Synthesis and structure activity relationship of 1, 3-benzo-thiazine-2-thiones as selective HDAC8 inhibitors

Wolff, Benjamin; Jänsch, Niklas; Sugiarto, Wisely Oki; Frühschulz, Stefan; Lang, Maraike; Altintas, Rabia; Oehme, Ina; Meyer‐Almes, Franz‐Josef

doi:10.1016/j.ejmech.2019.111756

Cited by 22 publications

(9 citation statements)

References 35 publications

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“…The selectivity of other non-hydroxamate inhibitors was explained by the occupation of the transition area between the active site and the acetate release channel at the bottom of the conserved binding pocket [17]. This binding mode is also proposed for recently discovered non-hydroxamate inhibitors with benzothiazine scaffold [18,19]. So called linkerless HDAC8 inhibitors ( Fig.…”

Section: Introductionmentioning

confidence: 85%

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

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Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K-562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC 50-9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC 50-28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC 50-104.2 μM) and human fibroblasts (HS27) (CC 50-105.0 μM). Thus, among this novel series of TZD *

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Section: Introductionmentioning

confidence: 85%

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

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“…1,3-Benzothiazine analogs were shown to be extremely robust against mM concentrations of GSH and able to penetrate cell membranes. Compound 92 reduced the proliferation of SK-N-BE(2)-C neuroblastoma cells in the µM range, similarly to the reference compound PCI-34051 [166]. Intracellular inhibition of HDAC8 was demonstrated by increased acetylation of the specific bona fide substrate acetyl-SMC3 and led to a patent [167].…”

Section: Carbamate Scaffold Warheadsmentioning

confidence: 99%

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Frühauf

Meyer‐Almes

2021

Molecules

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Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.

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“…Ligand binding and enzyme activity of HDAC8 have been shown to depend largely on the flexibility of the neighboring loops [ 23 , 24 , 25 , 26 , 27 , 28 ]. The high malleability of the binding region allows the accommodation of ligands that are highly chemically and structurally divergent, including SAHA [ 25 ], PCI-34051 [ 20 ], tropolones [ 29 ], largazole analogs [ 26 ], 1,3-benzo-thiazine-2-thiones [ 17 ], meta-substituted benzhydroxamic acids [ 18 ], and so-called linkerless HDAC8 inhibitors [ 19 ]. Crystal structures of HDAC8 complexes with non-selective linear inhibitors showed no participitation of M274 during side pocket formation [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…The hydroxamic acid PCI-34051 has an IC 50 -value of 10 nM and a selectivity more than 200-fold higher than other HDAC isozymes. Consequently, PCI-34051 has been the most commonly used reference compound for studying the biological role of HDAC8 in cellular systems [ 11 , 15 , 16 , 17 ]. Huang et al developed branched ortho-aryl-N-hydroxycinnamides as HDAC8-selective inhibitors, including o-ACHA which inhibits HDAC8 with an activity similar to PCI-34051 and has antiproliferative effects against several cancer cell lines [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors

Jänsch

Lang

Meyer‐Almes

2022

IJMS

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HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors.

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Synthesis and structure activity relationship of 1, 3-benzo-thiazine-2-thiones as selective HDAC8 inhibitors

Cited by 22 publications

References 35 publications

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors

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