Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8

Abstract

As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report the synthesis and biological evaluation of the trifluoromethylketone analogue of L-arginine, (S)-2-amino-8,8,8-trifluoro-7-oxo-octanoic acid (10). While this novel amino acid was initially designed as a potential inhibitor of human arginase I, it exhibits no measurable inhibitory activity against this enzyme. Surprisingly, however, 10 is a potent inhibitor of human histone deacetylase 8, with IC50 = 1.5 ± 0.2 μM. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC50 = 110 ± 30 μM. The lack of inhibitory activity against human arginase I may result from unfavorable interactions of the bulky trifluoromethyl group of 10 in the constricted active site. Since the active site of histone deacetylase 8 is less constricted, we hypothesize that it accommodates 10 as the gem-diol, which mimics the tetrahedral intermediate and its flanking transition states in catalysis. Therefore, we suggest that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones.

Synthesis and evaluation of N8-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase

“…However, each compound differs in the nature of its head group designed to mimic substrate or tetrahedral transition state binding to the active site Zn 2+ ion. Most of these Zn 2+ -binding groups have been successfully incorporated into effective inhibitors of HDACs 29, 33–39 and other metallohydrolases. 40–43 …”

“…For instance, inhibitors of the mammalian N 8 -acetylspermidine deacetylase have been described earlier, some of which exhibit low nanomolar inhibitory activity. 26, 27 So far, the HDAC inhibitor M344 28 and the trifluoromethylketone analogue of l -arginine 29 are the only compounds reported to inhibit the bacterial polyamine deacetylase in the low and mid-micromolar range, respectively. 18, 29 Here, we report the synthesis of new polyamine derivatives as well as new synthetic routes for some of the previously described mammalian N 8 -acetylspermidine deacetylase inhibitors.…”

“…26, 27 So far, the HDAC inhibitor M344 28 and the trifluoromethylketone analogue of l -arginine 29 are the only compounds reported to inhibit the bacterial polyamine deacetylase in the low and mid-micromolar range, respectively. 18, 29 Here, we report the synthesis of new polyamine derivatives as well as new synthetic routes for some of the previously described mammalian N 8 -acetylspermidine deacetylase inhibitors. 26, 27 All compounds synthesized in the current study are analogues of N 8 -acetylspermidine bearing different functional groups targeting Zn 2+ coordination.…”

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

“…These two t-PFMKs showed potent inhibition (low-micromolar to sub-micromolar range) towards four HDAC isoforms [ 127 ]. Another example in this regard is represented by ( S )-2-amino-8,8,8-trifluoro-7-oxo-octanoic acid ( Figure 17 ), which is actually an l -Arg analogue initially designed by Ilies M. et al as a potential inhibitor of human arginase I that showed activity towards HDAC8 in the low-micromolar range (IC 50 = 1.5 μM) [ 128 ]. More recently (2018), Moreno-Yruele and Olsen C.A.…”

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

“…4 Due to their role in various biological functions, HDAC inhibition has become a promising epigenetic target for the treatment of cancer. 5 HDAC inhibitors (HDACis) are structurally diverse and are classified into various groups as hydroximates, [6][7][8] cyclic tetrapeptides, 9 benzamides, 10,11 electrophilic ketones, 12 and carboxylic acids. 13 Two HDACis (vorinostat and romidepsin) have been approved by the United States Food and Drug Administration for the treatment of cutaneous T-cell lymphoma.…”