Current Medicinal Chemistry - Volume 15, Issue 3, 2008

This minireview aims to demonstrate that (i) natural nanotubes play important roles in chemical signaling and (ii) they represent one of the deep functional similarities between neural and immune synapses. We also pay attention to the related receptor assemblies and possibilities of chemically synthesized carbon nanotubes to simulate functions of the natural ones.

With the advances in molecular biology and biochemistry new imaging and treatment modalities based on the biological properties of tissues have been developed where important progress has been achieved using antibodies and peptides. This paper will concentrate on peptide vectors. When labeled with therapeutic radioisotopes these agents are suitable for endoradiotherapy and exploit the targeting potential for highly specific treatment which has been realized for antibodies against CD20 or peptides binding to somatostatin receptors. This novel class of pharmaceuticals offers the potential to develop specific therapies beyond the possibilities of current chemotherapy and radiation therapy. Furthermore, these achievements can be seen as proof of principle and encourage more research towards the identification of new specifically binding molecules. Activities towards the development of new biomolecules can be based on biotechnology methods. Rational design uses informations obtained from structure-activity relationship studies and conformational analyses of peptide structures. This approach relies on the identification of lead compounds and screening of various derivatives of these compounds. In contrast to rational design the central idea of black box approaches is to create vast libraries of possible variants of molecules and screen the population for the few compounds that show the property of interest. The attracting feature relies on the huge number of candidate molecules that can be used for further evaluation. After the characterization of the structure-function relationships for the lead compounds found in this process further improvement by rational design of analogs can be performed.

Positron Emission Tomography has become a powerful scientific and clinical tool probing biochemical processes in the human body. Their clinical applications have proven to be vital in the evaluation and diagnosis of diseases. This is due, in large part, to advances in instrumentation and synthetic chemistry. Carbon-11 is a valuable radionuclide in PET as it virtually permits the synthesis of radiolabelled versions of any compound of interest. The syntheses with carbon-11 present several features: limited number of labelled precursors, sub-micromolar amounts of the starting materials, and a need for the introduction of the radioisotope as late as possible in the synthesis. All of these reasons have restricted complex radiosyntheses. The short half-life of carbon-11 (20.4 min) requires the rapid preparation and purification of carbon-11 labelled molecules. Those have to be carried out immediately before use from cyclotron produced precursors ([11C]CO2, [11C]CO, [11C]CH4) or reagents rapidly prepared from them ([11C]CH3I, [11C]COCl2, [11C]HCN). As a consequence carbon-11 has been underused compared to fluorine-18. However, because of the increasing molecular complexity and diversity of biologically active compounds, there is a need for new methodologies giving access in short time and high yield to radioactive 11C-probes. The aim of this review is to emphasize the methodologies used in this field and to give a comprehensive overview of the numerous advances, which occurred over the past decade. In addition, for each labelling technique or reaction reported, a special attention has been brought to classify the applications in function of the targeted medical domain.

In this review it is shown that nimesulide, a selective cyclooxigenase-2 (COX-2) inhibitor, is different from other selective COX-2 inhibitors and classical non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effect mechanism of nimesulide (inhibition of inflammatory mediators) is similar to other classic NSAIDs, but the protective effect of nimesulide on classic NSAIDinduced ulcers elucidates the difference between nimesulide and these other drugs. It is known that the selective COX-2 inhibitor nimesulide prevents NSAID-induced ulcers, while celecoxib and rofecoxib, which are more selective to COX-2, failed to prevent these ulcers. Nimesulide produces gastro-protective effects via a completely different mechanism. In addition, while selective COX-2 inhibitors increase the risk for cardiovascular diseases, nimesulide does not exert significant cardiotoxicity. This data suggests that gastrointestinal side effects of classic NSAIDs cannot be related to the COX-1 inhibition alone and also suggest that nimesulide is an atypical NSAID, which is different from both non-selective and selective COX-2 inhibitors.

In this review, benefits and side-effects of current and emerging therapies to treat and prevent pathological bone loss are described. Bisphosphonates are the antiresorptive compounds most widely used in the treatment of bone-loss associated diseases. They are generally well-tolerated although have recently been associated with osteonecrosis of the jaw and other complications. Therapies modulating estrogen receptor activation are indicated in the prevention and treatment of either breast cancer or osteoporosis in postmenopausal women. Thus, hormone replacement therapy is effective in prevention of osteoporosis, but its long-term use can increase the risk of breast cancer, stroke and embolism. Tamoxifen benefits all stages of breast cancer, but its use may lead to uterine cancer and thromboembolism. Raloxifene is approved in prevention of breast cancer and treatment of postmenopausal osteoporosis, but its use can increase the risk of fatal stroke. Aromatase inhibitors are superior to tamoxifen at advanced stages of disease and as adjuvants, but their use increase fracture incidence. Fulvestrant is as effective as aromatase inhibitors in the treatment of advanced breast cancer and does not cause bone fractures. Another antiresorptive available for the treatment of postmenopausal osteoporosis, Paget's disease and hypercalcemia is calcitonin, which also exhibits analgesic effects. A promising antiresorptive agent currently in clinical trials is denosumab. Aditional therapies for osteoporosis that decrease fracture risk consist of PTH-like anabolic agents and the dual action bone agent strontium ranelate. Antiseptics and antibiotics are used extensively in periodontal disease intervention to target bacterial biofilm, although hostdirected therapies are also being developed.

Octacalcium phosphate (Ca8H2(PO4)6.5H2O; OCP) has been advocated to be a precursor of biological apatite crystals in bone and tooth. Recent studies, using physical techniques, showed that OCP is present as a transient phase during biological apatite formation in human dentin, porcine enamel and murine bone. However, there is still a controversy regarding the chemical nature of the first mineral formed in the biominerals. A number of studies have demonstrated that synthetic OCP shows bone regenerative and biodegradable characteristics, rather than other calcium phosphate bone substitute materials, such as hydroxyapatite (Ca10(PO4)6(OH)2; HA) ceramic. It seems likely that synthetic OCP may be an alternative to autogenous bone graft. It is known that OCP contains alternative layers of water molecules and an apatite structure, and that the transition of OCP to HA is likely to be spontaneous and irreversible. The conversion process induces modification of local environment adjacent to OCP surface, including the changes in adsorption of serum proteins and concentration of calcium and inorganic phosphate ions. This article reviews the possible application to bone regeneration by synthetic OCP and the mechanism to enhance bone regeneration in relation to biological mineralization in bone and tooth.