Current Medicinal Chemistry - Volume 17, Issue 7, 2010

In regenerative medicine, stem cells are currently considered ideal candidates for the treatment of diseases and injuries of the nervous system, for which, at present, there are no effective treatments. Promising results have been shown by clinical trials for neurodegenerative diseases such as Parkinson's diseases, but also for demyelinising disorders and traumatic lesions of the brain and spinal cord. The proof-of-principle is that the replacement of damaged cells and the restoration of function can be accomplished by the transplantation of embryonic or adult stem cells. Advancements in stem cell biology were recently propelled by the ability to generate induced pluripotent stem (iPS) cells from fibroblasts of several neurodegenerative diseases (e.g. Parkinson's and Huntington's diseases, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy). In this review, we discuss the molecular basis of stem cell therapy and the advancement of research on regenerative medicine for diseases and injuries of the nervous system.

The targeting of tubulin is an important mechanism for cancer chemotherapy. However, limitations such as resistance, toxicity and incomplete tumour elimination associated with individual anti-cancer drugs have led to a need for combination therapy in cancer. It is therefore relevant to ask whether two or more drugs might be combined in a single hybrid molecule to advantageous effect. This review provides an overview of the hybrid drugs thus far investigated, in which at least one component targets tubulin. The rationale behind this approach is that the hybrid drug may have activity enhanced above and beyond that of the equivalent drug combination, or have an otherwise improved clinical outcome. Particular emphasis is placed on the investigation of activity in multidrug-resistant cancer cell lines. Attention is drawn to the difficulties encountered when developing hybrid drugs, with respect to in vivo metabolism-tracking, increased molecular bulk, and optimisation of the drug dosage ratio. The actual and potential advantages and disadvantages of such hybrid drugs when compared to single drugs or drug combinations are discussed critically and promising directions for future research is highlighted.

Multiple sclerosis (MS) is considered to be an autoimmune disease leading to inflammatory demyelination and axonal damage in the central nervous system (CNS). Current treatments involve non-specific immunosuppression and immunomodulation. The development of monoclonal antibodies for therapeutic use allows targeting of specific immune mechanisms. Natalizumab, a monoclonal antibody directed against α4β1 integrin that plays a crucial role in the transmigration of immune cells across the blood-brain-barrier, has been licensed for relapsing-remitting (RR) MS in 2006. Rituximab, directed against CD20 expressed on pre B-cells and B-cells has been tested successfully in a phase II trial and suggests that several B-cell dependent mechanisms may be relevant to the mode of action. Alemtuzumab, targeting CD52 expressed on T-cells, B-cells, monocytes and macrophages, has also shown to be effective in early RRMS and phase III trials are currently ongoing. Daclizumab binds to CD25, the alpha chain of the interleukin (IL)-2 receptor, and is also being tested for RRMS. Beside the clinical data the results from these clinical trials give also new insights into the pathogenesis of MS. We critically discuss the potential but also the pitfalls and potential hazards of these new therapeutic strategies.

The saccharin ring system has gained considerable attention in the past decades, especially in the field of medicinal chemistry. The wide applicability of saccharin derivatives remains the driving force behind the constant development of novel routes and methods that provide new access to the construction of saccharin. Since the functionalization of this heterocycle has proved difficult, except for N- and O-alkylation, novel strategic approaches are much sought-after and thus constitute a great value to any medicinal chemist. In addition to the synthetic novelties introduced into the synthesis and functionalization of this particular heterocycle, the numerous newly discovered biological activities of saccharin and its derivatives are also reviewed. Saccharin may be considered to constitute a privileged framework on account of its role as a key structural element in several biologically active compounds ranging from enzyme inhibitors to receptor ligands and beyond.

In many different species, lactate dehydrogenase (LDH) constitutes a major checkpoint of anaerobic glycolysis, by catalyzing the reduction of pyruvate into lactate. This enzyme has recently received a great deal of attention since it may constitute a valid therapeutic target for diseases so different as malaria and cancer. In fact, the isoform expressed by Plasmodium falciparum (pfLDH) is a key enzyme for energy generation of malarial parasites. These species mostly depend on anaerobic glycolysis for energy production, since they lack a citric acid cycle for ATP formation. Therefore, inhibitors of pfLDH would potentially cause mortality of P. falciparum and, to this purpose, several small organic molecules have been recently designed and developed with the aim of blocking this new potential antimalarial chemotherapeutic target. Moreover, most invasive tumour phenotypes show a metabolic switch (Warburg effect) from oxidative phosphorylation to an increased anaerobic glycolysis, by promoting an upregulation of the human isoform-5 of lactate dehydrogenase (hLDH-5 or LDH-A), which is normally present in muscles and in the liver. Hence, inhibition of hLDH-5 may constitute an efficient way to interfere with tumour growth and invasiveness. This review provides an overview of the LDH inhibitors that have been developed up to now, an analysis of their possible isoform-selectivity, and their therapeutic potentials.