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Design, Synthesis, and Antiproliferative Activity of Selective Histone Deacetylases 6 Inhibitors Containing a Tetrahydropyridopyrimidine Scaffold.

ABSTRACT: The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-d]pyrimidin-7(6H)-yl)-N-hydroxy-8-oxooctanamide (8f), inhibited HDAC6 with IC₅₀ of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, 8f elevated the levels of acetylated α-tubulin in a dose-dependent manner. In vitro, 8f inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC₅₀ of 2.8, 3.20, and 3.25 μM, respectively. Moreover, 8f showed good antiproliferative activity against a panel of tumor cells.

SUBMITTER: Wang B

PROVIDER: S-EPMC10648541 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Antiproliferative Activity of Selective Histone Deacetylases 6 Inhibitors Containing a Tetrahydropyridopyrimidine Scaffold.

Wang Bin B Liu Youcai Y Zhang Lejing L Wang Yajuan Y Li Zhaoxi Z Chen Xin X

Molecules (Basel, Switzerland) 20231029 21

The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-d]pyrimidin-7(6H)-yl)-N-hydroxy-8-oxooctanamide (8f), inhibited HDAC6 with IC50 of 6.4 nM, and showed > 48-fold selectivity over other subtypes ...[more]

PMID: 37959743

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