Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy.

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors.

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile.

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 (HDACis) is the selectivity for single HDAC isoforms over unspecific pan inhibition to minimize off-target toxicity. Utilizing the carborane moiety as a fine-tuning pharmacophore, we herein present a robust solid phase synthetic approach towards tailor-made HDACis meeting both ends of the selectivity spectrum, namely pan inhibition and highly selective HDAC6 inhibition.