Current Medicinal Chemistry - Volume 14, Issue 1, 2007

This review discusses antibacterial peptides from the perspective of development into clinically useful chemotherapeutic drugs using short lactoferricin based peptides as examples. The review shows how important features for antibacterial activity can be identified and explored using the molecular properties of a range of natural and non-natural amino acids. The results have been further refined quantitatively using a “soft-modelling” approach where important structural parameters that influence the antibacterial activity of 15-residue model peptides were identified. The review describes how this knowledge is utilised to generate pharmacophores for antibacterial efficacy. These pharmacophores turn out to be surprisingly small and relatively consistent between typical Gram-negative and Gram-positive bacteria leading to the discovery of a novel class of short synthetic cationic antimicrobial peptides. These compounds are found to have high antibacterial activity against several bacterial strains that are resistant to commercial antibiotics, and are promising as future clinical candidates for treatment of infections caused by several clinically relevant pathogens.

Two of the main pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques and neurofibrillary tangles. Significant evidence supports a critical and probable causative role of βamyloid (Aβ) plaque formation. Since neuroprotective treatments are typically most effective at early stages of injury, the detection and measurement of Aβ load in living brain should be performed at early and perhaps even presymptomatic stages of AD. Two primary targets of molecular imaging research with positron emission tomography (PET) are to develop surrogate markers (radioligands) for assessing disease progression and for monitoring the efficacy of developmental therapeutics. Here, we review the current status of radioligand development for PET imaging of Aβ aggregates. General structure-activity relationships have emerged, including the identification of at least three different ligand binding sites in various Aβ aggregates and recognition of the general structural requirements for ligand binding at each site. Also a few radioligands applicable to imaging Aβ plaques in living human brain with positron emission tomography (PET) have emerged, including [11C]PIB, [11C]SB- 13 and [18F]FDDNP.

Beta-blockers are a very important group of drugs widely used for the treatment of cardiovascular diseases. All aryloxyaminopropanols are chiral and show different stereoselectivity in their pharmacodynamic and pharmacokinetic properties for each enantiomer. The more potent beta-adrenoceptor blocking activity is generally associated with (S)-enantiomers. Most beta-blocking agents are sold as racemates although (R)- enantiomers not only show in some cases lack of activity but might be responsible for undesirable effects. Among reports on the direct enzymatic resolution of the most representative beta-blocker propranolol, the most interesting is N-acetylation method with commercially available lipases to yield (S)-Nacetylpropranolol. Another type of the one-step (S)-isomer biocatalytic preparation from racemic mixture of propranolol is the biodegradation with the fungus. Biocatalytic methods of obtaining homochiral beta-blockers that are focused on production of versatile precursors are widely described in literature. The strategies based on the use of glycidol and derivatives as C-3 synthones have been shown to be extremely useful for the introduction of the 2-propanol chain on the aromatic system. Halohydrins are the established intermediates in the preparation of optically active beta-blockers. Its resolution by esterhydrolases has been used as a standard alternative in preparation of the homochiral propranolol. Additionally, the enzymatic resolution of the following intermediates was reported: 1-azido-3- aryloxy-2-propanols, 4-(1-aryloxy)-3-hydroxybutyric acid esters, glycerol and cyanohydrin derivatives. However, even the highly enantioselective lipase-catalyzed process can only provide 50% of the starting racemate in an optically active form. An alternative method such as a reduction of a prochiral ketone by various strains of yeast might quantitatively provide an enantiomeric product with a yield greater than 50%. The reported substrates for microbial reductions were: 1-halo-aryloxypropan-2-ones and 1-acetoxyaryloxypropan- 2-ones.

Airway inflammation is an outcome of complex interactions of multiple cell types in an inflammatory network. In recent years, it has become clear that a single target approach is unlikely to be effective for the treatment of inflammatory airway diseases such as asthma. This recognition suggests an alternative approach of targeting multiple cell types and/or mediators. Airway smooth muscle (ASM) cells are unique in serving the dual function of bronchoconstriction and inflammation in the airway system. ASM cells respond to a large array of external stimuli such as acetylcholine, bradykinin, inflammatory cytokines, and cyclic stretch with the expression of inflammatory mediators such as cytokines and cyclooxygenase products. Ca2+ influx through voltage-gated and transient receptor potential channels are important mechanisms of Ca2+-dependent transcription in ASM cells. Calcineurin and Ca2+, calmodulin-dependent kinase (CaMK) are Ca2+-sensitive enzymes that regulate the activation of the two transcription factors, nuclear factor of activated T-cells (NFAT) and cyclic AMP response element binding protein (CREB). Erk1/2 and p38 mitogen-activated protein kinases are signaling enzymes that couple receptor activation to gene transcription by phosphorylating CREB and stabilizing mRNA against de-adenylation. CREB is a unique transcription factor that is phosphorylated by both CaMK II and Erk1/2 MAPK. Nuclear factor κB (NFκB) appears to be a universal transcription factor that regulates the transcription of almost all inflammatory genes. Detailed understanding of the cellular components and interactions in the inflammatory network of the airway system may lead to rational targeting of multiple cells and mediators in the treatment of airway inflammation.

Angiogenesis plays a key role in the development of cancer and is precondition for tumor growth, invasion and spread. Therefore, numerous angiogenesis inhibitors have been developed, of which some show potential to defeat cancer in preclinical and clinical trials. However, response to antiangiogenic treatments is often delayed and marked by high interindividual variability making a closely mashed and efficient observation of the patient necessary. Therefore, surrogate markers which specifically catch early response to tumor therapy are highly desirable. Functional parameters like relative blood volume, perfusion and vessel permeability can be assessed using T1 and T2*-weighted dynamic contrast-enhanced (DCE) MRI. Various reports are available on this topic but results are controversial. During antiangiogenic therapies some authors describe pronounced changes in blood volume: others find effects only on vessel permeability or perfusion. These conflictive observations can be attributed to the different tumor models, therapies, measurement techniques and contrast agents (CA). Particularly the choice of the optimal CA is considered to be essential for a successful characterization of tumor angiogenesis. Often therapy effects on vessel permeability only become apparent, when blood pool CA are used. This article reviews the current state of DCE and molecular MRI of angiogenesis. Besides a general introduction of the different measurement and postprocessing methods and its previous applications, design, structure and use of different types of CA are the main focus of this article.

The chemokine receptor, CXCR4, is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 system plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, etc. This system has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA) and pulmonary fibrosis. Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were characterized as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. Based on our knowledge of pharmacophores of T140, CXCR4 antagonists, such as FC131, were previously found by the efficient utilization of cyclic pentapeptide libraries. This review article focuses on our recent research on the development of low molecular weight CXCR4 antagonists including FC131 analogs, in which structural tuning of the cyclic peptide ring and chemical modifications were performed for an increase in potency and a reduction of the peptide character.

Statins are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. Statins reduce serum cholesterol levels by reversibly inhibiting 3-hydroxy-3- methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, in the nanomolar range. Mounting evidence suggests that in addition to their vascular effects such as stabilization of atherosclerotic plaques and decreased carotid intimal-medial thickness, statins have additional properties such as endothelial protection via actions on the nitric oxide synthase system as well as antioxidant, antiinflammatory and anti-platelet effects. These effects of statins might have potential therapeutic implications in various neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, the major protective mechanisms of statins and their applicability to the treatment of neurological disease are summarized. Although further experiments are required, currently available data would seem to indicate that clinical trials to determine the safety and efficacy of statins in a number of disorders are warranted.

Influenza is a disease that deeply affects millions of people every year. There has not been any drug effective against all strains. Neuraminidase (NA) is the major surface glycoprotein of the influenza virus, which possesses critical enzymatic activity and has been considered as a suitable target for designing agents against influenza viruses. Here we review the structure and functions of this enzyme and touch upon the structureactivity relationship (SAR) of existing influenza neuraminidase inhibitors (NAIs).