Amino acids (AAs) are key structural motifs with widespread applications in organic synthesis, biochemistry, and material sciences. Recently, with the development of milder and more versatile radical‐based procedures, the use of strategies relying on radical chemistry for the synthesis and modification of AAs has gained increased attention, as they allow rapid access to libraries of novel unnatural AAs containing a wide range of structural motifs. In this Minireview, we provide a broad overview of the advancements made in this field during the last decade, focusing on methods for the de novo synthesis of α‐, β‐, and γ‐AAs, as well as for the selective derivatisation of canonical and non‐canonical α‐AAs.

Due to their abundance and readily available synthesis, alcohols provide ideal handles for the selective derivatisation of organic molecules. Radical chemistry offers versatile strategies for the conversion of Csp³−O bonds into a wide range of Csp³−C, Csp³−H, or Csp³−heteroatom bonds. In these reactions, alcohols are readily derivatised with an activator group which can undergo facile mesolysis to generate a primary, secondary, or tertiary open‐shell species that can engage in further transformations. These strategies are particularly effective at overcoming steric limitations associated with nucleophilic substitution pathways. Despite their potential, the use of radical deoxyfunctionalisation reactions as a general strategy for the synthesis of useful and complex molecules remains underutilised. In this Review, we highlight recent advancements in this exciting field in which photocatalysis, transition metal catalysis or electrochemistry are used to initiate the radical processes.

Aminosäuren (AS) sind wichtige Strukturmotive mit vielfältigen Anwendungsmöglichkeiten in der organischen Synthese, der Biochemie und den Materialwissenschaften. In jüngster Zeit hat mit der Entwicklung milderer und vielseitigerer Verfahren der Einsatz von radikalchemischen Methoden für die Synthese und Modifikation von AS größere Aufmerksamkeit gewonnen, da sie einen schnellen Zugang zu einer Vielzahl neuartiger unnatürlicher AS (UAS) mit einer breiten Palette von Strukturmotiven ermöglichen. In diesem Kurzaufsatz geben wir einen umfassenden Überblick über die Fortschritte, die in diesem Bereich in den letzten zehn Jahren erzielt wurden und konzentrieren uns dabei auf Methoden für die De‐novo‐Synthese von α‐,β‐ und γ‐AS sowie auf die selektive Derivatisierung kanonischer und nichtkanonischer AS.

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC₅₀ = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC₅₀ = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure–activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel^®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.