Topics in Medicinal Chemistry

The biochemistry, pharmacology and epidemiology of selenium and selenium-containing compounds continue to be subjects of considerable interest from the viewpoint of public health. Selenium has a long history of association with human health and disease, and we now recognize that this element is an essential nutrient that is critical to key cellular processes. We now know that the selenoproteins constituting the human selenoproteome are encoded by 25 genes in the human genome, and much progress is being made in our understanding of selenium metabolism and the health effects of selenium metabolites in normal and disease states. The idea that selenium-containing dietary supplements might be effective in preventing disease has gone through both optimistic and pessimistic phases in recent years, and the future prospects for such a nutritional approach are unclear at the present time. In contrast, a significant number of promising efforts are underway that are aimed at designing and developing pharmaceutical agents that are selenium-based or that target specific aspects of selenium metabolism. This chapter focuses on some of these efforts to develop new selenium-based anticancer, antioxidant, antihypertensive, antiviral, immunosuppressive, and antimicrobial agents. While most of the efforts that entail designed organoselenium compounds – as opposed to inorganic selenium metabolites – are still at the preclinical stage, evidence is emerging that selenium-based compounds can operate via several beneficial biochemical and pharmacological mechanisms. Since our understanding of the biology, biochemistry and pharmacology of selenium and selenoproteins is rapidly expanding, we can anticipate that the coming years will bring further development of new selenium-based pharmaceutical agents with therapeutic potential against human diseases.

Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein–protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

Selenium (Se) is an essential element to humans and animals. Since its diverse functions were discovered, its importance has been more and more revealed. After the discovery of selenium as a key component of many proteins, significant research efforts have been focused on its therapeutic and nutritional potentials and possible impacts on human and animal health. To date, 25 selenoprotein genes have been identified in humans and animals, where selenium exists in the form of an amino acid, selenocysteine (Sec). Sec incorporation into selenoproteins occurs through a unique process by recognizing UGA stop codon via the Sec-charged tRNA for delivering Sec into proteins. Most selenoproteins are antioxidant proteins and play critical roles in maintaining redox balance in living systems by removing reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). These reactive species are major threats to bio-macromolecules, such as DNAs, RNAs, proteins, lipids, and carbohydrates. They may cause molecular oxidation and DNA damage/mutation, alter gene expression patterns, weaken the immune system, and even lead to neurological disorders and other pathological conditions. As potential drugs and/or nutritional supplements, selenium-functionalized molecules (SeFMs) have shown benefits in preventing and/or treating many diseases, such as cancer, cardiovascular diseases, thyroid diseases, diabetes, AIDS, rheumatoid arthritis (RA), and neurodegenerative diseases. These promising results and therapeutic potentials of SeFMs have attracted tremendous attention from academia and pharmaceutical and biotech industries. However, further fundamental research and investigation are required to discover the ideal chemical, biochemical, and biological forms of selenium, appropriate dosages, and mechanisms of the selenium biological actions, since the tolerance window of selenium in humans may be limited.

Heat shock proteins (HSPs) are part of a highly conserved genetic survival system originally discovered by Ferruccio Ritossa in 1962 (Ritossa, Riv Ist Sieroter Ital 37:79–108, 1962). Members of this family function as molecular chaperones that stabilize protein folding (De Maio, Shock 11:1–12, 1999). HSP47 is a molecular chaperone that is essential for collagen biosynthesis (Ishida et al., Mol Biol Cell 17:2346–2355, 2006; Matsuoka et al., Mol Biol Cell 15:4467–4475, 2004; Nagai et al., J Cell Biol 150:1499–1506, 2000). This chaperone is a potential therapeutic target, as it has been observed to be upregulated in collagen-producing cells in several fibrotic conditions (Taguchi et al., Acta Histochem Cytochem 44:35–41, 2011). The recent resolution of a HSP47 crystal structure has provided new insights into the chaperone’s mechanism of action (Widmer et al., Proc Natl Acad Sci U S A 109:13243–13247, 2012) with implications for future drug design. This review will summarize our current understanding of the biochemistry of HSP47-collagen interactions and the potential of HSP47 as a therapeutic target in fibrotic conditions. It will also discuss the current pharmacological inhibitors and the identification of new HSP47 small-molecule inhibitors.

Contrast agents have long helped researchers and physicians alike delineate boundaries, but new diagnostic information is always sought after. A new field of molecularly targeted CT agents hopes to fill this void and supply physicians with prognostic information to find better treatments for patients. Borrowing from drug delivery and design, nanoparticles and similar platforms are being explored to help visualize complex biologic processes with never before seen resolution and fidelity. We discuss the development of this field and feasibility of translating some of these prospects to the clinic. in chemistry, molecular biology, and engineering have molded this field emphasizing the early detection and treatment of diseases at the molecular and cellular level. Myriads of nanomedicine platforms have been proposed and developed and tested in laboratories and in preclinical models. However, very few have been translated to clinical trials. It is therefore a critical issue to recognize the factors affecting their eventual application in human. Better understanding of biological and biophysical obstacles encountered by these agents is necessary. Toward this aim, we critically review our present understanding of the biological obstacles encountered by the nano-agents, which we hope will motivate more studies to tune these technologies for future translational and clinical applications.