Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones

Shchekotikhin, Andrey E.; Glazunova, Valeria A.; Dezhenkova, Lyubov G.; Luzikov, Yu. N.; Sinkevich, Yuri B.; Kovalenko, L. V.; Buyanov, V. N.; Balzarini, Jan; Huang, Fong Chun; Lin, J. G.; Huang, Hsu Shan; Shtil, Alexander A.; Preobrazhenskaya, M. N.

doi:10.1016/j.bmc.2009.01.047

Cited by 40 publications

(35 citation statements)

References 11 publications

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“…56 However, the toxic effects are strongly dependent on the substitution pattern, and many anthraquinone derivatives, namely, those lacking phenolic functions and/or basic side chains, have been found to be nontoxic or may even exhibit antioxidant, antimutagenic, or other beneficial properties. 33,[57][58][59][60] One of the most potent compounds of the present series, the anthracenylamino-substituted derivative 52, belongs to the group of polyaromatic hydrocarbons (PAHs) for some of which carcinogenic properties have been described. 61 Anthracene itself has been tested for carcinogenicity in mice in several studies and for mutagenicity in bacteria, yeast, and cultured mammalian cells.…”

Section: Resultsmentioning

confidence: 99%

Development of Potent and Selective Inhibitors of ecto-5′-Nucleotidase Based on an Anthraquinone Scaffold

et al. 2010

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ecto-5'-Nucleotidase (eN, CD73) plays a major role in controlling extracellular adenosine levels. eN inhibitors have potential as novel drugs, for example, for the treatment of cancer. In the present study, we synthesized and investigated a series of 55 anthraquinone derivatives as potential inhibitors of eN, 11 of which are novel compounds and another 11 of which had previously been described but have now been synthesized by an improved method. We identified several potent inhibitors of rat eN. The most potent compounds were 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (45, PSB-0952, K(i) = 260 nM) and 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (52, PSB-0963, 150 nM), with 52 being the most potent eN inhibitor described to date. Selected compounds were further characterized and found to exhibit a competitive mechanism of inhibition. Investigations of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and the P2Y receptor subtypes P2Y(2), P2Y(4), P2Y(6), and P2Y(12) showed that compound 45 exhibited the highest degree of selectivity (>150-fold).

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Section: Resultsmentioning

confidence: 99%

Development of Potent and Selective Inhibitors of ecto-5′-Nucleotidase Based on an Anthraquinone Scaffold

et al. 2010

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“…Besides, within the series of anthra[2,3- b ]thiophene-5,10-dione we identified bis(guanidine) derivative (compound 1 ; Fig. 1A) as a potent inhibitor of polydeoxynucleotide synthesis in TRAP assay [19]. One may suggest that strong basicity and delocalization of charges in the guanidine groups of side chains attributed to this effect.…”

Section: Introductionmentioning

confidence: 90%

Disordering of Human Telomeric G-Quadruplex with Novel Antiproliferative Anthrathiophenedione

et al. 2011

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Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (Kass∼106 M−1) for human telomeric antiparallel quadruplex d(TTAGGG)4 and duplex d(TTAGGG)4∶d(CCCTAA)4. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.

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“…The influence of compound 10 on topoisomerase I activity was studied as described. 26 The reaction mixture (20 μL) contain ing DNA (0.25 μg) (pBR322 plasmid; Fermentas, Lithuania) and compound 10 was incubated for 30 min at 37 °C in the buffer: TRIS HCl (35 mmol L -1 , pH 8.0), KCl (72 mmol L -1 ), MgCl 2 (5 mmol L -1 ), dithiothreitol (5 mmol L -1 ), spermidine (2 mmol L -1 ), bovine serum albumin (100 μg mL -1 ); all the reagents were from Sigma, USA. The reaction was terminated by addition of sodium dodecyl sulfate (final concentration 1%), proteinase K was add ed for 40 min at 37 °C.…”

Section: [(2 Chloro 4 Trifluoromethylquinolin Yl)methyl]quina Zolin 4mentioning

confidence: 97%

Synthesis of fluoromethyl-containing analogs of antitumor alkaloid luotonin A

et al. 2010

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A convenient method for the synthesis of hitherto unknown 3 bromomethyl 2 chloro 4 fluoromethylquinolines has been developed. Coupling of 3 bromomethyl 2 chloro 4 trifluo romethylquinoline with 4(3H) quinazolinone with subsequent intramolecular Heck cyclization leads to 7 trifluoromethylluotonin, an analog of the antitumor alkaloid luotonin A. 7 Trifluo romethylluotonin retains the antitumor activity including apoptosis of cultured tumor cells and inhibiting DNA topoisomerase I.

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Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones

Cited by 40 publications

References 11 publications

Development of Potent and Selective Inhibitors of ecto-5′-Nucleotidase Based on an Anthraquinone Scaffold

Development of Potent and Selective Inhibitors of ecto-5′-Nucleotidase Based on an Anthraquinone Scaffold

Disordering of Human Telomeric G-Quadruplex with Novel Antiproliferative Anthrathiophenedione

Synthesis of fluoromethyl-containing analogs of antitumor alkaloid luotonin A

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