Mini Reviews in Medicinal Chemistry - Volume 13, Issue 4, 2013

This mini-review will provide an overview on the recent studies of structure and thermodynamics of RNA aptamers that target drug molecules. These aptamers are studied to provide insight into RNA drug interactions. This interaction is important due to the many roles RNA plays in cell biology.

Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways. Besides the approved use in sleep disorders, modafinil has been investigated for the treatment of fatigue, impaired cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized.

Schistosomiasis is a devastating worldwide widespread tropical disease that currently affects more than 230 million people, making it an issue of great socioeconomic and public health importance. Unfortunatelly there is a single drug for the treatment of all forms of schistosomiasis, praziquantel, which was introduced in therapy in 1980. The article goes by antimony compounds, emetine, hydantoin, nitrofurans, lucanthone, hycanthone, oxamniquine derivatives and organophosphates until it finally gets to praziquantel derivatives. The intent of this review is to provide a panorama of drugs that were and are being used in human chemotherapy looking to the past to improve rational design drugs in the future. Not only clinical used compounds will be shown but also synthesized and tested compounds in vitro and in vivo in animal models which haven't yet to be used in humans. Prospects for drug discovery and vaccines to be used in the treatment and prevention of schistosomiasis, clinical trials, concerns about the resistance/decreased effectiveness of the treatment, and patent database will also be discussed. At the end of the review the reader will notice that much has been done but much still needs to be done yet.

In medicinal chemistry, one of the most studied molecules in recent history is taxol. Taxol is a versatile natural product that is used in various cancer treatment regimens. It is administered to patients with breast, lung, and ovarian cancers, and is currently being studied for the treatment of squamous cell carcinoma of the oral cavity and tongue. Taxol has been tested in a number of research and clinical phase trials to determine feasibility, toxicity, and cytotoxicity against oral squamous cell carcinoma as a single drug regimen and as a contributing drug component in treatment plans. This paper reviews over forty articles that examine cell lines, murine models, and human results for the response of taxol against squamous cell carcinoma (SCC) of the oral cavity and the tongue.

The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug–LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed.

Angiogenesis is the process of formation of new blood vessels due to over expression of VEGF (vascular endothelial growth factor) which plays a critical role in the growth and development of all solid tumor types. With the advancement in understanding of tumor angiogenesis and VEGF, there have been a number of agents developed to target VEGF for the treatment of cancer. These targeted agents can affect downstream VEGF signal transduction by unique mechanisms at different cellular and extracellular levels. FDA has recently approved Aflibercept or VEGF-Trap in August 2012 for the treatment of colorectal cancer. It is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting VEGF-A, VEGF-B and placental growth factor. VEGF-Trap exerts its antiangiogenic effects through regression of tumor vasculature, remodelling or normalization of surviving vasculature and inhibition of new tumor vessel growth. In this review, pre-clinical and clinical data have been summarized for aflibercept alone and in combination with chemotherapy to explore its efficacy and benefits in ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, glioblastoma, adenocarcinoma and renal cell cancer xenograft models.

The aim of this review is to summarize the physiological and pharmacological aspects of ghrelin. Obesity can be defined as an excess of body fat and is associated with significant disturbances in metabolic and endocrine function. Obesity has become a worldwide epidemic. In obesity there is a decreased growth hormone (GH) secretion, and the altered somatotroph secretion in obesity is functional. Ghrelin is a peptide that has a unique structure with 28 amino-acids and an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. The pathophysiological mechanism responsible for GH hyposecretion in obesity is probably multifactorial, and there is probably a defect in ghrelin secretion. Ghrelin is the only known circulating orexigenic factor, and has been found to be reduced in obese humans. Ghrelin levels in blood decrease during periods of feeding. Due to its orexigenic and metabolic effects, ghrelin has a potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal and cardiac disease, and age-related frailty. Theoretically ghrelin receptor antagonists could be employed as anti-obesity drugs, blocking the orexigenic signal. By blocking the constitutive receptor activity, inverse agonists of the ghrelin receptor may lower the set-point for hunger, and could be used for the treatment of obesity. In summary, ghrelin secretion is reduced in obesity, and could be partly responsible for GH hyposecretion in obesity, ghrelin antagonist or partial inverse agonists should be considered for the treatment of obesity.

Recently, interest in small peptide molecules as potential drug candidates has revived. In this review, two series of synthetic peptides and their selective effects on the inflammatory response have been described, focusing on the intracellular pathways involved and on their therapeutic potential. A series of FDLFDLF analogs has been synthesized, including either N- t-Boc or different N-ureido substituents. The free acid derivatives as they are good candidates as antiinflammatory drugs are able to antagonize the multiple neutrophil functions evoked by N-formyl-L-methionyl-L-leucyl-Lphenylalanine (fMLF), i.e. chemotaxis, superoxide anion production and lysozyme release. Their methyl-ester derivatives are ineffective. The second series of peptides derives from the endogenous protein kinase C (PKC) inhibitor PKI55, a 55-amino acid protein, whose synthesis is induced by PKC activation, so that a feedback loop of inhibition is established. In vitro experiments showed that PKI55 inhibits recombinant PKC isoforms α, β1, β2, γ, δ, ζ, ε; to identify the minimal amino acid sequence of PKI55 protein maintaining the inhibitory effects on PKC, peptides derived from both C- and N-terminal sequences have been synthesized. The N-terminal peptides 5 (MLYKLHDVCRQLWFSC), 8 (CRQLWFSC) and 9 (CRQLW), that in human neutrophils retain the inhibitory activity on PKC, decrease the chemotaxis, and, in mice, display anti-inflammatory and analgesic action, after both central and peripheral administration of very low doses. Furthermore, the peptide 5 shows neuroprotective activity in a model of cerebral ischemia in vitro, favouring the recovery of synaptic function. These findings suggest interesting possible therapeutic applications for these peptides.

The piperidin-4-ones have been reported as versatile intermediates. They have been synthesized using a variety of methods, including Mannich reaction and stereoselective synthesis. The piperidin-4-ones have been reported to possess various pharmacological activities, including anticancer and anti HIV activities. The pharmacophore can be suitably modified in order to achieve better receptor interactions and biological activities. The renewed interest in the nucleus has re-established the importance of piperidin-4-ones in medicinal chemistry. The review intends to discuss the current research trends in the synthetic protocols, characterization, stereochemistry and important biological activities of piperidin-4-ones during the last decade.

Ideally a drug should be administered in a form that it exerts its pharmacological action at the target site using the lowest concentration possible and without undesirable effects. Drug targeting is the approach which is followed for the purpose. Among different approaches preparation of synthetic glycosides of target drug and administering them orally is one of the most recent approaches. The drug glycoside on reaching colonic region releases the active drug through enzymatic action. This approach has been detailed with different successful examples. Synthetic drug-glycosides, besides being used as drug targeting agents, have been shown to exhibit varied biological activities such as antineoplastic, antidiabetic, antiinfllamatory etc., which have been reviewed. Synthetic approaches to O-, C-, N-, S glycosides have been discussed.

Research into metal complexes of known antimalarial drugs have been known for 30 years. Initial exploration into this field was fairly slow and largely limited to the synthesis of the complexes and reporting of antiplasmodial efficacy. In the last five years this approach has shifted substantially. Increasingly papers dealing with the mechanism of action, the speciation of the complexes, and other aspects of the interaction of these complexes in the biological system are appearing. This shift in focus indicates that the application of bioinorganic and bioorganometallic chemistry are beginning to mature into well established fields of research. This paper tracks the development of this field from the humble beginnings to the development of a substantial body of research.

Pyrroloquinoxalines have proved to be a very attractive scaffold for medicinal chemist in the recent past. These compounds were extensively studied as bioactive compounds and many of them are known to be biologically and medicinally useful molecules, such as anti-HIV agents, antimalarial agents, antagonist agents, anticancer agents, and PARP-1 inhibitors. Additionally, pyrroloquinoxalines are also important intermediates for the construction of 5-HT3 receptor agonists. In this review the developments in biological activities and synthetic methodologies of pyrroloquinoxalines are discussed.

Polar regions are remote and challenging areas on the earth. In view of the unique environment and the severe competition in polar regions, it's considered that the ecological system might be the producer of new compounds with diversity biological activities. This review is an attempt to consolidate the studies about 97 natural products isolated from Antarctic and Arctic organisms including microbes, algae, sponges, bryozoans, and tunicates and so on published in the recent years. The emphasis is mainly about the new compounds, source organisms and biological activities, which signifies the immense competence of Antarctic and Arctic organisms as bioactive natural products producers.