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 tomography 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.

Keywords: fluorination; fluorine; fluorine-18; histone deacetylase (HDAC); histone deacetylase inhibitors (HDACis); positron emission tomography (PET); potency; selectivity; suberoylanilide hydroxamic acid (SAHA); vorinostat.

Figure 1

Chemical structures of some HDACis considering the pharmacophore consisting of cap, linker, and zinc-binding group (ZBG).

Scheme 1

Fluorination in the synthetic pathway of fluorinated hydroxamic acids via reductive amination by Aboukhatwa et al. [33].

Scheme 2

Fluorination in the synthetic pathway of fluorinated hydroxamic acids via alkylation by Aboukhatwa et al. [33].

Scheme 3

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Wang et al. [34].

Scheme 4

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Goehringer, Peng, et al. [35].

Scheme 5

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Meyners et al. [36].

Scheme 6

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Toutah et al. [37].

Scheme 7

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Walton et al. [38].

Scheme 8

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Vu et al. [39].

Scheme 9

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Liu et al. [40].

Scheme 10

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Erdeljac et al. [41].

Scheme 11

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Ariawan et al. [42].

Scheme 12

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Strebl et al. [43].

Scheme 13

Fluorination in the synthetic pathway of fluorinated hydroxamic acids by Hendricks, Keliher, et al. [44].

Scheme 14

Fluorination in the two synthetic pathways (A,B) of fluorinated hydroxamic acids by Strebl et al. [45]. Radiochemical procedures for MGS1–2 (A) and MGS3 (B).

Scheme 15

Fluorination in the synthetic pathway of fluorinated benzamides by Jayathilaka et al. [47].

Scheme 16

Fluorination in the synthetic pathway of fluorinated benzamides by Bonomi et al. [48].

Scheme 17

Fluorination in the synthetic pathway of fluorinated benzamides by La et al. [49].

Scheme 18

Fluorination in the synthetic pathway of fluorinated benzamides via Suzuki reaction by Ibrahim et al. [50].

Scheme 19

Fluorination in the synthetic pathway of fluorinated benzamides via amide-coupling reactions by Ibrahim et al. [50].

Scheme 20

Fluorination in the synthetic pathway of fluorinated benzamides by Schäker-Hübner et al. [51].

Scheme 21

Fluorination in the synthetic pathway of fluorinated benzamides by Liu et al. [40].

Scheme 22

Fluorination in the radiosynthetic pathway of fluorinated benzamides by Bonomi et al. [48].

Scheme 23

Fluorination in the radiosynthetic pathway of [¹⁸F] Fluoroethyl-INER1577 by Li et al. [52].

Scheme 24

Fluorination in the radiosynthetic pathway of [¹⁸F] Fluoroethyl-INER1577 by Li et al. [53].

Scheme 25

Fluorination in the synthetic pathway of fluorinated thiols by Chuman et al. [55].

Scheme 26

Fluorination in the synthetic pathway of fluorinated thiols by Wen et al. [56].

Scheme 27

Fluorination in the synthetic pathway of fluorinated short-chain fatty acids via alkylation by Lübke et al. [59].

Scheme 28

Fluorination in the synthetic pathway of fluorinated short-chain fatty acids via bromofluorination by Lübke et al. [59].

Figure 2

Chemical structure of largazole.

Scheme 29

Fluorination in the synthetic pathway of fluorinated cyclic peptides by Zhang, Liu, Gao, et al. [60,61].

Figure 3

Chemical structures of fluorinated hydroxamic acids by Salmi-Smail et al. [68].

Figure 4

Chemical structures of fluorinated hydroxamic acids by Luckhurst [69].

Figure 5

Chemical structure of fluorinated hydroxamic acid by Yao, Li et al. [70].

Figure 6

Chemical structure of fluorinated hydroxamic acid (PTG-0861) by Gawel, Shouksmith, Raouf, Nawar et al. [71].

Figure 7

Chemical structure of fluorinated benzamide (CBUD-1001) by Kim, La et al. [72].

Figure 8

Chemical structure of Merck60.

Figure 9

Chemical structures of fluorinated hydroxamic acids by Chen et al. [80,81].

Figure 10

Chemical structure of fluorinated hydroxamic acids by Sandrone et al. [83].

Figure 11

Chemical structures of fluorinated HDAC6-addressing PROTACs by Keuler, König, Bückreiß et al. [85].

Figure 12

Chemical structure of fluorinated BLT by Sankaranarayanapillai et al. [86,87].

Figure 13

Chemical structures of four INER-1577 derivatives by Chen et al. [92].