What makes selenoenzymes--seen from a chemist's view--so special that they cannot be substituted by just more analogous or adapted sulfur proteins? This review compiles and compares physicochemical properties of selenium and sulfur, synthetic routes to selenocysteine (Sec) and its peptides, and comparative studies of relevant thiols and selenols and their (mixed) dichalcogens, required to understand the special role of selenium in selenoproteins on the atomic molecular level. The biochemically most relevant differences are the higher polarizability of Se- and the lower pKa of SeH. The latter has a strikingly different pH-dependence than thiols, with selenols being active at much lower pH. Finally, selected typical enzymatic mechanisms which involve selenocysteine are critically discussed, also in view of the authors' own results.

Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.

Various human illnesses, including several types of cancer and infectious diseases, are related to changes in the cellular redox homeostasis. During the last decade, several approaches have been explored which employ such disturbed redox balances for the benefit of therapy. Compounds able to modulate the intracellular redox state of cells have been developed, which effectively, yet also selectively, appear to kill cancer cells and a range of pathogenic microorganisms. Among the various agents employed, certain redox catalysts have shown considerable promise since they are non-toxic on their own yet develop an effective, often selective cytotoxicity in the presence of the 'correct' intracellular redox partners. Aminoalkylation, amide coupling and multicomponent reactions are suitable synthetic methods to generate a vast number of such multifunctional catalysts, which are chemically diverse and, depending on their structure, exhibit various interesting biological activities.

Triple‐T trick! Traceless tosylhydrazone‐based triazole formation is readily achieved by reacting primary amines with functional α,α‐dichlorotosylhydrozones under ambient conditions. This fast and efficient alternative affords exclusively 1,4‐substituted triazole “click products” with complete retention of configuration. Primary amines, inherent to many natural products, can be modified in this way without protecting group manipulations.

Multicomponent Passerini and Ugi reactions enable the fast and efficient synthesis of redox-active multifunctional selenium and tellurium compounds, of which some show considerable cytotoxicity against specific cancer cells.

Selenocysteine containing peptoids and peptide-peptoid conjugates were synthesized by combinatorial Ugi-MCRs (multicomponent reactions) in water: for the first time, an acetal (selenoacetal 2a) was used in Ugi-MCR to furnish selenocysteine peptoids in one step as model compounds for selenocysteine peptides and proteins.

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