Light‐Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy

Abstract

Cancer treatment suffers from limitations that have a major impact on the patient's quality of life and survival. In case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to non-selective toxicity. Photopharmacology allows a novel approach to address these problems, as it employs external, local activation of chemotherapeutic agents using light. We report here the development of photoswitchable Histone Deacetylase inhibitors as potential antitumor agents. Analogs of the clinically used chemotherapeutic agents Vorinostat, Panobinostat and Belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both on HDACs activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photo-activation of HDAC inhibition, to avoid severe side effects in chemotherapy.

HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

“…Thus, HDAC activity was determined in lung tissue homogenates using an HDAC activity assay employing the conversion of a pro-fluorogenic substrate as described previously34. Total HDAC activity was reduced in cigarette smoke-exposed mice compared to air-exposed mice (Fig.…”

“…The HDAC inhibition assay was performed in triplicate as described before34. Briefly, the respective human recombinant HDAC enzymes (BPS Bioscience, San Diego, CA, USA) were incubated in absence and/or in presence of various concentrations MS-275, SAHA and the pro-fluorogenic substrate at room temperature for 60 min.…”

“…The HDAC activity in the resulting nuclear lung extracts was determined using an assay described before34. Shortly, nuclear extracts were serial diluted in 40 μL of HDAC buffer (25 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl 2 ).…”

The Art of Building Small: From Molecular Switches to Motors (Nobel Lecture)

“…This was realized with an azobenzene-modified version of SAHA, ahistone deacetylase (HDAC)inhibitor used in anticancer chemotherapy. [47] Here the photochemically accessible less stable cis-isomer is nearly as active (in vitro) as the clinically applied drug and it reverts to the inactive form; either by visible light irradiation or at hermal isomerization process,t he rate of which can be controlled by molecular design. These approaches could provide unconventional solutions to mitigate the often severe side effects of commonly used chemotheurapeutic agents.Aparticular attractive scenario is to directly use the information acquired by modern imaging techniques to guide the light-activation of the switchable chemotherapeutic agent for high-precision treatment of,e .g., inaccessible and small tumors.O fc ourse,i t should be emphasized that, prior to clinical use of such drug switching strategies,many hurdles need to be overcome.…”

Precise modulation of neuronal activity with synthetic photoswitchable ligands

“…Another paper describes a family of PCLs based on diacylglycerols, lipid signaling molecules, which provides photocontrol of a host of cellular targets (including protein kinase C) that, through phosphorylation of effector proteins, can modulate synaptic strength and the exocytosis of neurotransmitters[41]. Finally, two papers revealed PCL inhibitors of histone deacetylase, an enzyme that plays a role in gene expression and physiological processes like neuroplasticity[42,43]. …”