Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel δ-lactam-based histone deacetylase (HDAC) inhibitors

Kim, Hwan Mook; Lee, Kiho; Park, Bum Woo; Ryu, Dong Kyu; Kim, Kangjeon; Lee, Chang Woo; Park, Song Kyu; Han, Jung Whan; Lee, Hee Yoon; Lee, Hyun Yong; Han, Gyoonhee

doi:10.1016/j.bmcl.2006.04.091

Cited by 31 publications

(13 citation statements)

References 20 publications

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“…The present authors recently discovered a novel series of HDAC inhibitors, which incorporates structural features of -lactam ring as the linker domain (Kim et al 2006(Kim et al , 2007. The aim of the current studies was to investigate the in vitro metabolism of the -lactam-based HDAC inhibitors using N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)propanamide (KBH-A40) as the model compound (for a chemical structure, see Figure 1) in an effort to characterize their pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

In vitrometabolism of KBH-A40, a novelδ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

Kim

Park

et al. 2008

Xenobiotica

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1. The metabolism of KBH-A40, a novel -lactam-based histone deacetylase (HDAC) inhibitor, was investigated in vitro using human liver microsomes and serum. After 60-min incubation in human liver microsomes with -nicotinamide adenine dinucleotide phosphate (NADPH) or uridine diphosphate glucuronic acid (UDPGA), the residual KBH-A40 was 90.6% AE 5.1% and 28.9% AE 2.0% (t 1/2 ¼ 26 min), respectively, suggesting that KBH-A40 is likely predominantly metabolized by glucuronidation, rather than by cytochrome P450 (CYP)-mediated oxidation. Consistently, KBH-A40 glucuronide was the only metabolite identified following incubations of KBH-A40 with human liver microsomes in the presence of both NADPH and UDPGA.2. KBH-A40 was not notably degraded when incubated with human serum for 60 min. In contrast, KBH-A40 was rapidly hydrolysed to its carboxylic acid form in rat serum (t 1/2 ¼ 13 min).3. Taken collectively, the results suggest that KBH-A40 is likely metabolized in man predominantly by glucuronidation of its hydroxamic acid moiety, with negligible biotransformation elsewhere in the molecule.

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Section: Introductionmentioning

confidence: 99%

In vitrometabolism of KBH-A40, a novelδ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

Kim

Park

et al. 2008

Xenobiotica

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“…86 Previously, the authors had reported a class of δ-lactam based HDAC inhibitors. 87 However, structural optimization revealed the smaller λ-lactam core was more suitable for the narrow hydrophobic tunnel of the HDAC6 catalytic pocket. 86 Recently, Kwon et al claimed the suppression effect of A452 on the viability of diverse tumor cells was independent of p53.…”

Section: Hdac6 Inhibitors Bearing Hydroxamic Acid-based Zbgmentioning

confidence: 99%

“…A452 ( 10 ) was initially identified as a λ-lactam based HDAC6 inhibitor by Han et al, in 2011 (Figure ). Previously, the authors had reported a class of δ-lactam based HDAC inhibitors . However, structural optimization revealed the smaller λ-lactam core was more suitable for the narrow hydrophobic tunnel of the HDAC6 catalytic pocket .…”

Section: Hdac6 Inhibitors Bearing Hydroxamic Acid-based Zbgmentioning

confidence: 99%

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

Zhang

Qin-Ma

et al. 2021

J. Med. Chem.

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Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.

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“…The γ ‐lactam moiety was used as a connecting unit between the CAP and the carbon chain that terminated with the hydroxamic acid. Previously, it was proved that the γ ‐lactams core insert better than δ ‐lactams into hydrophobic pocket of HDAC active site and they showed better activity as HDACIs . All the prepared γ ‐lactam analogs were evaluated for HDAC inhibition and cancer cell growth inhibition against PC‐3, MDA‐MB‐231, ACHN, HCT‐15, NCI‐H23, NUGC‐3, and LOX‐IMVI cell lines.…”

Section: Chemical Classes Of Histone Deacetylases Inhibitorsmentioning

confidence: 99%

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Zagni

Floresta

Monciino

et al. 2017

Medicinal Research Reviews

110

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Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T-cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.

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Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel δ-lactam-based histone deacetylase (HDAC) inhibitors

Cited by 31 publications

References 20 publications

In vitrometabolism of KBH-A40, a novelδ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

In vitrometabolism of KBH-A40, a novelδ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

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