Balancing Histone Deacetylase (HDAC) Inhibition and Drug‐likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors

Abstract

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the "foot-pocket" in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D 7.4 ) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising "capless" HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.

Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

“…1 H-NMR (400 MHz, CDCl 3 ) δ 9.66 (s, 1H), 8.63 (d, J = 8.9 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.9, 2.3 Hz, 1H), 7.59–7.50 (m, 2H), 7.21–7.10 (m, 2H), 1.56 (s, 9H); 19 F-NMR (377 MHz, CDCl 3 ) δ −114.12 (ddd, J = 13.8, 8.6, 5.2 Hz); 13 C-NMR (76 MHz, CDCl 3 ) δ 162.98 (d, J = 247.9 Hz), 152.35, 136.34, 135.08, 134.51 (d, J = 3.2 Hz), 134.28, 134.12, 128.55 (d, J = 8.2 Hz), 123.73, 121.41, 116.21 (d, J = 21.7 Hz), 82.16, 28.36 (in accordance with literature [ 55 ]).…”

“…1 H-NMR (300 MHz, CDCl 3 ) δ 7.52–7.43 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.13–7.03 (m, 2H), 6.99–6.90 (m, 2H), 6.24 (s, 1H), 3.85 (s, 2H), 1.53 (s, 9H); 19 F-NMR (282 MHz, CDCl 3 ) δ −116.04 ( 1 H decoupled); 13 C-NMR (75 MHz, CDCl 3 ) δ 162.94 (d, J = 246.1 Hz), 153.96, 140.23, 138.41, 137.15, 128.59 (d, J = 8.02 Hz), 125.11, 124.31, 118.56, 116.25, 115.63 (d, J = 21.38 Hz), 80.86, 28.48 (in accordance with literature [ 55 ]).…”

“…The reduction in compound 2c (1.0 g, 3.0 mmol) was performed according to the general procedure A2a in 50 mL EA/MeOH (1:1, v/v) to give after purification by flash chromatography (silica, gradient PE/EA: 4:1 → 1.5:1 → 1:1) compound 3c (895 mg) as white-beige solid in quantitative yield. 1 [55]).…”

“… a < 10% inhibition at 10,000 nM; b < 30% inhibition at the given concentration; c data taken from reference [ 55 ]. …”

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

“…Schäker-Hübner and co-workers [ 51 ] also synthesized a series of novel benzamides. The Boc-protected intermediates containing fluorine were obtained via the Suzuki reaction of tert -butyl-(4-bromo-2-nitrophenyl)carbamate with alkyl boronic acids ( Scheme 20 ).…”