Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors

Angibaud, Patrick; Emelen, Kristof Van; Decrane, Laurence; Brandt, Sven Van; Holte, Peter ten; Pilatte, Isabelle; Roux, Bruno; Poncelet, Virginie; Speybrouck, David; Quéguiner, Laurence; Gaurrand, Sandrine; Marien, Ann; Floren, Wim; Janssen, Lut; Verdonck, Marc; Dun, Jacky Van; Gompel, Jacky Van; Gilissen, RMCA mammalogy - Emmanuel; Mackie, Claire; Jardin, Marc Du; Peeters, Jozef; Noppe, M.; Hijfte, Luc Van; Freyne, Eddy; Pagé, Martin; Janicot, Michel; Arts, Janine

doi:10.1016/j.bmcl.2009.10.118

Cited by 16 publications

(14 citation statements)

References 22 publications

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“…For our study, we used three such alkynes and converted them to the corresponding aryl vinyl boronic acids [21] and subsequently to the isoxazole derivatives. [Scheme 3] The yields for the catechol hydroboration, hydrolysis (43–61%) and coupling steps for the representative compounds 5n–p [22–24] were very satisfactory (43–61%). Conversion to the isoxazole derivatives 3n–p also proceeded in good yields (73–93%).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor

Haddad

Gershman

Dilis

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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A series of 3,5-bis (4-hydroxyphenyl) isoxazoles bearing a styryl/alkyl vinyl group at the 4-position were prepared and evaluated as ligands for the estrogen receptor-alpha (ERα). The target compounds were prepared using the Suzuki reaction to couple an iodo-isoxazole intermediate with a series of styryl/alkenyl boronic acids, followed by O-demethylation. The products were evaluated for their estrogen receptor-α ligand binding domain (ERα-LBD) binding affinity using a competitive binding assay. The 4-(4-hydroxystyryl) derivative 4h displays binding properties similar to those of the previously described pyrazole class of ER ligands, indicating that the ERα-LBD tolerates the presence of the added vinyl group at the 4-position of the isoxazole ring.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor

Haddad

Gershman

Dilis

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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“…Five potent and diverse HDAC3Is were selected from the literature, i.e., 15k [ 29 ], 8d [ 30 ], R306465 [ 31 ], SAHA [ 32 ], and MS-275 [ 32 ] (cf. Figure 2 ).…”

Section: Methodsmentioning

confidence: 99%

A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors

Xia

Wang

et al. 2017

IJMS

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Histone deacetylase 3 (HDAC3) has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS) is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.e., MUBD-HDAC3 to the evaluation of structure-based VS (SBVS) and ligand-based VS (LBVS) combinatorial approaches. We have identified FRED (Chemgauss4) docking against a structural model of HDAC3, i.e., SAHA-3 generated by a computationally inexpensive “flexible docking”, as the best SBVS approach and a common feature pharmacophore model, i.e., Hypo1 generated by Catalyst/HipHop as the optimal model for LBVS. We then developed a pipeline that was composed of Hypo1, FRED (Chemgauss4), and SAHA-3 sequentially, and demonstrated that it was superior to other combinations in terms of ligand enrichment. In summary, we present the first highly-validated, rationally-designed VS strategy specific to HDAC3 inhibitor discovery. The constructed pipeline is publicly accessible for the scientific community to identify novel HDAC3 inhibitors in a time-efficient and cost-effective way.

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“…Examples of potent HDAC8 inhibitors include 2-piperazinyl-5-pyrimidylhydroxamic acid derivatives. For this series, despite the absence of selectivity among the different isoforms in class I, compound (1) exhibited an IC 50 value of 0.9 nM against HDAC8 and an antiproliferative effect against human ovarian cancer A2780 (IC 50 = 29 nM) (Angibaud et al, 2010) (Figure 6). A selective HDAC8 inhibition was described for the phenyltriazole derivative (2) discovered after screening of an in-house large set of small molecules, followed by molecular optimization.…”

Section: Compounds At the Preclinical Stagementioning

confidence: 99%

Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

Freitas

Deberaldini

Gomes

et al. 2021

Front. Cell Dev. Biol.

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The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

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Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors

Cited by 16 publications

References 22 publications

Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor

Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor

A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors

Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

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