Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα

Lara, Lorena Infante; Sledge, Alexis; Laradji, Amine; Okoro, Cosmas O.; Osheroff, Neil

doi:10.1016/j.bmcl.2016.12.011

Cited by 11 publications

(2 citation statements)

References 27 publications

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“…A study has reported that amino acid residues Gly488, Gly506, Ser763, Ser800, Ala801, Ser802, and Pro803, as well as ASP463, Arg487, and Met766 are involve in the Topo II binding interactions near DNA region [30] [31] [32], and it is evident that most of the first-line agents for treating cancer are Topo II poisons, such as etoposide (non-intercalator), and m-amsacrine (intercalator) [5]. A study on novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives has reported that Cl, F, and Br substituted at C7 acted as covalent, rather than interfacial, topoisomerase II poisons and that an amino group at C9 was critical for activity [33]. Thus, compound 58b and 58e could be DNA non-intercalator of topo IIβ while others will be non-Topo II poisons but catalytic inhibitors of topo IIα and topo IIβ.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors

Oyedele,

Fatoki,

Dalvie

et al. 2023

OJMC

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Cancer is a leading cause of death globally, claiming about 9.6 million lives and approximately 420 million new cases of cancer will be diagnosed in the world by the year 2025. The aim of this study was to synthesize and computationally evaluate pharmacological potential of some derivatives of 9-amino-3phenylacridone, as topoisomerase II (Topo II) inhibitors. In this study, 10 derivatives of 3-phenyl-9-aminoacridone were chemically synthesized and characterized, and the potential pharmacological indications of these compounds were computationally predicted by methods such as ADMET prediction, molecular target prediction and molecular docking. The results showed that two derivatives (58e and 58j) were non-permeant of blood-brain barrier, and this property was found similar to that of amsacrine and etoposide. The results of molecular docking of the ten derivatives of 3-phenyl-9-aminoacridone that were synthesized in this work showed that the synthetic compounds (58a-j) and the standard drugs have overall best binding affinities for human acetylcholine esterase than butyrylcholinesterase, and overall best binding affinities for human topo IIα than human topo IIβ. Overall, the results of this study suggest that the synthetic compounds 58a, 58c, 58f, 58g, and 58i could probably inhibit topo IIα by catalytic inhibition as seen with amsacrine, but only 58b and 58e possessed DNA non-intercalation properties as seen with etoposide, serving as topo II poison. In conclusion, this study showed that 3-phenyl-9-aminoacridone derivatives are potential inhibitor of topo IIα/β both by catalytic inhibition and poison as non-intercalator of DNA.

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Section: Discussionmentioning

confidence: 99%

Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors

Oyedele,

Fatoki,

Dalvie

et al. 2023

OJMC

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“…Unfortunately, many of the above methods suffer from a number of drawbacks, such as prolonged reaction conditions, low yields of products, use of hazardous solvent, use of excess catalyst and tedious workup procedure. In continuation of our research program involving the synthesis of fluorine "carrier reagents" and their use for the synthesis of complex trifluoromethyl-containing organic systems of medicinal importance [29] [30] [31] [32] [33]. Herein, we describe the first report of a facile synthesis of 9-(4-phenyl-substituted)-3.6-bis(trifluomethyl-3,4,5,6,7,9-hexahydro-1H-xanthe ne-1,8(2H)-diones.…”

Section: Introductionmentioning

confidence: 99%

Facile Synthesis of Bis-Trifluoromethyl 1,8-Dioxo-Octahydroxanthene Derivatives

Okoro¹,

Ogunwale²,

Oyedele³

2019

IJOC

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Xanthene and Xanthenediones are structural components of several bioactive and semi-synthetic molecules. This work described an expeditious synthesis of novel and hitherto unreported bis-trifluoromethyl xanthene dione derivatives. The reaction of two equivalents of 5-trifluoromethyl cyclohexane-1,3dione with substituted aromatic aldehydes in the presence of ethanol containing 1 -2 drops of HCl was facile under microwave irradiation. Short reaction time (25 min), good to excellent yields (80% -95%), good atom economy, and simple workup are the major advantages of the above procedure. Moreover, the fluorinated products represent synthetically useful stable intermediates that could find applications in pharmaceutical, agricultural and material industries.

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Acridine derivatives as inhibitors/poisons of topoisomerase II

Kožurková

2021

J of Applied Toxicology

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The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.

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Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα

Cited by 11 publications

References 27 publications

Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors

Synthesis, SAR, and in Silico ADME Screening Studies of Some 9-Amino-3-Phenylacridone Derivatives as Topoisomerase II Inhibitors

Facile Synthesis of Bis-Trifluoromethyl 1,8-Dioxo-Octahydroxanthene Derivatives

Acridine derivatives as inhibitors/poisons of topoisomerase II

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