The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

Abstract

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal–chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomo-graphy of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

Monofluoromethylation of N-Heterocyclic Compounds

“…Modern organofluorine chemistry studies the synthetic approaches for the modification of functional groups with fluorine to change the physicochemical and pharmacological properties of candidates for drugs, materials and synthetic intermediates. All this emphasizes the great importance of fluorine derivatives in medicinal [15,[20][21][22][23][24], agricultural [25,26] and synthetic organic chemistry [24,[27][28][29][30][31].…”

“…The introduction of fluorine atoms is an effective approach to the development of new drugs and agrochemicals [9][10][11][12][13][14][15][16]. Fluorine atoms increase resistance to biological processes and permeability through cell membranes, provide good binding to enzyme targets and increase target selectivity.…”

Transferrin Receptor-Mediated Cellular Uptake of Fluorinated Chlorido[N,N′-bis(salicylidene)-1,2-phenylenediamine]iron(III) Complexes

“…28 Its incorporation can influence the physicochemical properties, the pharmacokinetic and pharmacodynamic as well as the metabolism and thus the efficacy of drugs. 29,30 The cytotoxic properties of the chlorido[salophene]iron(III) complexes have been attributed in numerous studies 12,[14][15][16]19,25 to induction of apoptosis and necrosis, as determined by Annexin V/propidium iodide (PI) staining and/or caspase-3 induction.…”

Recent progress on radiofluorination using metals: strategies for generation of C–18F bonds

“…[8][9][10][11] Thus, in the pharmaceutical and medical fields, numerous biologically active compounds or drugs containing C-F bonds have been reported and used as antidepressants, anti-inflammatory agents, antimalarial drugs, antipsychotics, antiviral agents, steroids, and general anesthetics. [12][13][14][15][16][17][18][19][20][21][22] In addition, the study of carbon-fluorine-18 bond construction has enabled the development of molecular imaging techniques, particularly positron emission tomography (PET). This progress is achieved by applying research on the formation of C- 18 F bonds to synthesize clinical imaging agents.…”