The Pd( ii )/Cu( ii )-catalysed double functionalization of carbon–carbon multiple bonds in domino processes has emerged in recent years as a fruitful tool for the rapid synthesis of complex molecular scaffolds.

This review highlights the development of palladium-catalyzed C–H and N–H functionalization reactions involving indole derivatives. These procedures require unactivated starting materials and are respectful of the basic principle of sustainable chemistry tied to atom economy.

Cell-penetrating peptides (CPPs) have emerged as powerful tools in terms of drug delivery. Those short, often cationic peptides are characterized by their usually low toxicity and their ability to transport diverse cargos inside almost any kinds of cells. Still, one major drawback is their nonselective uptake making their application in targeted cancer therapies questionable. In this work, we aimed to combine the power of a CPP (sC18) with an integrin-targeting unit (c[DKP-f3-RGD]). The latter is composed of the Arg-Gly-Asp peptide sequence cyclized via a diketopiperazine scaffold and is characterized by its high selectivity toward integrin α_vβ₃. The two parts were linked via copper-catalyzed alkyne–azide click reaction (CuAAC), while the CPP was additionally functionalized with either a fluorescent dye or the anticancer drug daunorubicin. Both functionalities allowed a careful biological evaluation of these novel peptide-conjugates regarding their cellular uptake mechanism, as well as cytotoxicity in α_vβ₃ integrin receptor expressing cells versus cells that do not express α_vβ₃. Our results show that the uptake follows a “kiss-and-run”-like model, in which the conjugates first target and recognize the receptor, but translocate mainly by CPP mediation. Thereby, we observed significantly more pronounced toxic effects in α_vβ₃ expressing U87 cells compared to HT-29 and MCF-7 cells, when the cells were exposed to the substances with only very short contact times (15 min). All in all, we present new concepts for the design of cancer selective peptide–drug conjugates.

Introduction: The development of drug candidates with a defined selectivity profile and a unique molecular structure is of fundamental interest for drug discovery. In contrast to the costly screening of large substance libraries, the targeted de novo design of a drug by using structural information of either the biological target and/or structure–activity relationship data of active modulators offers an efficient and intellectually appealing alternative. Areas covered: This review provides an overview on the different techniques of de novo drug design (ligand-based drug design, structure-based drug design, and fragment-based drug design) and highlights successful examples of this targeted approach toward selective modulators of therapeutically relevant targets. Expert opinion: De novo drug design has established itself as a very efficient method for the development of potent and selective modulators for a variety of different biological target classes. The ever-growing wealth of structural data on therapeutic targets will certainly further enhance the importance of de novo design for the drug discovery process in the future. However, a consistent use of the terminology of de novo drug design in the scientific literature should be sought.