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Development of Thiazolidinedione-Based HDAC6 Inhibitors to Overcome Methamphetamine Addiction.

ABSTRACT: Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound 6b exerts an excellent inhibitory activity against HDAC6 with an IC50 value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound 6b dose-dependently induces the acetylation level of ?-tubulin via inhibition of HDAC6 in human neuroblastoma SH-SY5Y cell line. Moreover, compound 6b efficiently reverses methamphetamine-induced morphology changes of SH-SY5Y cells via regulating acetylation landscape of ?-tubulin. Collectively, compound 6b represents a novel HDAC6-isoform selective inhibitor and demonstrates promising therapeutic potential for the treatment of methamphetamine addiction.

SUBMITTER: Sharma C

PROVIDER: S-EPMC6940941 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Development of Thiazolidinedione-Based HDAC6 Inhibitors to Overcome Methamphetamine Addiction.

Sharma Chiranjeev C Oh Yong Jin YJ Park Byoungduck B Lee Sooyeun S Jeong Chul-Ho CH Lee Sangkil S Seo Ji Hae JH Seo Young Ho YH

International journal of molecular sciences 20191209 24

Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound 6b exerts an excellent inhibitory activity against HDAC6 with an IC50 value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound 6b dose-dependently induces the acetylation level of α-tubulin via inhib ...[more]

PMID: 31835389

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