S
tar
ting from a yeas
t pheno
typic screening performed on 21 compounds, we described
the iden
tifica
tion of
two small molecules (
9 and
18) able
to significan
tly reduce
the
S. cerevisiae cell grow
th,
thus miming
theeffec
t of GCN5 dele
tion mu
tan
t. Tes
ted on a GCN5-dependen
t gene
transcrip
tion assay, compounds
9 and
18 gave a high reduc
tion of
the repor
ter ac
tivi
ty. In
S. cerevisiae his
tone H3
terminal
tails assay,
the H3ace
tyla
tion levels were highly reduced by
trea
tmen
t wi
th 0.6-1 mM
9, while
18 was effec
tive only a
t 1.5mM. In human leukemia U937 cell line, a
t 1 mM
9 and
18 showed effec
ts on cell cycle (arres
t in G1 phase,
9), apop
tosis (
9), and granulocy
tic differen
tia
tion (
18). When
tes
ted on U937 cell nuclear ex
trac
ts
to evalua
te
their his
tone ace
tyl
transferase (HAT) inhibi
tory ac
tion, bo
th compounds were able
to reduce
the enzymeac
tivi
ty when used a
t 500
ti
ties/mgr.gif">M. Ano
ther quinoline, compound
22, was syn
thesized wi
th
the aim
to improve
the ac
tivi
ty observed wi
th
9 and
18. Tes
ted in
the HAT assay,
22 was able
to reduce
the HAT ca
taly
ticac
tion a
t 50 and 25
ti
ties/mgr.gif">M,
thereby being comparable
to anacardic acid, curcumin, and MB-3 used as references.Finally, in U937 cells, compounds
9 and
18 used a
t 2.5 mM were able
to reduce
the ex
ten
t of
the ace
tyla
tionlevels of his
tone H3 (
9) and
-
tubulin (
9 and
18). In
the same assay,
22 a
t lower concen
tra
tion (100
ti
ties/mgr.gif">M)showed
the same hypoace
tyla
ting effec
ts wi
th bo
th his
tone and non-his
tone subs
tra
tes.