Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells

Ocasio, Cory A.; Sansook, Supojjanee; Jones, Rhiannon N.; Roberts, Justin M.; Scott, Thomas G.; Tsoureas, Nikolaos; Coxhead, Peter; Guille, Matthew; Tizzard, Graham J.; Coles, Simon J.; Hochegger, Helfrid; Bradner, James E.; Spencer, John

doi:10.1021/acs.organomet.7b00437

Cited by 28 publications

(23 citation statements)

References 47 publications

(85 reference statements)

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“…In a previous publication, we [ 9 ] reported the synthesis of the novel HDACi Pojamide ( N 1 -(2-aminophenyl)- N 8 -ferrocenyloctanediamide, 1), a ferrocene-containing o -aminoanilide that can be activated in cells to a Fe III species. This compound displays an optimal arrangement of a ferrocene cap—which can be oxidized—a linker, and a benzamide zinc-binding motif, as opposed to the more common hydroxamic acid, to enable selective inhibitory activity toward HDAC3, one of the major class I HDACs.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells

Luparello

Asaro

Cruciata

et al. 2019

IJMS

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We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated that only the first two compounds at 70 μM concentration caused an approximate halving of cell number after 24 h of exposure, whereas the tetrafluoroborate derivative exerted no effect on cell survival nor proliferation. Flow cytometric and protein blot analyses were performed on cells exposed to both Pojamide and the ferrocenyladipamide derivative to evaluate cell cycle distribution, apoptosis/autophagy modulation, and mitochondrial metabolic state in order to assess the cellular basis of the cytotoxic effect. The data obtained show that the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the onset of non-apoptotic cell death conceivably linked to a down-regulation of autophagic processes and an impairment of mitochondrial function with an increase in intracellular reactive oxygen species. Our work expands the list of autophagy-regulating drugs and also provides a further example of the role played by the inhibition of autophagy in breast cancer cell death. Moreover, the compounds studied may represent attractive and promising targets for subsequent molecular modeling for anti-neoplastic agents in malignant breast cancer.

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Section: Introductionmentioning

confidence: 99%

“…Compound 3 is a preformed, independently synthesized, oxidized analog of 1. Such a Fe III derivative is postulated to be formed in 1-treated cells when sodium nitroprusside oxidant is added, but it is a charged species and, therefore, is supposedly poorly permeable in cells if administered exogenously [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells

Luparello

Asaro

Cruciata

et al. 2019

IJMS

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“…We have previously reported the incorporation of ferrocene, as a phenyl bioisostere, into a variety of different molecules for biological evaluation [ 25 , 26 , 27 , 28 ]. From our previous research, we envisaged that the introduction of a ferrocene group to a known MNK1/2 inhibitor ( Figure 2 a) would both enhance the binding potency and potentially confer other desirable biological properties to the molecules.…”

Section: Introductionmentioning

confidence: 99%

Probing the Anticancer Action of Novel Ferrocene Analogues of MNK Inhibitors

et al. 2018

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Two novel ferrocene-containing compounds based upon a known MNK1/2 kinase (MAPK-interacting kinase) inhibitor have been synthesized. The compounds were designed to use the unique shape of ferrocene to exploit a large hydrophobic pocket in MNK1/2 that is only partially occupied by the original compound. Screening of the ferrocene analogues showed that both exhibited potent anticancer effects in several breast cancer and AML (acute myeloid leukemia) cell lines, despite a loss of MNK potency. The most potent ferrocene-based compound 5 was further analysed in vitro in MDA-MB-231 (triple negative breast cancer cells). Dose–response curves of compound 5 for 2D assay and 3D assay generated IC50 values (half maximal inhibitory concentration) of 0.55 µM and 1.25 µM, respectively.

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“…23 Hyperacetylation has the opposite effect, increasing tumourrepressor gene expression. As a result, the development of HDAC inhibitors as anticancer agents has been actively pursued, [24][25][26][27][28][29][30][31] with four drugs, including vorinostat (suberoyl anilide hydroxamic acid, SAHA,), 32 approved for treatment of cutaneous T-cell lymphomas and multiple myeloma. SAHA (Figure 1) comprises a hydroxamic acid group that chelates Zn 2+ in a cavity in the enzyme active site, a hydrophobic chain that penetrates the narrow cavity and a phenyl head group that sits at the entrance to the cavity.…”

Section: Introductionmentioning

confidence: 99%

Perfluorinated HDAC inhibitors as selective anticancer agents

et al. 2017

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A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new compounds show up to 5-fold greater activity against cancer cells than healthy cells. This selectivity is in contrast to SAHA, which is more active against the healthy cell line than the cancer cell line tested. Finally, we report an increase in activity for SAHA under mild hyperthermia, indicating that it could be an interesting candidate to use in combination with thermal therapy.

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Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells

Abstract: John (2017) Pojamide: An HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells. Organometallics, 36 (17). pp. 3276-3283.

Cited by 28 publications

References 47 publications

Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells

Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells

Probing the Anticancer Action of Novel Ferrocene Analogues of MNK Inhibitors

Perfluorinated HDAC inhibitors as selective anticancer agents

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