Synthesis and structure–activity relationship of histone deacetylase (HDAC) inhibitors with triazole-linked cap group

Chen, Po C.; Patil, Vishal; Guerrant, William; Green, Patience; Oyelere, Adegboyega K.

doi:10.1016/j.bmc.2008.03.050

Cited by 86 publications

(88 citation statements)

References 31 publications

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“…In contrast, allowing compound 67b to bind zinc prior to interacting with its target protein neutralizes its inhibitory effect, presumably by preventing 67b from removing the zinc that is normally bound by its target protein. This result confirms the principal role of zinc chelation in the Cited from references (Chen et al 2008;Patil et al 2010)-activities against HeLa nuclear extract (HDAC 1 and 2). mechanism of action of the compounds described.…”

Section: Structure-activity Relationship (Sar) Of Splicing Inhibitionsupporting

confidence: 82%

“…However, the exact relationship between zinc chelation, protein acetylation state, and splicing inhibition is not clear, as only a limited set of HDAC inhibitors (HDACis) was screened. In the present work, we sought to clarify this relationship by screening a HDACi library that was structurally more diverse (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a,b;Patil et al 2010). We report here the elucidation of unique molecular features that confer splicing inhibition upon zinc-chelating agents with HDAC inhibition activity.…”

Section: Introductionmentioning

confidence: 92%

“…To this end, we first screened a small (63-member), yet structurally diverse HDACi library (see Supplemental Table S1 for the structures) at 100 mM using a conventional in vitro splicing assay. The HDAC inhibition activity of compounds in the screened library against HDAC1 and HeLa cell nuclear extract HDACs ranges from single digit-to mid-nanomolar (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a;Patil et al 2010). Despite their potency, these HDACis did not broadly inhibit splicing.…”

Section: Screening Of Structurally Diverse Hdacis For Splicing Inhibimentioning

confidence: 99%

“…Remarkably, compound 24 has an HDAC inhibition activity 15 times higher than that of compound 25 (Table 1; Patil et al 2010), yet both compounds stalled spliceosome assembly to approximately the same extent. Another intriguing observation is the fact that compound 9 (Supplemental Table S1), an analog of 24 with a single methylene chain deletion and a more than eightfold stronger HDAC inhibition than 24 (Chen et al 2008), was not identified as a splicing inhibitor in the primary screen. These data, together with the fact that only two structurally related compounds have been identified among the 63 diverse potent HDACis, suggest that the target(s) of these compounds responsible for splicing inhibition may not be HDACs.…”

Section: Screening Of Structurally Diverse Hdacis For Splicing Inhibimentioning

confidence: 99%

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Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

Patil

Canzoneri

Samatov

et al. 2012

RNA

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The removal of intervening sequences (introns) from a primary RNA transcript is catalyzed by the spliceosome, a large ribonucleoprotein complex. At the start of each splicing cycle, the spliceosome assembles anew in a sequentially ordered manner on the pre-mRNA intron to be removed. We describe here the identification of a series of naphthalen-2-yl hydroxamate compounds that inhibit pre-mRNA splicing in vitro with mid-to high-micromolar values of IC 50 . These hydroxamates stall spliceosome assembly at the A complex stage. A structure-activity analysis of lead compounds revealed three pharmacophores that are essential for splicing inhibition. Specifically, a hydroxamate as a zinc-binding group and a 6-methoxynaphthalene cap group are both critical, and a linker chain comprising eight to nine methylene groups is also important, for the specific binding to the docking site of a target protein molecule and precise positioning of the zinc binding group. As we found no correlation between the inhibition patterns of known histone deacetylases on the one hand and pre-mRNA splicing on the other, we conclude that these compounds may function through the inhibition of the activities of other, at present, unknown spliceosomeassociated zinc metalloprotein(s).

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Section: Structure-activity Relationship (Sar) Of Splicing Inhibitionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 92%

Section: Screening Of Structurally Diverse Hdacis For Splicing Inhibimentioning

confidence: 99%

Section: Screening Of Structurally Diverse Hdacis For Splicing Inhibimentioning

confidence: 99%

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Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

Patil

Canzoneri

Samatov

et al. 2012

RNA

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“…Chen et al identified compounds (78), that were several folds more potent than SAHA. [143] A subset of these compounds also inhibited the proliferation of DU-145 cells. Due to their anticipated resistance to intracellular peptidases, these triazole-linked HDAC inhibitors were expected to display improved in vitro activity relative to the common amide-based inhibitors.…”

Section: Antifungal and Antibacterialsmentioning

confidence: 98%

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Agalave

Maujan

Pore

2011

Chemistry An Asian Journal

1,167

508

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The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

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2018

Privileged Structures in Drug Discovery

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Synthesis and structure–activity relationship of histone deacetylase (HDAC) inhibitors with triazole-linked cap group

Cited by 86 publications

References 31 publications

Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

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