Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Luckhurst, Christopher A.; Aziz, Omar; Beaumont, Vahri; Bürli, Roland W.; Breccia, Perla; Maillard, Michel; Haughan, Alan F.; Lamers, Marieke; Leonard, Philip; Matthews, Kim L.; Raphy, Gilles; Stott, Andrew J.; Muñoz-Sanjuán, Ignacio; Thomas, Beth Ann; Wall, Michael E.; Wishart, Grant; Yates, Dawn; Dominguez, Celia

doi:10.1016/j.bmcl.2018.11.009

Cited by 37 publications

(50 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that a number of HDAC inhibitors such as SAHA, MS-275, tubastatin A, and valproic acid have low brain uptake due to poor blood-brain barrier (BBB) permeability, highlighting their limitation as clinical applications for CNS diseases 22–27 . Only a handful of CNS-penetrant HDAC inhibitors have recently been reported for their therapeutic potential in CNS disorders 28–32 . Despite the challenges and difficulties in the drug discovery of CNS therapeutics, the potential therapeutic benefits of HDAC inhibitors in CNS diseases prompted us to develop CNS penetrant HDAC inhibitors structurally distinct from the previous reported CNS-penetrant HDAC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

Choi

Park

Chae

et al. 2019

Sci Rep

View full text Add to dashboard Cite

To develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

Choi

Park

Chae

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…threefold improvement in cellular activity over the unsubstituted phenyl and other fluorophenyl isomers. 92 However, 14 presented poor bioavailability (8%) and negligible brain exposure. For this reason, after novel docking evaluations, the authors noticed the possibility of introducing groups able to perform additional pistacking interactions with Phe871 in the linker-cap region through modifications at the para-position of the phenyl group.…”

Section: Case Studies Of Hdac Inhibition Associated With Ndsmentioning

confidence: 99%

“…For this reason, after novel docking evaluations, the authors noticed the possibility of introducing groups able to perform additional pistacking interactions with Phe871 in the linker-cap region through modifications at the para-position of the phenyl group. 92 The direct attachment of heteroaromatic capping groups at the para-position of the phenyl linker was sought to achieve more suitable bioavailability and CNS exposure. HDAC6 inhibition is associated with few adverse effects, 5 which makes this target interesting in the design of compounds to treat NDs.…”

Section: Case Studies Of Hdac Inhibition Associated With Ndsmentioning

confidence: 99%

“…Other studies were also conducted starting from the benzhydryl derivative 10 to generate new potent and selective analogs with suitable PK properties and adequate brain exposure (Figure 9). 92 These efforts led to the discovery of compound 14 , where the ortho ‐fluorophenyl subunit that interacts with the selectivity pocket conferred ca . threefold improvement in cellular activity over the unsubstituted phenyl and other fluorophenyl isomers 92 .…”

Section: Case Studies Of Hdac Inhibition Associated With Ndsmentioning

confidence: 99%

See 1 more Smart Citation

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Rodrigues

Pinheiro

Sagrillo

et al. 2020

Medicinal Research Reviews

View full text Add to dashboard Cite

Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented.

show abstract

“…The HAs are much weaker acids as compared with the corresponding carboxylic acids despite having identical carbon chains, however, they possess stronger abilities for selectively chelating metal ions [2]. As a metal binding group, HA are also widely used as a metalloenzyme inhibitor, including tyrosinase inhibitors [3], histone deacetylase inhibitors [4,5,6,7], and HIV-integrase inhibitors [8]. Additionally, they have a wide spectrum of biological activities, such as anticancer [9,10], antituberculosis [11,12], anti-hepatitis C virus [13], and antibacterial [14] properties.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of N-Methyl Fatty Hydroxamic Acids from Ketapang Seed Oil Catalyzed by Lipase

Suhendra¹,

Gunawan²,

Hajidi³

2019

Molecules

View full text Add to dashboard Cite

N-methyl fatty hydroxamic acid (N-MFHA), which is a derivative of hydroxamic acid (HA), was synthesized from ketapang seed oil (Terminalia catappa L.). In general, HAs have wide applications due to their chelating properties and biological activities. N-MFHAs were synthesized using immobilized lipase (Lipozyme TL IM) in biphasic medium which was the ketapang seed oil dissolved in hexane and N-methylhydroxylamine dissolved in water. The products were characterized through color testing and FT-IR spectroscopy after purification. Various factors affecting the enzyme activity investigated in the study included the effect of incubation time, the amount of lipase used, and the temperature. On the basis of the results, the optimum conditions for the synthesis of N-MFHA obtained are 25 h of incubation time, a temperature of 40 °C, and a ratio of 1:100 for the amount of enzyme (g)/oil (g). At the optimum conditions of the reaction, 59.7% of the oils were converted to N-MFHA.

show abstract

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Cited by 37 publications

References 26 publications

Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

Synthesis and Characterization of N-Methyl Fatty Hydroxamic Acids from Ketapang Seed Oil Catalyzed by Lipase

Contact Info

Product

Resources

About