Discovery of new more selective and potent Histone deacetylase inhibitors is one of the most promising therapeutical approach for tumor growth arrest and proliferation control. Natural cyclotetrapeptide FR235222 (1) from Acremonium sp. was identified as potent immunosuppressant and HDAC inhibitor with low-nanomolar range activity against HDACs Class I and IIa. The strong potency elicited by FR235222, even thought the cyclotetrapeptide scaffold is a good cupping group (CAP), is due to its natural Zinc-Binding group (ZBG), based on the α-hydroxyketone moiety. Herein we report the synthesis and the biological evaluation of amides as molecular simplification of natural cyclotetrapeptide (1), in order to evaluate their antiproliferative and HDAC inhibition activities. Linear derivatives show interesting results in terms of antiproliferative effects.

SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULES DERIVATIVES OF THE NATURAL HISTONE DEACETYLASE INHIBITOR FR235222

RANDINO, ROSARIO;D'URSI, Anna Maria;RODRIQUEZ, Manuela
2014

Abstract

Discovery of new more selective and potent Histone deacetylase inhibitors is one of the most promising therapeutical approach for tumor growth arrest and proliferation control. Natural cyclotetrapeptide FR235222 (1) from Acremonium sp. was identified as potent immunosuppressant and HDAC inhibitor with low-nanomolar range activity against HDACs Class I and IIa. The strong potency elicited by FR235222, even thought the cyclotetrapeptide scaffold is a good cupping group (CAP), is due to its natural Zinc-Binding group (ZBG), based on the α-hydroxyketone moiety. Herein we report the synthesis and the biological evaluation of amides as molecular simplification of natural cyclotetrapeptide (1), in order to evaluate their antiproliferative and HDAC inhibition activities. Linear derivatives show interesting results in terms of antiproliferative effects.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4534257
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