Abstract:
:Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure-activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Oger F,Lecorgne A,Sala E,Nardese V,Demay F,Chevance S,Desravines DC,Aleksandrova N,Le Guével R,Lorenzi S,Beccari AR,Barath P,Hart DJ,Bondon A,Carettoni D,Simonneaux G,Salbert Gdoi
10.1021/jm901561usubject
Has Abstractpub_date
2010-03-11 00:00:00pages
1937-50issue
5eissn
0022-2623issn
1520-4804journal_volume
53pub_type
杂志文章abstract::Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a defin...
journal_title:Journal of medicinal chemistry
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