Mini Reviews in Medicinal Chemistry - Volume 10, Issue 9, 2010

The present mini-review highlights the recent developments on different classes of synthetic hybrids of natural and/or unnatural bioactive compounds, the utilization of which is very promising, as distinct features of each component can be hybridized and their properties leveraged. Particular stress is put on the respective mode of action and the corresponding rationale behind covalent combinations of various bioactive agents to increase their therapeutic potential, facilitate their administration, to reduce harmful side effects and/or to overcome the problem of multi-drug resistance. This rather recent approach has already found applications in the development of new anti-cancer, anti-Alzheimer, antimalaria, anti-microbial therapeutics and other novel compounds with unprecedented bioactivity.

Pyrrolidine scaffold has been widely used to design a variety of N-heterocyclic derivatives towards various targets. Amongst them, matrix metalloproteins (MMPs) and aminopeptidase N (APN) represent two kinds of important metalloproteinase targets which have been proved to be tightly related to tumor proliferation, invasion, metastasis and angiogenesis. As a result, their respective inhibitors, namely MMP inhibitors (MMPIs) and APN inhibitors (APNIs), have been systematically studied in our group for many years. Recent advances in the elucidation of MMPIs and APNIs based on the pyrrolidine platforms are briefly reviewed in this paper.

Synthetic nucleoside mimics are important candidates for antiviral and anticancer drugs. Ribavirin, the first antiviral nucleoside drug, is unique in its antiviral activity with mutilple modes of action, which are mainly due to its special triazole heterocycle as nucleobase. Additionally, introducing aromatic functionalities to the nucleobase is able to confer novel mechanisms of action for nucleoside mimics. With the aim to combine the special characteristics of unnatural triazole heterocycles with those of the appended aromatic groups on the nucleobases, novel 1,2,4-triazole nucleoside analogs bearing aromatic moieties were designed and developed. The present short review summarizes the molecular design, chemical synthesis and biological activity of these triazole nucleoside analogs. Indeed, the discovery of antiviral and anticancer activities shown by these triazole nucleosides as well as the new mechanism underlying the biological activity by one of the anticancer leads has validated the rationale for molecular design and impacted us to further explore the concept with the aim of developing structurally novel nucleoside drug candidates with new modes of action.

Certain xenobiotics are given in the “prodrug” form. Either the human body, or one compartment of the body, or the targeted virus itself metabolizes the prodrug into its active form. The bioprecursor form of drugs is used for a wide variety of reasons, namely: to make drug penetration into the target organ (mainly to the brain through the blood-brainbarrier) possible, eliminate unpleasant taste, alter (either increasing or decreasing) the half life of the active component or supply more than one active components to the body.

Endocrine-disrupting chemicals (EDCs) are a group of diversely natural compounds or synthetic chemicals that can interfere with the programming of normal endocrine-signalling pathways during pre- and neonatal life, thus leading to adverse consequences later in life. In addition, early life exposure to EDCs may alter gene expression and consequently transmit these effects to future generations.

Adiponectin is a collagen-like protein expressed in adipose tissue. Low serum adiponectin is associated with insulin resistance, atherogenic hyperlipidemia and arterial hypertension. High serum adiponectin predicted a reduced risk of myocardial infarction. Other surveys have shown that high levels of serum adiponectin were a predictor of future cardiovascular disease and mortality. These paradoxical findings might be explained through the concept of the reversal epidemiology in the adiponectin physiology. According to this hypothesis, this protein would behave as an insulin sensitizing and cardioprotective factor in the health state and as a wasting marker in the advanced states of disease.

Imaging the N-methyl-D-aspartate receptors (NMDARs) in the living human brain by positron emission tomography (PET) or single photon emission computed tomography (SPECT) would provide useful information on the role of these receptors in ischemia and in various neurological disorders such as degenerative diseases, epilepsy or schizophrenia. To assess NMDAR radiotracer development and to propose perspectives, we overviewed the PET and SPECT candidate radioligands developed until now. Labelled molecules of interest were classified in three groups according to their binding site: intrachannel pore site blockers, glycine site inhibitors and NR2B selective subunit antagonists.