Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.

Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.

ChemMedChem (2020-04-30)

Michael Morgen, Raphael R Steimbach, Magalie Géraldy, Lars Hellweg, Peter Sehr, Johannes Ridinger, Olaf Witt, Ina Oehme, Corey J Herbst-Gervasoni, Jeremy D Osko, Nicholas J Porter, David W Christianson, Nikolas Gunkel, Aubry K Miller

PMID32348628

摘要

We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.

材料

产品编号

品牌

产品描述

P4333

Sigma-Aldrich

青链霉素, Solution stabilized, with 10,000 units penicillin and 10 mg streptomycin/mL, 0.1 μm filtered, BioReagent, suitable for cell culture

T4049

Sigma-Aldrich

胰蛋白酶-EDTA 溶液, 0.25%, sterile-filtered, BioReagent, suitable for cell culture, 2.5 g porcine trypsin and 0.2 g EDTA, 4Na per liter of Hanks′ Balanced Salt Solution with phenol red

T3924

Sigma-Aldrich

胰蛋白酶-EDTA 溶液, 1 ×, sterile; sterile-filtered, BioReagent, suitable for cell culture, 0.5 g porcine trypsin and 0.2 g EDTA, 4Na per liter of Hanks′ Balanced Salt Solution with phenol red