Mini Reviews in Medicinal Chemistry - Volume 17, Issue 4, 2017

Tetrodotoxin (TTX) found in diverse variety of animals including puffer fishes, some newts, frogs and limited number of non-vertebrate species (6 different phyla). The saxitoxin (STX) and the TTX are small molecules composed of 7,8,9 guanidinium and 1,2,3 guanidinium groups, respectively in their structures. These groups provide positive charge to the molecules and are believed to interact with negatively charged Glu755 and Asp400 residues in domain II and I of the sodium channel strongly. The pharmacokinetic studies (absorption, distribution and accumulation) reported on Takifugu rubripes, Takifugu pardalis, Takifugu niphobles, Takifugu vermicularis, Takifugu snyderi, etc. revealed that higher concentration of TTX is accumulated in liver than in the skin or other tissues. Although TTX is also accumulated in the skin of various marine species (secretory glands) and the excess of TTX are emitted through skin which acts as a defence agent for those species. STX showed high toxicity on crab and other animals, due to its accumulation in the tissues and resistance to the sodium channel proteins. It concluded that TTX and STX based toxicities are developed on the species by the absorption, distribution and accumulation of toxins in tissues. Also the ingestion of these species (marine species) as food may allow transferring toxin to the human being.

In the previous parts of the series the antiviral agents used in genital herpes, genital HPV infection and therapeutic options in HIV infections were presented. The sexual contact is one of the major routes in the transmission of HBV and also possible modes of transmission of HCV. In this review we present the clinical indications, mechanisms of action, and side effects of presently available medication for the management of HBV and HCV infections. Currently a revolution is happening in the therapy of chronic hepatitis, especially caused by HCV. Direct-acting antivirals promise to open a new era in treating of chronic HCV infection. Efficacious, simplified and well tolerated interferon-free, and in some cases ribavirin-free regiments are available already and several other inhibitors currently are in the clinical trials.

Deep Vein Thrombosis (DVT) has been known as a common medical problem all over the world. Thrombus traveling in blood vessels may lead to pulmonary embolism (PE), associated with high rates of mortality. Anticoagulant therapy is the mainstay treatment of DVT. Common anticoagulants, Vitamin K antagonists (VKAs), unfractionated heparin (UFH) and Low-molecular-weight heparin (LMWH) have been used in clinical application over decades, but can increase the risk of hemorrhage. Thereby, several new oral anticoagulants (NOACs) have been developed, which includes direct thrombin inhibitors (DTI) and direct factor Xa inhibitors. To be contrast with VKAs and UFH, NOACs have many advantages such as rapid offset action, few drug/food interactions and no need for routine coagulation monitoring, etc. Many NOACs are still being evaluated in Phase III clinical trials such as Betrixaban and Darexaban (YM150). However, NOACs still have problems to be solved such as lack of antidotes and laboratory monitoring, high drug costs, etc. Besides, several agents have already shown the potential to be new anticoagulants. Factor Xa play an important role in thrombin generation and coagulation pathway. Thus, the new compounds directly targeting on factor Xa for prevention DVT are highly anticipated. DPC423, a new series of 6-substituted coumarin derivatives and Phenyltriazolinones as potent factor Xa inhibitors have been recently reported. Recent studies revealed that agents extracted from botanicals not only have anti-coagulant effects but also possess other pharmacological activities such as anti-inflammation to alleviate the post-thrombotic syndromes. All the evidence above suggests that many new compounds might have great potential to be more effective and safe oral anticoagulants.

B-RAF gene is a component of the MAPK pathway that plays a very important role in cell division, survival, proliferation, and many other cellular functions. Mutations of the B-RAF (such as V600E-B-RAF) lead to melanoma, which is one of the leading causes of death worldwide. R progress is being done aiming at improved therapy in the future. The existing melanoma therapy is left out with poor overall survival, drug resistance, and many side effects. With the recent approval of new drugs, there is a hope for melanoma patients for complete cure and better life quality. However, there is still a need for improved, safe, and complete therapy for advanced melanoma. This review describes melanoma caused by V600E-B-RAF gene mutation, its pathway, drugs available and recently approved drugs, and future prospects to be overcome.

Liposomes and nanoliposomes as small vesicles composed of phospholipid bilayer (entrapping one or more hydrophilic or lipophilic components) have recently found several potential applications in medicine and food industry. These vesicles may protect the core materials from moisture, heat and other extreme conditions. They may also provide controlled release of various bioactive agents, including food ingredients at the right place and time. Potential applications of enzyme-loaded liposomes are in the medical or biomedical field, particularly for the enzymereplacement therapy, as well as cheese industry for production of functional foods with improved health beneficial impacts on the consumer. Encapsulation process has a recondite impact on enzymes. In fact, liposome preparation techniques may alter the pH and temperature optima, affinity of the enzyme to substrate (Km), and maximum rate of reaction (Vmax). In addition, in this paper, the impact of process variables on the kinetic characteristics of enzymes encapsulated in liposomes was investigated. Also, the effects of enzyme entrapment in liposomes, prepared by different methods, on the catalytic efficiency of enzyme, as well as its kinetic properties and stability compared to native (free) enzymes has been reviewed.

The humans worldwide are facing obesity as a major clinical threat because it is linked with cardiovascular diseases which often have serious consequences. Treatments available for body weight loss do not produce permanent weight loss and they often bear some side effects. To achieve safer antiobesetic therapeutics, researchers are moving towards plant-based therapeutic formulations. Many phytomolecules have been identified as anti-lipolytic functions but none of them have reached up to the clinical level. So there is an essential need to develop effective anti-obesetic medications which not only produce sufficient weight loss but also lack side effects. Plants may prove promising option for the same. In this article, medications and surgical procedures have been reviewed and dealt for weight loss and the role of phytomolecules in anti-obesetic therapeutics has been explored.

Extracted from Euphorbia, ent-Abietane lactones can be classified into several categories, such as Jolkinolides and Helioscopinolides, according to their structural features. The study of ent- Abietane lactones could date back to 1972, when Jolkinolide A and B were first isolated from Euphorbia jolkini Boiss. Since then, many other ent-Abietane lactones have been extracted from different species of Euphorbia. Their bio-activities include anti-tumor activity, anti-inflammatory activity as well as anti-bacterial activity. Among them, derivatives of Jolkinolide B draw the most attention for their high anti-tumor activity. There are many studies focus on the syntheses of Jolkinolides. In 1989, the first and efficient synthesis of Jolkinolides was accomplished by Katsumura et al. Their strategy to construct the last ring of Jolkinolides contributes a lot to the following studies. In the following thirty years, there are also other semi-syntheses of Jolkinolides conducted, basing on different starting materials. In this review, we will give a brief clarification of ent-Abietane lactones, as well as their bio-activities and syntheses.