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. 2014 Jul 8;5(9):973-8.
doi: 10.1021/ml5000959. eCollection 2014 Sep 11.

Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity

Elisa Giacomini  1 , Angela Nebbioso  2 , Alfonso Ciotta  2 , Cristina Ianni  3 , Federico Falchi  1 , Marinella Roberti  3 , Manlio Tolomeo  4 , Stefania Grimaudo  5 , Antonietta Di Cristina  5 , Rosaria Maria Pipitone  5 , Lucia Altucci  6 , Maurizio Recanatini  3
Affiliations

Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity

Elisa Giacomini et al. ACS Med Chem Lett. .

Erratum in

Abstract

Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibition. Among the other, trans -6 showed the most interesting biological profile, as it exhibited a strong pro-apoptotic activity in tumor cell lines in comparison with both of its parent compounds and a marked HDAC inhibition.

Keywords: HDAC inhibition; Multifunctional ligands; antiproliferative activity; chimeric compound; stilbene.

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Figures

Figure 1
Figure 1
(A) SAHA. (B) Representative terphenyl and stilbene derivatives endowed with pro-apoptotic or differentiating activity.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Figure 2
Figure 2
Left: apoptosis/necrosis evaluation, by Annexin V/PI doubling staining by flow cytometric assays on U937 cells treated with 5 μM trans-6 or SAHA (taken as positive control) for 48 h. All points were tested in triplicate with error bars indicating the standard deviation. Right: Western blot for caspase 8 after a stimulation of 24 h for U937 cells and 48 h for MCF-7 cells; compounds were used at concentration of 5 μM. ImageJ was used to quantify protein expression levels. The ERKs signal accounts for equal loading.
Figure 3
Figure 3
Western blot analyses carried out for the indicated targets in U937 and MCF-7 cells after 24 h of treatment. ImageJ was used to quantify protein expression. Histone H1, H4, and ERKs indicate equal loading. SAHA and trans-6 were used at concentration of 5 μM.
Figure 4
Figure 4
(A) Proliferation analysis in real time of MCF-7 cells treated with 5 μM SAHA or trans-6 as CI (cell index) vs time (left) within 36 h and as doubling time (right) within the interval 10–18 h. (B) Migration analysis in real-time of MCF-7 cells treated with 5 μM trans-6 as CI vs time (left) within 27 h and as slope within 24 h.
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