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A 18β-glycyrrhetinic acid conjugate with Vorinostat degrades HDAC3 and HDAC6 with improved antitumor effects.

Abstract：

:Semisynthetic 18β-glycyrrhetinic acid (GA) analogues bearing 1-en-2-cyano-3-oxo substitution on ring A have enhanced antitumor effects with reduced levels of HDAC3 and HDAC6 proteins. Aiming to inhibit both HDAC protein and activity, we developed a hybrid molecule by tethering active GA analogue methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and Vorinostat (SAHA). We tested the proper hybrid approaches of GA with hydroxamic acid and turned out that GA conjugated with SAHA by a piperazine linker was the best. The conjugate (15) of CDODA-Me and SAHA linked through a piperazine group was a potent cytotoxic agent against cancer cells with apoptosis induction. Compound 15 was more effective than the simple combination of CDODA-Me and SAHA to induce apoptosis. Mechanistic studies revealed that 15 was less effective than SAHA to inhibit HDAC activity, but was more effective than CDODA-Me to decrease the levels of HDAC3 and HDAC6 proteins with upregulated levels of acetylated H3 and acetylated α-tubulin. Compound 15 represents a new HDAC3 and HDAC6 inhibitor by reducing protein levels.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Huang M,Xie X,Gong P,Wei Y,Du H,Xu Y,Xu Q,Jing Y,Zhao L

doi

10.1016/j.ejmech.2019.111991

subject

Has Abstract

pub_date

2020-02-15 00:00:00

pages

111991

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)31143-2

journal_volume

188

pub_type

杂志文章

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