Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (sirtuin) inhibitors

Article abstract of DOI:10.1021/jm050100l

In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)-amino]-N-(1-phenylethyl) benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2′-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3-13 times less potent than sirtinol, whereas the 2′-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.

Full text of DOI:10.1021/jm050100l

Design, Synthesis, and Biological Evaluation of Sirtinol Analogues as Class III
Histone/Protein Deacetylase (Sirtuin) Inhibitors
Antonello Mai,* Silvio Massa, Siva Lavu, Riccardo Pezzi, Silvia Simeoni, Rino
Ragno, Francesca R. Mariotti, Francesco Chiani, Giorgio Camilloni, and David A.
Sinclair*
Supporting Information

Binding Mode Analysis of 7 and 8
Previous docking studies53 revealed that (R)- and (S)-sirtinol (9 and 10), while
mimicking the backbone of the p53, could act as Ac-K binding site competitors by
blocking the entrance channel of the acetylated lysine. Differently, in the present
paper meta- and para-sirtinol (7 and 8) are showed to bind the Sir2-Af2 enzyme in a
more efficient fashion, by fully occupying either the Ac-K or the NAD+ substrate
binding sites (Figure A).

Figure A. (R)-7 (1), (S)-7 (2), (R)-8 (3), and (S)-8 (4) docked conformations. In yellow
colored carbon atoms it is displayed the inhibitor binding mode obtained in the absence of
both the NAD+ and Ac-K substrates. In green colored carbon atoms is reported the
inhibitor docked conformation in the presence of only the p53 substrate. For
interpretation purposes the NAD+ and Ac-K volumes are displayed in white and cyan,
respectively. 5 Å core of the Sir2-Af2 (white wire) is also displayed. For the sake of
clarity hydrogen atoms are omitted
1
2
3
4

Analyses
calculated, %
found, %
H
compd
MW
C
H
N
C
N
1
2
394.47
378.47
319.36
291.31
290.32
272.31
394.47
394.47
394.47
394.47
79.17
82.51
75.22
74.22
74.47
79.40
79.17
79.17
79.17
79.17
5.62
5.86
5.37
4.50
4.86
4.44
5.62
5.62
5.62
5.62
7.10
7.40
4.39
4.81
9.65
10.29
7.10
7.10
7.10
7.10
79.29
82.19
75.44
73.95
74.61
79.22
79.32
78.85
79.36
78.95
5.68
5.81
5.41
4.46
4.90
4.38
5.70
5.52
5.64
5.54
6.85
7.72
4.18
5.08
9.52
10.47
6.88
7.44
6.91
7.28
3
4
5
6
7
8
9
10