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.


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 ...