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Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation.

ABSTRACT: The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn(2+) were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of ?-tubulin.

SUBMITTER: Bhansali P

PROVIDER: S-EPMC3208063 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation.

Bhansali Pravin P Hanigan Christin L CL Casero Robert A RA Tillekeratne L M Viranga LM

Journal of medicinal chemistry 20111010 21

The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn(2+) were syn ...[more]

PMID: 21936551

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