Implantable HDAC-inhibiting chemotherapeutics derived from hydrophobic amino acids for localized anticancer therapy.

Epigenetic targeting of different cancers by inhibiting particular histone deacetylase (HDAC) isozymes is a promising treatment approach against cancer. Development of locally-implantable molecular inhibitors of HDAC (henceforth called HDACi) promises high tumour site concentration and reduced systemic degradation of the HDACi. Herein, we report the design of such implantable HDACi based on amphiphilic derivatives of hydrophobic amino acids endowed with a hydroxamic acid (hxa)-based zinc-binding residue. The amino acids present in HDACi influenced the HDAC isozyme that could be inhibited most effectively; the l-phenylalanine derivative 4e inhibited the HDAC6 isozyme most potently (IC50 ∼ 88 nM), while the l-isoleucine derivative 4h was most effective against the isozyme HDAC2 (IC50 ∼ 94 nM). We also noticed that the l-Phe derivative 4e was up to 5× more potent towards inhibiting HDAC6 than its optical antipode 4f derived from d-Phe. This was rationalized in terms of the varying extent of penetration of the enantiomeric inhibitors inside the catalytic tunnel of the enzyme. Since the isozymes HDAC6 and HDAC2 are overexpressed in different cancer cells, 4e and 4h elicited selective anticancer activity in different cancer cell lines. Additive therapeutic action of the combination therapy of 4e and 4h was observed on lung cancer cells that overexpress both these isozymes. Further, 4e formed implantable self-assembled hydrogels that achieved sustained and selective killing of cancer cells in the vicinity of implantation.

Amphiphilic phenylalanine derivatives that temporally generate reactive oxygen species from water in the presence of Au(iii) ions.

Amphiphilic derivatives of phenylalanine (ADFs) have strong self-assembling propensities and yield low molecular weight hydrogels on multiple occassions. The interaction of ADFs with metal ions can result in the morphological changes in the self-assemblies. Herein, we report the interesting consequences of the interaction between four N-protected ADFs with Au(iii) ions. In the case of ADF 1, the original nanofibrillar morphology of the self-assemblies spontaneously transformed into uniform nanoglobules of ∼80 nm in diameter upon addition of Au(iii) ions. A subsequent reduction of the Au(iii) ions to Au(0) nanoparticles (AuNPs) and the surface decoration of the nanoglobules with AuNPs were observed in the course of the next six to eight hours. Simultaneously, multiple reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), hydroxyl radicals (˙OH), singlet oxygen and superoxide ions were also found to be present in the reaction medium. These ROS originate from water used as the reaction medium. The ROS production and the reduction of Au(iii) were inhibited upon deaeration of the reaction medium and the use of heavy water (D2O) or organic solvents as the reaction medium, while an increase in the pH of the aqueous medium intensified both these processes. We exploited the temporal ROS generation using the mixture of 1 and Au(iii) ions towards anticancer therapy by enhancing the intracellular ROS levels. It is expected that this effort can be expanded into a viable anticancer therapy in the near future by modulating the amount and the rate of ROS-generation through judicious choice of the peptidic ligands and metal ions.