Current Medicinal Chemistry - Volume 16, Issue 2, 2009

The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) γ agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.

For decades, the focus of therapy to mitigate cardiovascular risk has been to lower low density lipoprotein cholesterol (LDL-C), so called “bad cholesterol”. Widespread use of statins has resulted in a large body of clinical experience, which indicates that lower LDL-C levels do indeed correlate with decreased risk of cardiovascular and coronary artery diseases (CVD and CAD). Given these findings, recommended targets for LDL-C levels are continually being revised lower. Interestingly, however, even at low LDL-C levels there remains a substantial residual risk of CVD and CAD, particularly in patients with additional contributing factors. Recent post-hoc analyses of several large lipid modulation trials specifically assessing high density lipoprotein cholesterol (HDL-C) have revealed that increased HDL-C levels confer additional benefit against risk of CVD and CAD, even when LDL-C levels are already low. Human clinical outcomes trials that specifically target increasing HDL-C have not yet been conducted. However, the strong epidemiological inverse correlation between HDL-C and CVD risk remains. Discovery efforts aimed at increasing circulating levels of HDL-C have increased dramatically in recent years. This review will cover recent efforts and agents being developed such as cholesterol ester transfer protein inhibitors and nicotinic acid receptor agonists among other potential strategies.

Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.

Lipid-based drug carriers, such as liposomes or drug/lipid complexes, have been extensively investigated in a large number of therapeutic protocols such as gene therapy, drug delivery, drug targeting and antibacterial treatments, in preclinical and clinical trials. Many formulations composed of natural and/or synthetic amphiphiles have been studied. Many synthetic lipids and surfactants have been designed and tested in order to improve liposomes and lipid complexes performances, such as fusion with cellular membrane, cellular uptake, target selectivity, transfection efficiency, low toxicity. Among these, gemini surfactants have been shown to be highly effective in delivering genetic material to cells, and also have been shown promising as synthetic additives in liposome formulations for drug delivery. The encouraging results obtained in gene therapy have given impulse to chemist creativity: an extensive selection of pH sensitive, sugar-, aminoacid- , and peptide-based gemini surfactants have been developed, many of which have shown good biological features. This review focuses on recent progress in gemini surfactant based formulations and their applications in different therapeutic protocols.

The transport mechanisms of ascorbic acid (AA) are described. The metabolism of AA and its function as an antioxidant are covered in some detail. Subsequently, indications for postoperative substitution are discussed. The supplementation of up to 300 mg of AA per day in postoperative intensive care unit patients during par-/enteral nutrition is recommended to prevent hypovitaminosis. It is not clear if this is the optimal dosage of AA in postoperative/-trauma patients. New aspects for an AA substitution are discussed.

Drug design has become inconceivable without the assistance of computer-aided methods. In this context in silico was chosen as designation to emphasize the relationship to in vitro and in vivo testing. Nowadays, virtual screening covers much more than estimation of solubility and oral bioavailability of compounds. Along with the challenge of parsing virtual compound libraries, the necessity to model more specific metabolic and toxicological aspects has emerged. Here, recent developments in prediction models are summarized, covering optimization problems in the fields of cytochrome P450 metabolism, blood-brain-barrier permeability, central nervous system activity, and blockade of the hERGpotassium channel. Aspects arising from the use of homology models and quantum chemical calculations are considered with respect to the biological functions. Furthermore, approaches to distinguish drug-like substances from nondrugs by the means of machine learning algorithms are compared in order to derive guidelines for the design of new agents with appropriate properties.

Postprandial lipemia has emerged as an independent risk factor for coronary artery disease. In this systematic review we examined the effect of the medications used for the management of dyslipidemia on postprandial lipemia. Statins, beyond their effects on fasting lipid levels, reduce also postprandial lipemia mainly by inhibiting the production of apoB containing lipoproteins from the liver and thus increasing the clearance of triglyceride-rich lipoproteins of either liver or intestinal origin. Fibrates decrease fasting triglyceride and increase high density lipoprotein cholesterol levels. Besides, fibrates are particularly potent drugs in the reduction of postprandial lipemia; they decrease the production or triglyceride-rich lipoproteins and increase their clearance by enhancing the activity of lipoprotein lipase.

Prenylated indole derivatives are hybrid natural products containing both aromatic and isoprenoid moieties and are widely spread in plants, fungi and bacteria. Some of these complex natural products, e.g. the ergot alkaloids ergotamine and fumigaclavine C as well as the diketopiperazine derivative fumitremorgin C and its biosynthetic precursors tryprostatin A and B, show a wide range of biological and pharmacological activities. Prenyl transfer reactions catalysed by prenyltransferases represent key steps in the biosynthesis of these compounds and often result in formation of products which possess biological activities distinct from their non-prenylated precursors. Recently, a series of putative indole prenyltransferase genes could be identified in the genome sequences of different fungal strains including Aspergillus fumigatus. The gene products show significant sequence similarities to dimethylallyltryptophan synthases from fungi. We have cloned and overexpressed six of these genes, fgaPT1, fgaPT2, ftmPT1, ftmPT2, 7- dmats and cdpNPT from A. fumigatus in E. coli and S. cerevisiae. The overproduced enzymes were characterised biochemically. Three additional prenyltransferases, DmaW-Cs, TdiB and MaPT were identified and characterised in a Clavicipitalean fungus, Aspergillus nidulans and Malbranchea aurantiaca, respectively. Sequence analysis and alignments with known aromatic prenyltransferases as well as phylogenetic analysis revealed that these enzymes belong to a new group of “aromatic prenyltransferases”. They differ clearly from membrane-bound aromatic prenyltransferases from different sources and soluble prenyltransferases from bacteria. The characterised enzymes are soluble proteins, catalyse different prenyl transfer reactions on indole moieties of various substrates and do not require divalent metal ions for their enzymatic reactions. All of the enzymes accepted only dimethylallyl diphosphate as prenyl donor. On the other hand, they showed broad substrate specificity towards their aromatic substrates. Diverse tryptophan derivatives and tryptophancontaining cyclic dipeptides were accepted by these enzymes, providing a new strategy for convenient production of biologically active substances, e.g. by chemoenzymatic synthesis.

Cytochrome P450s are the most important enzymes responsible for phase I drug metabolism. The polymorphic nature of cytochrome P450s largely influences individual drug responses, drug-drug interactions and induces adverse drug reactions. By far, thirty crystal structures of eight mammalian cytochrome P450s (CYP 2C5, 2C8, 2C9, 3A4, 2D6, 2B4, 2A6 and 1A2) have been published. This review focuses on the recent studies on the structures of cytochrome P450s: some characteristic features of these enzymes and many essential, conserved amino acids in the active sites have been identified. These results are of fundamental importance for drug development and understanding the metabolism for both endogenous and xenobiotic substrates. With the help of computational methods, the structural information will provide insights into personalization of drug treatments in both proper drug therapy and appropriate dosage of a certain drug.

Temozolomide (TMZ) is an oral anticancer agent approved for the treatment of newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has shown comparable efficacy with respect to dacarbazine, the reference drug for metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile, TMZ is under clinical investigation for brain metastasis from solid tumors and refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl adducts mainly represented by N-methylpurines. However, its antitumor activity has been mainly attributed to O6-methylguanine, since tumor cell sensitivity inversely correlates with the levels of O6-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Therefore, an increasing number of studies have been performed in order to identify patients who will benefit from TMZ treatment on the basis of their molecular/genetic profile. Unfortunately, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of the clinical response in cancer patients. Thus, different approaches have been developed to abrogate resistance or to increase the efficacy of TMZ and for many of them investigation is still underway. Herein, we provide an overview on the recent findings of preclinical and clinical studies on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with different mechanisms of action or radiotherapy, anti-angiogenic agents and other biological modulators.