Novel acridinedione derivatives: Design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies

Alvala, Mallika; Bhatnagar, Shubhmita; Alvala, Ravi; Jeankumar, Variam Ullas; Manjashetty, Thimmappa H.; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.bmcl.2012.03.030

Cited by 39 publications

(20 citation statements)

References 35 publications

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“…SIRT1 expression levels in this cell line have been previously reported (Alvala, et al 2012). pS2 mRNA expression was not induced by estrogen, as expected, nor by sirtinol, compared to untreated control (data not shown, but see the empty-vector controls in Fig.…”

Section: Resultssupporting

confidence: 67%

SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells

Moore

Faller

2012

Journal of Endocrinology

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In prostate and breast cancer, the androgen and estrogen receptors mediate induction of androgen- and estrogen-responsive genes respectively, and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD+)-dependent class III histone deacetylase (HDAC) that has been linked to gene silencing, control of the cell cycle, apoptosis and energy homeostasis. In prostate cancer, SIRT1 is required for androgen-antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is estrogen receptor-alpha (ERα)-dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERα in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase (PI3K) activity. Phosphorylated ERα subsequently accumulates in the nucleus, where ERα binds DNA ER-response elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER-signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ERα-mediated activation and target gene transcription. Like ligand-dependent activation of ERα, SIRT1 inhibition-mediated ERα activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.

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Section: Resultssupporting

confidence: 67%

SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells

Moore

Faller

2012

Journal of Endocrinology

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“…Cyclopropyl, phenyl, or phenylethyl substituents at the N1 position of the dihydropyridine ring lead to compounds that can inhibit SIRT1 and SIRT2, but not SIRT3 (Table 1, entries 5) [96]. Another potent SIRT1 inhibitor (Table 1, entry 6) in a series of acridinedione derivatives shows anticancer activity with dose dependent increase in acetylation of SIRT1 target p53 K382[97]. …”

Section: Sirtuin Inhibitorsmentioning

confidence: 99%

Sirtuin Inhibitors as Anticancer Agents

2014

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Sirtuins are a class of enzymes with nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylase function. By deacylating various substrate proteins, including histones, transcription factors, and metabolic enzymes, sirtuins regulate various biological processes, such as transcription, cell survival, DNA damage and repair, and longevity. Small molecules that can inhibit sirtuins have been developed and many of them have shown anti-cancer activity. Here we summarize the major biological findings that connect sirtuins to cancer and the different types of sirtuin inhibitors developed. Interestingly, biological data suggest that sirtuins have both tumor-suppressing and tumor-promoting roles. However, most pharmacological studies with small molecule inhibitors suggest that inhibiting sirtuin is a promising anti-cancer strategy. We discuss possible explanations for this discrepancy and suggest possible future directions to further establish sirtuin inhibitors as anticancer agents.

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“…Acridinediones are a highly important class of organic compounds, since they possess a wide range of pharmaceutical and biological activities such as a positive ionotropic effect promoting the entry of calcium to the intracellular space [2], anticancer activity [3], enzyme and tumour cell inhibition [4], antimicrobial activity and cytotoxicity [5]. They have structural similarity to 1,4-dihydropyridines (1,, which are well known intermediates in the synthesis of several pharmaceuticals including those for the treatment of hypertension and cardiovascular diseases [6].…”

Section: Introductionmentioning

confidence: 99%

“…3,6,4,6,7,9,hexahydroacridine-1,8-dione, 4a yellow solid. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm): 0.95 (s, 6H); 1.06 (s, 6H); 2.13-2.30 (m, 8H); 5.09 (s, 1H); 7.06 (t, J = 7.5 Hz, 1H); 7.19 (t, J = 7.5 Hz, 2H); 7.34 (d, J = 7.0 Hz, 2H); 7.96 (s, 1H…”

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confidence: 99%

An Efficient One-Pot Four-Component Synthesis of 9-Aryl-Hexahydroacridine-1,8-Dione Derivatives in the Presence of a Molecular Sieves Supported Iron Catalyst

Magyar

Hell

2019

Catal Lett

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A series of 9-aryl-hexahydroacridine-1,8-diones are synthetized with good to excellent yields (50-99%) via a one-pot fourcomponent reaction of dimedone, aromatic aldehydes and ammonium acetate in the presence of 4 Å molecular sieves modified with iron(III) as an efficient heterogeneous catalyst, in ethanol. The process offers the advantages of high yields, mild reaction conditions and easy work-up procedure. The catalyst can be reused without significant loss of activity.

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Novel acridinedione derivatives: Design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies

Cited by 39 publications

References 35 publications

SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells

SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells

Sirtuin Inhibitors as Anticancer Agents

An Efficient One-Pot Four-Component Synthesis of 9-Aryl-Hexahydroacridine-1,8-Dione Derivatives in the Presence of a Molecular Sieves Supported Iron Catalyst

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