (JNKs) to protect islets. In type 2 diabetes, a cell-permeable peptide of JNK inhibitor markedly improves insulin resistance and ameliorates glucose tolerance in diabetic mice. JNKs are classic stress-activated protein kinases and many cellular stresses have been shown to stimulate JNK activation. In this review, we show some of the most recent contributions to the advancement of knowledge of the JNK pathway and several possibilities for the treatment of diabetes using protein transduction technology and the JNK inhibitory peptide.

Convenient synthesis of the α-mannosidase inhibitor mannostatin A from myo-inositol is described by a method, which is generally applicable for provision of aminocyclopentanols of biological interest. Elucidation of structure-inhibitory activity relationships was carried out by chemical modification, leading to discovery of a very potent amino(methoxy)cyclopentanetriol. Similar studies of the trehalase inhibitor trehazolin stimulated development of a new type of aminocyclopentanol glycosidase inhibitor featuring ring contract mimicking of valiolamine, with implications for understanding of the structure and activity relationships of glycosidase inhibitors of this type.

There is much evidence for participation of electron transfer (ET) functionalities in the physiological action of drugs and toxins. The main ET agents are quinones, metal complexes, aromatic nitro compounds and iminium and imine species. Some are usually formed as metabolites. The last category, the least well known, is the focus of the review. First, examples of imines and iminiums in various bioactive classes are provided along with data on physiological activity, mechanism, ROS generation, lipid peroxidation, DNA damage, and electron affinic properties. Emphasis is on events at the fundamental molecular level. This review documents various iminoquinones, imine and iminium agents in the marine alkaloid category. Bioactivity is addressed in addition to other mechanisms. The conjugated members of those classes have the potential of participating in ET reactions which can generate reactive oxygen species or become involved in the central nervous system.

Normal pregnancy is associated with significant vascular remodeling in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. The pregnancy-associated vascular changes are largely due to alterations in the amount/activity of vascular mediators released from the endothelium, vascular smooth muscle and extracellular matrix. The endothelium releases vasodilator substances such as nitric oxide, prostacyclin and hyperpolarizing factor as well as vasoconstrictor factors such as endothelin, angiotensin II and thromboxane A2. Vascular smooth muscle contraction is mediated by intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Extracellular matrix and vascular remodeling are regulated by matrix metalloproteases. Hypertension in pregnancy and preeclampsia are major complications and life threatening conditions to both the mother and fetus, precipitated by various genetic, dietary and environmental factors. The initiating mechanism of preeclampsia and hypertension in pregnancy is unclear; however, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduction in the uteroplacental perfusion pressure and placental ischemia/hypoxia. This placental hypoxic state is thought to induce the release of several circulating bioactive factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and vascular receptor antibodies. Increases in the plasma levels and vascular content of these factors during pregnancy could cause an imbalance in the vascular mediators released from the endothelium, smooth muscle and extracellular matrix, and lead to severe vasoconstriction and hypertension. This review will discuss the interactions between the various circulating bioactive factors and the vascular mediators released during hypertension in pregnancy, and provide an insight into the current and future approaches in the management of preeclampsia.