Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum

Sperry, Jonathan; Lorenzo-Castrillejo, Isabel; Brimble, Margaret A.; Machín, Félix

doi:10.1016/j.bmc.2009.08.064

Cited by 37 publications

(22 citation statements)

References 47 publications

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“…The reasons for the increased potency against H460 cells are not clear, but it may possibly reflect altered interactions between human topoisomerase II (the cytotoxic target) and the pyranonaphthoquinones in this line. [49] Nevertheless, the series exhibited much less dose potency against H460 cells than clinically 50 values against this line in the low nanomolar range. [58,59] Activity of Pyranonaphthoquinone Derivatives against the Catalytic Activity of Human IDO in LLTC-IDO Cells Next we examined the series' ability to inhibit the catalytic activity of IDO-1 in a cellular context by determining the extent to which each compound inhibited the production of the L-tryptophan catabolite, L-kynurenine, in the human IDO-1 overexpressing LLTC-IDO cells.…”

Section: Resultsmentioning

confidence: 95%

“…An initial examination of these compounds had shown that they could act as topoisomerase II-targeting agents and were thus potentially cytotoxic. [49] Using IC 50 assays, we measured the growth inhibitory effects of these compounds against the murine Lewis lung carcinoma cell line LLTC, and LLTC-IDO cells, which have been stably transfected to express human recombinant IDO-1. As a representative human tumour cell line we also examined their activity against the human non-smallcell lung carcinoma cell line, H460.…”

Section: Resultsmentioning

confidence: 99%

“…Our research group has a long-standing [46] interest in the synthesis of natural products possessing a pyranonaphthoquinone moiety, [48] along with their chemical modification in order to improve their respective bioactivities. [49,50] Thus, the potent IDO-1 inhibitory properties displayed by annulin B and exiguamine A, combined with our ongoing interest regarding the synthesis and biological properties of pyranonaphthoquinone derivatives led us to initiate the testing of pyranonaphthoquinones bearing the core structure 1, which displays a combination of the structural features present in both annulin B and exiguamine A (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

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Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

et al. 2013

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A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

et al. 2013

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“…Some naphthoquinones have exhibited topoisomerase inhibition effects. [52][53][54] Among these naphthoquinones, β-lapachone was first reported as a topoisomerase I catalytic inhibitor, 55 and subsequently, Frydman et al 52 reported β-lapachone to be a weak topoisomerase II poison that, unlike prototypical poisons, also inactivates the enzyme upon drug/enzyme pre-incubation. However, the effects of β-lapachone on topoisomerases remain controversial, as this naphthoquinone has been shown to be both a topoisomerase I inhibitor 55 and activator 56 as well as a topoisomerase II inhibitor in in vitro systems.…”

Section: Resultsmentioning

confidence: 99%

Potent antileukemic action of naphthoquinoidal compounds: evidence for an intrinsic death mechanism based on oxidative stress and inhibition of DNA repair

Cavalcanti¹,

Cabral²,

Rodrigues³

et al. 2013

J. Braz. Chem. Soc.

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O presente estudo descreve a acentuada atividade citotóxica da nor-β-lapachona, seus derivados arilamino substituídos, naftoquinonas iodadas e metilada, além de nor-β-lapachonas 1,2,3-triazólicas, contra quatro linhagens de células de leucemia humana (HL-60, K562, Molt-4 e Jurkat). Nor-β-lapachonas arilamino substituídas foram identificadas com potente atividade, revelando-se como potenciais protótipos contra as linhagens tumorais descritas. Estudos utilizando o ensaio cometa evidenciaram danos ao ácido desoxirribonucleico (ADN) causado pelos derivados arilamino substituídos devido o aumento dos níveis intracelulares de espécies reativas de oxigênio (ERO's). Células de HL-60 foram selecionadas para a continuidade dos estudos de mecanismos moleculares subjacentes e apoptose induzida pelos derivados quinoidais foi observada por análise de citometria de fluxo. Cepas de Saccharomyces cerevisiae foram utilizadas para uma investigação preliminar sobre o mecanismo de ação em topoisomerases de ADN. Os estudos sugerem que, aparentemente, a citotoxidade dos compostos não envolve a inibição de topoisomerases, mas que o tratamento prejudica a atividade de reparação do ADN, provocando assim a morte celular. A capacidade em induzir apoptose e aberrações cromossômicas em fibroblastos de pulmão de hamster chinês (células V79) também foi investigada. Núcleos apoptóticos foram observados e nossos estudos indicam uma correlação entre dano ao ADN e apoptose.The current study describes that nor-β-lapachone and its arylamino derivatives, iodinated and methylated naphthoquinones and nor-β-lapachone-based 1,2,3-triazoles exhibited pronounced cytotoxic effects against four human leukemia cell lines (HL-60, K562, Molt-4 and Jurkat). Nor-β-lapachones arylamino substituted with potent activity were identified, revealing themselves as potential prototypes against tumor cell lines. Moreover, cells treated with these compounds showed DNA damage according to the standard comet assay, a finding that was, at least in part, due to increased intracellular levels of ROS. HL-60 cells were chosen to study the underlying molecular mechanisms of cytotoxicity. Drug-induced apoptosis in HL-60 cells was observed by flow cytometry analyses. Strains of Saccharomyces cerevisiae were used for a preliminary investigation into the mechanism of drug action on DNA topoisomerases. These results suggested that the cytotoxicity of these compounds apparently does not involve topoisomerase inhibition, but that treatment impairs DNA repair activity, thus triggering cell death. Considering their pro-oxidant properties, we investigated the ability of these compounds to induce apoptosis and chromosomal aberrations as micronuclei in Chinese hamster lung fibroblasts (V79 cells). Morphological apoptotic nuclei and micronuclei induction following drug treatment were observed, suggesting a correlation between DNA damage and apoptosis.Keywords: naphthoquinone, nor-β-lapachone, antileukemic activity, reactive oxygen species, genotoxicity, DNA repair Potent Antileukemic Action of...

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“…HL-60 cells present TOP2 (25) and its contribution to the process of apoptosis is unknown. For instance, pyranonapthoquinones such as eleuterin, ventiloquinone and thysanone and are able to inhibit TOP2 (26).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones

et al. 2012

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Abstract.Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self-sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-1CC (methyl 7-(4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido [4,5-c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in the treatment against cancer.

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Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum

Cited by 37 publications

References 47 publications

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

Potent antileukemic action of naphthoquinoidal compounds: evidence for an intrinsic death mechanism based on oxidative stress and inhibition of DNA repair

Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones

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