Mini Reviews in Medicinal Chemistry - Volume 8, Issue 13, 2008

The main objective of the MRMC is to publish concise reviews on important developments in medicinal chemistry and related disciplines. Since the inaugural publication in May 2001, MRMC has gained a considerable stature in the field of medicinal chemistry and is now regarded as a very respectable review Journal (Impact Factor 3.06). The success of MRMC is based on the deep commitment of outstanding Regional Editors (RE), eminent contributors, committed administrative and technical staff and members of the Editorial Advisory Board (EAB). A flow of excellent manuscripts continue to be received, reviewed and published. In this Special Issue, contributions from a Regional Editor and our Editorial Advisory Board Members (5) are presented. Andreas Hilgeroth (EAB) (Martin-Luther University, Halle, Germany) and his colleague present a review of selective kinase inhibitors as potential anticancer drugs. They also note that since these drugs are relatively new, perhaps, potential sideeffects might be found in future extended usage. Georg Petroianu (EAB), United Arab Emirates University, Al Ain, UAR) and co-worker discuss reactivation of organic phosphorus cholinesterase inhibitors utilizing pyridinium oximes. Paula I. Moreira (EAB) (University of Coimbra, Coimbra, Portugal) and co-workers present an overview on the antihyperglycymic and clinical effects of metformin in the treatment of Type 2 diabetes. Hugo Cerecetto (EAB) (Dep. Quimica Organica, Montevideo, Uruguay) and his co-worker discuss the developments of new chemical entities for treatment of third world parasitic diseases, especially Chagas disease. Ross P. McGeary (RE) (The University of Queensland, Brisbane, Australia) and co-workers survey the applications of Suramin in the treatment of African river blindness and sleeping sickness and many types of cancers. George Perry (EAB) (College of Sciences, University of Texas at San Antonio) and collaborators discuss antioxidant therapy in the treatment of Alzheimer disease. We wish to acknowledge our colleagues for their excellent contribution and for their efforts in the preparation of the manuscripts.

During the last two decades, protein kinases have emerged as a major target for cancer therapy and a large number of selective kinase inhibitors have been developed as potential anticancer drugs. To avoid unpredictable toxic effects, researchers usually aim at designing highly selective inhibitors. But since the formation and progression of a tumor has to be considered as a multifactorial process, which is dependent on different signalling pathways, it seems reasonable to establish anticancer therapies that target several kinases associated with tumor growth. In general, this can be achieved by two different strategies, either by concomitantly using a combination of a set of selective kinase inhibitors or by administering a single agent, which simultaneously inhibits several kinases, a so called multi-kinase inhibitor. In this review, benefits and obstacles of both strategies are discussed. An overview over recently approved and newly upcoming multi-kinase inhibitors is given.

Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC50 (intrinsic oxime AChE inhibitory activity), of tan α (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD50) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC50) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan α) also have a high in vitro AChE inhibitory activity (low IC50) and have a low LD50 in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.

Type 2 diabetes is a major health problem associated with excess mortality and morbidity. Vascular complications are one of the most serious consequences of this disorder. Moreover, type 2 diabetes is also a risk factor for cerebral complications, including cognitive impairment and dementia. However, it has been shown that tight glycemic control contributes to reduce the incidence of diabetes-associated complications. Metformin is a potent antihyperglycemic agent widely used in the management of type 2 diabetes whose main actions are the suppression of gluconeogenesis and the improvement of glucose uptake and insulin sensitivity. This review is mainly devoted to describe the mechanisms of action underlying the antidiabetic effects of metformin. Furthermore, we will present evidence for the protective effects of metformin against diabetes-associated complications mainly cerebral and vascular complications. Finally, we will describe the few known side effects associated to this antidiabetic agent.

Chagas' disease is the major endemic disease in South and Central America caused by a trypanosomatid parasite (Trypanosoma cruzi). The current treatment relies on two old and nonspecific chemotherapeutic agents, Nifurtimox and Benznidazole. Despite the major advances that have been made in the identification of specific targets that afford selectivity, the drugs used today have serious side effects. Furthermore, differences in drug susceptibility among different T. cruzi isolates have led to varied parasitological cure rates depending on the geographical region. There is, therefore, an urgent need for the development of new antichagasic drugs. In this regard we have spent more than a decade in the search for more effective agents able to compromise the proliferation of T. cruzi. We began our research with our own compounds and then continued with compounds from other researcher groups. We systematically characterized representatives of a wide range of different chemical families. In this review we summarize our ongoing efforts to identify potential anti-T. cruzi agents using our compound-library. It is discussed and presented the structure- activity relationship observed among the different groups of chemical families.

Suramin is a polysulfonated polyaromatic symmetrical urea. It is currently used to treat African river blindness and African sleeping sickness. Suramin has also been extensively trialed recently to treat a number of other diseases, including many cancers. Here, we examine its modes of action and discuss its structure-activity relationships.

Alzheimer disease treatment has yet to yield a successful therapy that addresses the source of the damage found in brains. Of the varied proposed theories of AD etiology, reactive oxygen species (ROS) generation is cited as a common factor. Efforts to reduce the pathology associated with ROS via antioxidants therefore offer new hope to patients suffering from this devastative disease.

During the last few decades microporous and mesoporous materials have been considered for medical use due to biological properties and stability in biological environment. Zeolites have been investigated as drug carriers, and as adjuvants in anticancer therapy, dietetic supplements or antimicrobial agents. This review gives a brief overview of the major aspects of molecular sieves applications in medicine.

The epidermal growth factor receptor (EGFR) is the main tyrosine kinase receptor dysregulated or overexpressed in brain cancer types and its expression is directly correlated with tumor malignancy and unfavorable prognosis. Recently, the availability of endogenous EGFR ligands has been reported to be also regulated indirectly by the activation of several G-protein-coupled receptors (GPCRs) in many cancer cell types. This EGFR transactivation mechanism requires the initial activation of a GPCR that in turn induces the cleavage of membrane-bound EGFR ligands precursors via the involvement of the family of disintegrin and metalloproteases (ADAMs). The discovery of ADAMs in this transactivation mechanism led to the development of small molecule inhibitors. In this minireview we describe the expression of GPCR, ADAMs and EGFR ligands in human glioma brain tumors and the characteristics of small molecule ADAMs inhibitors. The addition of ADAM inhibitors to our pharmacological arsenal could enhance the outcome of combination therapies when using EGFR inhibitors against human brain tumors.

The purpose of this review is to discuss the recent developments related to the chemistry and medicinal properties of flavonoids. Major flavonoids that show well categorized structures and well defined structure functionrelationships are: flavans, flavanones, flavones, flavanonols, flavonols, catechins, anthocyanidins and isoflavone. The biological properties of flavonoids include antioxidant, anti-inflamatory, antitumoral, antiviral and antibacterial, as well as a direct cytoprotective effect on coronary and vascular systems, the pancreas and the liver. These characteristics place them among the most attractive natural substances available to enrich the current therapy options.