Current Medicinal Chemistry - Volume 16, Issue 1, 2009

In their structural multiplicity and in the extent to which they occur in nature the derivatives of benzofuran are significantly lesser than the isoelectronic analogue indoles. However, these heterocyclic compounds show a variety of pharmacological properties, and change of their structure offers a high degree of diversity that has proven useful for the search of new therapeutic agents. The broad spectrum of pharmacological activity in individual benzofurans indicates that this series of compounds is of an undoubted interest. From this point of view, synthetic methods may be of very useful aid in the production of specific structures characterized by given pharmacological qualities. Moreover from a drug discovery perspective, synthesis of chiral functionalized substituted benzofurans could be more interesting because they might constitute starting materials for the production of biologically active compounds. Taking into account the actual tendency directed toward the development of enantiomerically pure drugs, indeed there is a limited number of papers related to the preparation of enantiomers of benzofuran containing compounds, likely because of difficulties in their preparation with conventional methods. In this context, new approaches seem to expand the potentiality of the synthesis of substituted benzofurans, providing also convenient routes to enantiopure 2-substituted benzofurans.

Topological polar surface area (TPSA), which makes use of functional group contributions based on a large database of structures, is a convenient measure of the polar surface area that avoids the need to calculate ligand 3D structure or to decide which is the relevant biological conformation or conformations. We demonstrate the utility of TPSA in 2DQSAR for 14 sets of diverse pharmacological activity data. Even though a large pool of reports showing the importance of the classic 2D descriptors such as calculated logP (ClogP) and calculated molar refractivity (CMR) exists in the 2DQSAR literature, this is the first report to demonstrate the value of TPSA as a relevant descriptor applicable to a large, structurally and pharmacologically diverse set of classes of compounds. We also address the limitations of applicability of this descriptor for 2D-QSAR analysis. We observed a negative correlation of TPSA with activity data for anticancer alkaloids, MT1 and MT2 agonists, MAO-B and tumor necrosis factor-α inhibitors and a positive correlation with inhibitory activity data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria, trypanosomatids and CB2 agonists.

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the antiinfective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents.

Targeted therapy is considerably changing the treatment and prognosis of cancer. Progressive understanding of the molecular mechanisms that regulate the establishment and progression of different tumors is leading to ever more specific and efficacious pharmacological approaches. In this picture, ion channels represent an unexpected, but very promising, player. The expression and activity of different channel types mark and regulate specific stages of cancer progression. Their contribution to the neoplastic phenotype ranges from control of cell proliferation and apoptosis, to regulation of invasiveness and metastatic spread. As is being increasingly recognized, some of these roles can be attributed to signaling mechanisms independent of ion flow. Evidence is particularly extensive for K+ channels. Their expression is altered in many primary human cancers, especially in early stages, and they frequently exert pleiotropic effects on the neoplastic cell physiology. For instance, by regulating membrane potential they can control Ca2+ fluxes and thus the cell cycle machinery. Their effects on mitosis can also depend on regulation of cell volume, usually in cooperation with chloride channels. However, ion channels are also implicated in late neoplastic stages, by stimulating angiogenesis, mediating the cell-matrix interaction and regulating cell motility. Not surprisingly, the mechanisms of these effects are manifold. For example, intracellular signaling cascades can be triggered when ion channels form protein complexes with other membrane proteins such as integrins or growth factor receptors. Altered channel expression can be exploited for diagnostic purposes or for addressing traceable or cytotoxic compounds to specific neoplastic tissue. What is more, recent evidence indicates that blocking channel activity impairs the growth of some tumors, both in vitro and in vivo. This opens a new field for medicinal chemistry studies, which can avail of the many available tools, such as blocking antibodies, antisense oligonucleotides, small interfering RNAs, peptide toxins and a large variety of small organic compounds. The major drawback of this approach is that some ion channel blockers produce serious side effects, such as cardiac arrhythmias. Therefore, drug developing efforts aimed at producing less harmful compounds are needed and we discuss possible approaches toward this goal. Finally, we propose that a novel therapeutic tactic could be developed by unlocking ion channels from multiprotein membrane signaling complexes.

Micro- and macrovascular complications are major causes of disability and death in patients with diabetes mellitus. Functional impairment of endothelial activity precedes the development of morphological alterations during the progression of diabetes. This endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO), mainly due to accelerated NO degradation by reactive oxygen species (ROS). Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via several distinct mechanisms, increased oxidative stress seems to be the first alteration triggering several others. Mechanisms proposed to explain glucose- and lipid-induced vascular alterations in diabetes include accelerated formation of advanced glycation end-products (AGEs), protein kinase C activation, inflammatory signaling and oxidative stress. Insulin resistance with impaired PI 3-kinase effects decreases insulin mediated production of NO and reduces vasodilation, capillary recruitment and antioxidant properties of endothelium. Compensatory hyperinsulinemia enhances activation of intact MAP-kinase pathways and contributes to pro-atherogenic events by increasing secretion of endothelin-1 (ET-1), stimulating expression of adhesion molecules such as VCAM-1 and E-selectin, and inducing production of ROS. Conventional therapies to reduce hyperglycemia, dyslipidemia and insulin resistance may effectively improve endothelial function and delay the onset of vascular complications. Novel therapeutic approaches designed to inhibit AGEs formation, reduce PKC activation, decrease inflammatory signals and restore the ox/redox balance of endothelium may be predicted to ameliorate vascular function in diabetic state. This review summarizes the current knowledge on the most important mechanisms involved in endothelial dysfunction during diabetes. In addition, novel therapeutic strategies that may result from recently identified targets are also described.

Iron is one of the essential minerals that are required for a variety of molecules to maintain their normal structures and functions and for cells to live, grow, and proliferate. The homeostasis of iron results from a tightly coordinated regulation by different proteins involved in uptake, excretion and intracellular storage/trafficking. Although it is essential, iron can also be toxic once in excess amounts. Through Fenton reaction, iron as a transit mineral can generate various reactive oxygen or nitrogen species; therefore, abnormal metabolism of iron can lead to several chronic pathogenesis. Oxidative stress is one of the major causative factors for diabetes and diabetic complications. Increasing evidence has indicated that iron overload not only increases risks of insulin resistance and diabetes, but also causes cardiovascular diseases in non-diabetic and diabetic subjects. Temporal iron deficiency was found to sensitize insulin action, but chronic iron deficiency with anemia can accelerate the development of cardiovascular diseases in non-diabetic and diabetic patients. In this review, therefore, we will first outline iron homeostasis, function, and toxicity, and then mainly summarize the data regarding the roles of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications, as well as the possible links of iron to diabetes and diabetic complications. In the end, the possible therapy using iron chelators for diabetes and diabetic complications will also be discussed.