5-Membered cyclic hydroxamic acids as HDAC inhibitors

Mutule, Ilze; Borovika, Diana; Rozenberga, Elīna; Romanchikova, Nadezhda; Žalubovskis, Raivis; Шестакова, И.; Trapencieris, Pēteris

doi:10.3109/14756366.2014.912214

Cited by 11 publications

(11 citation statements)

References 24 publications

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“…Metalloenzymes can be inhibited by small molecules possessing metal-binding pharmacophores (MBPs) that coordinate to the active site metal ion, resulting in a bioinorganic complex [6]. Historically, MBPs such as carboxylic acids, phosphates, thiols, and hydroxamic acids have been utilized, but in recent years a broader repertoire of pharmacophores has been investigated [2, 7–10]. However, a detailed understanding of how the coordination chemistry of these MBPs is influenced and altered by the metalloenzyme active site is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms still play a significant role in ligand coordination. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

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Section: Introductionmentioning

confidence: 99%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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“…Their ability to chelate metal ions is the principald eterminant of their biological activity.E xamples shown in Figure 1i nclude microbial siderophores (procaryotic matabolites excreted into the extracellular spacet os cavenge, by chelation, iron neededf or growth and differentiation) [1] such as scabichelin(1), [2] oxachelin (2), [3] andt he simple N-hydroxy-3,4dihydroisoquinolin-1-one(3)i solated from Streptomyces griseus. [8] However, the in vivo effects of cyclic hydroxamic acids extendb eyondt hose mediated by metal chelation:e ven classical bacterial siderophores have been shownt oe xert signaling function, antibacterial activity,a nd facilitate adaptation to oxidative stress. [8] However, the in vivo effects of cyclic hydroxamic acids extendb eyondt hose mediated by metal chelation:e ven classical bacterial siderophores have been shownt oe xert signaling function, antibacterial activity,a nd facilitate adaptation to oxidative stress.…”

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confidence: 99%

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Bakulina

Bannykh

Dar’in

et al. 2017

Chemistry A European J

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The first application of multicomponent chemistry (the Castagnoli-Cushman reaction) toward the convenient one-step preparation of cyclic hydroxamic acids is described. Cyclic hydroxamic acids are close analogues of bacterial siderophores (iron-binding compounds) and form stable complexes with Fe ions as confirmed by spectrophotometric measurements. These compounds are potential components for the design of chelating agents for iron overload disease therapy, as well as siderophore-based carrier systems for antibiotic delivery across the bacterial cell wall.

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“…Apart from histone modification, HDACs also regulate the deacetylation of non-histone proteins, including transcription factors, chaperones, signalling molecules, and DNA repair proteins [19][20][21] . In recent years, inhibition of HDACs has emerged as a promising therapeutic target for cancers and several other diseases [22][23][24][25][26] . As a result, significant efforts have been made to identify HDAC inhibitors, leading to the approval of SAHA (vorinostat), FK228 (romidepsin), LBH589 (panobinostat), and PXD101 (belinostat) as anticancer drugs ( Figure 2) [27][28][29][30][31][32][33][34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

Song

Park

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI 50 values of 1.24 mM and 1.75 mM, whereas chlorambucil exhibits GI 50 values of 21.1 mM and 37.7 mM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNAdamaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of a-tubulin and histone H3. ARTICLE HISTORY

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5-Membered cyclic hydroxamic acids as HDAC inhibitors

Cited by 11 publications

References 24 publications

Effect of donor atom identity on metal-binding pharmacophore coordination

Effect of donor atom identity on metal-binding pharmacophore coordination

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

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