Alkyl-Substituted Polyaminohydroxamic Acids:  A Novel Class of Targeted Histone Deacetylase Inhibitors

  • 10.1021/jm0505009
  • Journal of Medicinal Chemistry
  • p 6350-6365, Volume 48, Issue 20,
  • journal-article
The reversible acetylation of histones is critical for regulation of eukaryotic gene expression. The histone deacetylase inhibitors trichostatin (TSA, 1), MS-275 (2) and suberoylanilide hydroxamic acid (SAHA, 3) arrest growth in transformed cells and in human tumor xenografts. However, 1−3 suffer from lack of specificity among the various HDAC isoforms, prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6−21. We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain. At 1 μM, compounds 12, 15 and 20 inhibited HDAC by 74.86, 59.99 and 73.85%, respectively. Although 20 was a less potent HDAC inhibitor than 1, it was more potent than 2, more effective as an initiator of histone hyperacetylation, and significantly more effective than 2 at re-expressing p21 Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6−21 represent an important new chemical class of HDAC inhibitors.

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Reproducible synthesis of compound 20

Synthesized (20) using the similar (not exactly same) procedure (Scheme 2) as was written in the paper.

1,4-Diaminobutane was firstly protected by mesitly chloride in DCM (overnight under reflux condition). The protected intermediate was then mono-alkylated with tosylated ...

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