Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6 - PubMed (original) (raw)

. 2008 Aug 14;51(15):4370-3.

doi: 10.1021/jm8002894. Epub 2008 Jul 22.

Affiliations

Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6

Alan P Kozikowski et al. J Med Chem. 2008.

Abstract

A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of approximately 2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.

PubMed Disclaimer

Figures

Figure 1

Figure 1

General structural features of compounds 1–11.

Figure 2

Figure 2

Compound 7 docked into the binding site of the current HDAC6 homology model.

Chart 1

Chart 1. Comparison of IC50 (nM) Values of Compounds 1–11 and SAHA against Class I and Class II HDACs

Scheme 1

Scheme 1. Synthesis of Compounds 15–17a

a Reactions and conditions: (a) ethyl chlorooximidoacetate, triethylamine, THF, rt, 16 h; (b) (Boc)2O, THF, reflux, 16 h.

Scheme 2

Scheme 2. Synthesis of Compounds 1 and 2a

a Reagents and conditions: (a) NaBH4, MeOH, rt, 30 min; (b) NaH (60%), DMF, 0 °C to rt, 1 h then methyl 5-bromovalerate, 0 to 70 °C, 12 h; (c) NH2OH·HCl, KOH, MeOH, rt, 15 min; (d) LiOH, THF, MeOH, H2O, 0 °C to rt, 1 h; (e) HCl·NH2(CH2)4COOMe, EDCI, HOBT, DIEA, DMF, 0 °C to rt, 12 h.

Scheme 3

Scheme 3. Synthesis of Compounds 3–11a

a Reagents and conditions: (a) LiOH, THF, MeOH, H2O, 0 °C to rt, 1 h; (b) HCl·NH2(CH2)_n_COOMe, EDCI, HOBT, DIEA, DMF, 0 °C to rt, 12 h; (c) NH2OH·HCl, KOH, MeOH, rt, 15 min; (d) TFA, CH2Cl2, 0 °C to rt, 2 h; (e) Ac2O, pyridine, CH2Cl2, 0 °C to rt, 5 h.

Similar articles

Cited by

References

    1. Butler KV, Kozikowski AP. Chemical origins of isoform selectivity in histone deacetylase inhibitors. Curr Pharm Des. 2008;14:505–528. - PubMed
    2. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discovery. 2006;5:769–784. and references cited therein. - PubMed
    3. Paris M, Porcelloni M, Binaschi M, Fattori D. Histone Deacetylase Inhibitors: From Bench to Clinic. J Med Chem. 2008;51:1505–1528. - PubMed
    1. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389:349–352. - PubMed
    2. Wolffe AP, Guschin D. Review: Chromatin structural features and targets that regulate transcription. J Struct Biol. 2000;129:102–122. - PubMed
    3. Kurdistani SK, Grunstein M, Grunstein M. Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol. 2003;4:276–284. - PubMed
    4. Struhl K, Moqtaderi Z. The TAFs in the HAT. Cell. 1998;94:1–4. - PubMed
    1. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:1210–1216. - PubMed
    1. Kelly WK, Zhu AX, Scher H, Curley T, Fallon M, Slovin S, Schwartz L, Larson S, Tong W, Hartley-Asp B, Pellizzoni C, Rocchetti M. Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer. Clin Cancer Res. 2003;9:2098. - PubMed
    2. Carducci MA, Gilbert J, Bowling MK, Noe D, Eisenberger MA, Sinibaldi V, Zabelina Y, Chen TL, Grochow LB, Donehower RC. Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120 h infusion schedule. Clin Cancer Res. 2001;7:3047–3055. - PubMed
    3. Sasakawa Y, Naoe Y, Inoue T, Sasakawa T, Matsuo M, Manda T, Mutoh S. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol. 2002;64:1079–1090. - PubMed
    1. Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res. 2004;91:137–168. - PubMed
    2. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources