Mini Reviews in Medicinal Chemistry - Volume 12, Issue 1, 2012

Expiration of some of the most profitable patents sustaining major pharmaceutical companies has been greeted with concern for the research pipeline. Yet, have the resources delivered innovation? Rational drug design has been followed with high throughput screening, neither living up to expectations. The quest for novelty has led back to fundamentals on lessons from academia and nature. While not the daring departure from the past, hoped for a decade ago with ‘high-tech solutions’, efforts resting on a firm foundation are essential to unraveling the web of complexity of chronic disease that now grips the industrialized world and is rapidly spreading to the developing world. Alzheimer disease, metabolic syndrome/diabetes, arthritis, and heart disease now define morbidity and mortality. While intervention at single points can offer some relief, it is at best to slow the process. Regenerative medicine may offer hope of renewal, but it may also fall short due to a poor understanding of system failure, or better stated, altered system homeostasis and reconfiguration, during aging and disease. Aging touches each of us, not just in decreased function, but in altered perspective, cognitively and fundamentally. Pleotrophic regulatory alterations are essential to maintaining evolutionarily acceptable function as we age. Intervention to disrupt these complex adaptations can deleteriously affect the course of aging as we have seen with anti-oxidant and antiamyloid therapies that disregard the biology driving disease. Therapeutics aligned to biology will be more effective. Fundamentals of biology: physiology, biochemistry, cell biology and yes evolutionary biology, must be brought to the table of medicinal chemistry.

2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models. The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.

The tripeptide glycine-proline-glutamate (GPE) is the naturally cleaved N-terminal tripeptide of insulin-like growth factor-1 (IGF-1) in brain tissues by an acid protease. Although GPE does not bind to IGF-1 receptors and its mode of action is not clear, in vitro studies have demonstrated its ability to stimulate acetylcholine and dopamine release, as well as to protect neurones from diverse induced brain injures. More importantly, GPE has been shown to have potent neuroprotective effects in numerous animal models of hypoxic-ischemic brain injury and neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. As a consequence, GPE was suggested to be a potential target for the rational design of neuroprotective agents. Unfortunately, the use of GPE as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. This review will focus on structural modifications performed on the GPE molecule in order to obtain bioactive analogues with increased pharmacokinetic profile useful for the treatment of central nervous system (CNS) injures and neurodegenerative disorders.

Highly toxic organophosphorus inhibitors of acetylcholinesterase referred as nerve agents are considered to be among the most dangerous chemical warfare agents. The oximes represent very important part of medical countermeasures of nerve agent poisonings. They are used to reactivate the nerve agent-inhibited acetylcholinesterase. Despite long-term research activities, there is no single, broad-spectrum oxime suitable for the antidotal treatment of poisoning with all organophosphorus agents. There are two approaches how to increase and broaden the effectiveness of antidotal treatment of poisoning with nerve agents - to develop new structural analogues of currently available oximes and/or to combine currently available or newly developed oximes. The review describes the evaluation of the potency of newly developed oximes (especially the oxime K203) or combinations of oximes to reactivate nerve agent-inhibited acetylcholinesterase and to counteract the acute toxicity of nerve agents in comparison with single commonly used oxime (obidoxime, trimedoxime or HI-6).

Ascorbic acid is a low molecular weight antioxidant well known as anti-scorbut acting vitamin C in humans, primates and guinea pigs. This review summarizes basic data about ascorbic acid in its physiological action point of view. It is divided into biochemistry of ascorbic acid synthesis, mechanism of antioxidant action and participation in anabolism, pharmacokinetics and excretion, exogenous ascorbic acid immunomodulatory effect and participation in infectious diseases, impact on irradiation and intoxication pathogenesis, and supplementary demands. The primary intention was to consider ascorbic acid not only as an antioxidant but also as a chemical compound affecting multiple pathways with a potential beneficial impact in many diseases and processes in human body.

Tetracyclines are an amazing class of chemical agents with multiple therapeutic potential. Structural modification of the original natural tetracyclines led to the synthesis and development of doxycycline and minocycline, compounds with higher lipophilicity, better oral pharmacokinetics and higher potency. Due to diverse pharmacological properties, these drugs are now under extensive investigation for use in the treatment of various disparate diseases. In recent years, several studies have conclusively reported anti-inflammatory, immune-modulating and neuroprotective effects of these compounds. There are currently over 200 ongoing clinical trials on tetracyclines. These studies extend over a wide range of diseases including dermatological diseases, behavior and mental disorders, immune system disorders, cardiovascular diseases, and cancer. In this review we will discuss the chemistry and pharmacology of these agents, and describe how their inhibitory effect on matrix metalloproteinase and on pro-inflammatory cytokines has kindled renewed interest in them. Based on the reports from pre-clinical and clinical trials, the therapeutic potential and application of tetracyclines may well be redefined and extensively extended.

Due to the rapid onset of resistance to most antibacterial drugs, research efforts are focusing on new classes of antibacterials with different mechanisms of action from clinically used antibacterials. Pleuromutilin derivatives have received more and more scientific attention for their unique mechanism of action. Two pleuromutilin derivatives, tiamulin and valnemulin have been successfully developed as antibiotics for veterinary use. Retapamulin, another pleuromutilin derivative has been approved for use in humans in April 2007 by Food and Drug Administration (FDA). It has been shown that there is rarely cross-resistance between pleuromutilin derivatives and other antimicrobial agents, and the development of resistance bacterial is still low. This review will demonstrate mechanism of action of pleuromutilin derivatives and reveal the structure-activity relationship (SAR) of pleuromutilin derivatives. Additionally, the pleuromutilin antibacterial derivative agents in the market, such as tiamulin, valnemulin and retapamulin, will be discussed. It is proposed that new antibacterial agents might be developed from pleuromutilin derivatives in the future.

The cell division cycle 25 (CDC25) family of proteins is a group of highly conserved dual-specificity phosphatases. They are key regulators of normal cell division and the cell response to DNA damage, and play a fundamental role in transitions between cell cycle phases during normal cell division, via the activation of CdK/cyclin complexes. Their abnormal expression, detected in a number of tumors, often correlated with a poor clinical prognosis, implies that their dysregulation is involved in malignant transformation. Thus, inhibition of these proteins represents an attractive therapeutic target in oncology, as evidenced from many patents and papers published on the subject in recent years. Hence, this review aims to provide an overview of recent developments in the field of CDC25 phosphatase inhibitor design since 2008.

The in vivo concentration of lysophospholipids (LPL) such as lysophosphatidylcholine (LPC) increases under different pathological conditions and, thus, LPL attract nowadays considerable diagnostic and pharmacological interest. LPL are particularly interesting because they possess pro- and anti-inflammatory properties and can be generated by two completely different pathways: either by the influence of (a) phospholipases and (b) different reactive oxygen species (ROS) that are generated in significant amounts under inflammatory conditions. This review provides a summary of the mechanisms by which LPL can be generated under in vitro and in vivo conditions. The focus will be on lysophosphatidylcholine (LPC) because this LPL is most abundant among all LPL and was, thus, most intensively studied so far. Additionally, biochemical, chromatographic and spectroscopic methods of LPL and LPC determinations will be discussed. Finally, the effects of LPL as signaling molecules and their roles in different pathologies such as infertility, cancer, atherosclerosis or inflammatory diseases are discussed. Special emphasis will be on the role of LPL in reproduction failures related to poor semen quality and, in that context, the potential role of LPC as a disease-indicative molecule.