3,3-dimethylacrylyl (compound 9 in Fig. 3) and isovaleryl moieties (compound 10 in
Fig. 3). The other acetyl-lysine analogs such as monofluoroacetyl, trifluoroacetyl
(compound 11 in Fig. 3), propionyl, and butyryl moiety (compounds 12 and 13 in
Fig. 3) increased the affinity toward yeast sirtuins but reduced the rate of the
formation of the O-alkylamidate intermediate [57].
HN
R
N
H
O
CH 3
S
O
O
O
n
propionyl-,n=1 (12)
butyryl-, n=2 (13)
thioacetyl- (7)
trifluoroacetyl- (11)
CH 3
Se
selenoacetyl- (8)
isovaleryl- (10)
O
3,3,-dimethylacrylyl- (9)
N
 -acetyllysine mimetics
O
N
H
O
O
H
N
HN
CH 3
S
Cbz-Lys(thioAc)-NH-Ph (16)
SIRT1: 2.7-10 M
SIRT2: 6-23 M
SIRT3: 28  ; >100 M
SIRT5: > 200 
SIRT6: > 200 
SIRT7: >200 
SIRT1: 0.24 M
SIRT2: 9.8 M
SIRT1: 0.37 M
SIRT2: 7.2 M
SIRT1: 11 M
SIRT2: 77 M
SIRT1: 12 M
SIRT2: 30 M
CH 3
O
SIRT1: 122 M
SIRT2: 223 M
acetyl- (6)
N
H
Ile
Arg
Phe
Asn Ser
Tyr
NH
O
Arg
Tyr
Ser
Asn
S
O
Ser
Ser
Cys
O
NH 2
SIRT1: 47 nM
SIRT2: 3.2 nM
SIRT3 480 nM
Trifluoroacetyl-lysine
macrocyclic peptide (14)
N
H
O
Arg
Ile
Arg
Ac
NH
O
SIRT1: 280 nM
SIRT2: 31 nM
SIRT3: 1000 nM
Trifluoroacetyl-lysine peptide (15)
O
N
H
O
O
H
N
NH
Cbz-Lys(thiomyristoyl)-NH-Ph (17)
Tyr NH 2
S
R=
SIRT1: 98 
SIRT2:28 nM
SIRT3: >200 
H 3 C
N
H
NH
O
O
H
NH
CH 3
H
N
NH 2
O
O
NH
CH 3
O
O
HN
O
S
N
S
Bivalent peptide (18)
SIRT1: 12.4 
SIRT2: >200 
SIRT3:>1000 
CF 3
CF 3
HN
O CF 3
Fig. 3 The structures of substrate-based sirtuin inhibitors and their IC 50 values
Sirtuin Inhibitors and Activators
61