We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging.

Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases.

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of histone deacetylase 6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin–proteasome pathway, with DC50 values of 3.5 and 19.4 nM, respectively. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.

The elevated expression of histone deacetylases (HDACs) in various tumor types renders their inhibition an attractive strategy for epigenetic therapeutics. One key issue in the development of improved HDAC inhibitors...

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of histone deacetylase 6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin−proteasome pathway, with DC50 values of 3.5 and 19.4 nM, respectively. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.

Multi‐Target‐Wirkstoffe stellen in der modernen Tumortherapie einen vielversprechenden Ansatz dar. Basierend auf dem bekannten Synergismus zwischen Histon‐Deacetylase‐Inhibitoren (HDACi) und alkylierenden Zytostatika präsentieren wir in dieser Arbeit die Entwicklung von alkylierenden HDACi, welche aus einer Pharmakophor‐Verknüpfungsstrategie hervorgegangen sind. Für die Synthese haben wir ein Protokoll entwickelt, bei dem Hydroxamsäuren an Festphasenharze immobilisiert und als vielseitig anwendbare Bausteine für die Synthese von funktionalisierten HDACi verwendet wurden. Verbindung 3 n zeigt eine signifikant bessere Induktion der Apoptose, Caspase‐3/7‐Aktivierung und Erzeugung von DNA‐Schäden als die Summe der biologischen Aktivitäten der einzelnen Pharmakophore. Um die Vielseitigkeit unserer beladenen Harze zu demonstrieren, wurde dieses Konzept auf die Synthese eines HDAC‐PROTAC 4 übertragen. Western‐Blot‐Experimente bestätigten, dass PROTAC 4 den Abbau von HDACs effizient induziert.

α-Aminoxy peptides represent an interesting group of peptidomimetics with high proteolytic stability and the ability to fold into specific, predictable secondary structures. Here, we present a series of hybrid peptides consisting of α-aminoxy acids and αamino acids with cationic and aromatic, hydrophobic side chains in an alternating manner synthesized using an efficient protocol that combines solution-and solid-phase synthesis. 2D ROESY experiments with a representative hexamer suggested the presence of a 7/8 helical conformation in solution. Biological evaluation revealed a significant impact of the peptide chain length and the N-terminal cap on the antimicrobial and anticancer properties of this series of hybrid peptides. The Fmoc-capped peptide 6e displayed the most potent antimicrobial activity against a panel of Gram-negative and Gram-positive bacterial strains (e. g. against E.

Selective histone deacetylase 6 (HDAC6) inhibitors are useful tools to study the function of the second catalytic domain of HDAC6, but they cannot interfere with (non)-enzymatic functions of HDAC6, which are mediated via the first catalytic domain or the ubiquitin binding domain. In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of HDAC6. Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin−proteasome pathway, with DC50 values of 3.7 and 13.3 nM, respectively. Moreover, HDAC6 degradation of A6 and intracellular (nucleocytoplasmic) localization of a fluorescein-labelled PROTAC (A7) was determined by fluorescence microscopy. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.