Alkyl-substituted polyaminohydroxamic acids: A novel class of targeted histone deacetylase inhibitors

Sheeba Varghese, Deepak Gupta, Tiffany Baran, Anchalee Jiemjit, Steven D. Gore, Robert A Casero, Patrick M. Woster

Research output: Contribution to journalArticle

Abstract

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 p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.

Original languageEnglish (US)
Pages (from-to)6350-6365
Number of pages16
JournalJournal of Medicinal Chemistry
Volume48
Issue number20
DOIs
StatePublished - Oct 6 2005

Fingerprint

Histone Deacetylase Inhibitors
Histones
Acids
Acetylation
Polyamines
Gene Expression Regulation
Heterografts
Gene expression
Chromatin
Tumors
Protein Isoforms
Leukemia
Derivatives
Growth
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Alkyl-substituted polyaminohydroxamic acids : A novel class of targeted histone deacetylase inhibitors. / Varghese, Sheeba; Gupta, Deepak; Baran, Tiffany; Jiemjit, Anchalee; Gore, Steven D.; Casero, Robert A; Woster, Patrick M.

In: Journal of Medicinal Chemistry, Vol. 48, No. 20, 06.10.2005, p. 6350-6365.

Research output: Contribution to journalArticle

Varghese, Sheeba ; Gupta, Deepak ; Baran, Tiffany ; Jiemjit, Anchalee ; Gore, Steven D. ; Casero, Robert A ; Woster, Patrick M. / Alkyl-substituted polyaminohydroxamic acids : A novel class of targeted histone deacetylase inhibitors. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 20. pp. 6350-6365.
@article{097bbd355304470d8ee3b7c3089712d9,
title = "Alkyl-substituted polyaminohydroxamic acids: A novel class of targeted histone deacetylase inhibitors",
abstract = "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 p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.",
author = "Sheeba Varghese and Deepak Gupta and Tiffany Baran and Anchalee Jiemjit and Gore, {Steven D.} and Casero, {Robert A} and Woster, {Patrick M.}",
year = "2005",
month = "10",
day = "6",
doi = "10.1021/jm0505009",
language = "English (US)",
volume = "48",
pages = "6350--6365",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",

}

TY - JOUR

T1 - Alkyl-substituted polyaminohydroxamic acids

T2 - A novel class of targeted histone deacetylase inhibitors

AU - Varghese, Sheeba

AU - Gupta, Deepak

AU - Baran, Tiffany

AU - Jiemjit, Anchalee

AU - Gore, Steven D.

AU - Casero, Robert A

AU - Woster, Patrick M.

PY - 2005/10/6

Y1 - 2005/10/6

N2 - 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 p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.

AB - 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 p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=26444441453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=26444441453&partnerID=8YFLogxK

U2 - 10.1021/jm0505009

DO - 10.1021/jm0505009

M3 - Article

C2 - 16190761

AN - SCOPUS:26444441453

VL - 48

SP - 6350

EP - 6365

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -