A carboline derivative as a novel mammalian DNA topoisomerase II targeting agent

Pognan, François; Saucier, Jean-Marie; Paoletti, Claude; Kaczmarek, Ł.; Nantka-Namirski, P; Mordarski, M; Peczyńska‐Czoch, Wanda

doi:10.1016/0006-2952(92)90341-f

Cited by 29 publications

(52 citation statements)

References 12 publications

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“…DIMIQ displayed strong antibacterial, antimycotic and cytotoxic activity in vitro as well as significant antitumor properties in vivo. 17,28,29) The influence of analogs of indolo [2,3-b] quinolines on cell cycle effects and their cytotoxicity have been extensively studied in vitro against several cell lines of different origin. Additionally, their ability to inhibit topoisomerase II activity was also evaluated.…”

Section: )mentioning

confidence: 99%

Membrane Perturbations Induced by New Analogs of Neocryptolepine

Jaromin

Korycińska

Pįętka-Ottlik

et al. 2012

Biological & Pharmaceutical Bulletin

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antihyperglycemic, 8,9) anti-inflammatory 10,11) and antimalarial activities.12-15) Phyto-Riker (Gihoc) Pharmaceuticals Ltd. (Accra, Ghana) has developed an herbal preparation (Phyto-laria ® ) from the dried root of C. sanguinolenta for the treatment of malaria. According to clinical studies, this tea-bag formulation of the root powder (2.5 g) has been shown to be highly effective in the treatment of acute uncomplicated malaria, with an overall cure rate of 93.5%. Moreover, the laboratory findings did not suggest any toxicity. 16)However, indoloquinoline alkaloids are quite a rare group of natural products. This fact caused significant interest for the synthesis of indoloquinoline alkaloid derivatives, because of their potential biomedical and pharmaceutical value. 1,[17][18][19][20][21][22][23][24][25][26][27] Previous studies have indicated that all indolo[2,3-b]-quinolines belonging to the 5H-series possess interesting biological activities, including inhibition of the growth of Gram-positive bacteria and pathogenic fungi, cytotoxicity against KB cells and stimulation of the formation of calf thymus topoisomerase II mediated DNA cleavage. 17) 5,11-Dimethyl-5H-indolo [2,3-b] quinoline (DIMIQ), a benzoiso-α-carboline derivative, is one of the most interesting and active representatives of this group (Fig. 1). DIMIQ displayed strong antibacterial, antimycotic and cytotoxic activity in vitro as well as significant antitumor properties in vivo. 17,28,29) The influence of analogs of indolo [2,3-b] quinolines on cell cycle effects and their cytotoxicity have been extensively studied in vitro against several cell lines of different origin. Additionally, their ability to inhibit topoisomerase II activity was also evaluated. 18,[30][31][32][33] Osiadacz et al. have performed energy calculations for different DIMIQ orientations inside the DNA duplex. The studies have shown that the most preferred intercalation position, characterized by the lowest complex energy, was the parallel orientation of the long DIMIQ axis and the neighbor base-pair axes. 34)Since therapeutic and toxic effects of drugs are strongly influenced by their lipid affinity, the study of interactions with membranes was necessary. It was also of major importance to Regular Article

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Section: )mentioning

confidence: 99%

Membrane Perturbations Induced by New Analogs of Neocryptolepine

Jaromin

Korycińska

Pįętka-Ottlik

et al. 2012

Biological & Pharmaceutical Bulletin

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“…9-OH-DIMIQ also showed a lug, her cytotoxic activity against the line of KB cells than its parent compound. Our previous studies of the interaction of DIMIQ with DNA and the ability of DIMIQ to induce the double-strand DNA breaks mediated by the topoisomerase 11, corroborated the need for the furtherance of our enzymatic assay in vitro for the 9-OH derivative under conditions established earlier (Pognan et al, 1992). We found (Table 1]) that .9-OH-DIMIQ interacted with DNA, raising the melting temperature for calf thymus DNA by 2°C and efficiently~stimulated DNA cleavage, producing a maximum (35%) of the cleavable complex at a concentration of 3 ~tM when purified calf thymus topoisomerase 1I and circular pSP65 DNA as substrates were used (Table 11).…”

Section: Dimiq 9-oh-dimiqmentioning

confidence: 65%

“…The ability of 9-OH-DIMIQ to modulate DNA topoisomerase 11 activity was determined m vitro, using calf thymus topoisomerase I1 and pSP65 as substrate DNA under conditions established earlier (Pognan, et al, 1992). D1MIQ was used as a standard…”

Section: Topoisomerase II Assaymentioning

confidence: 99%

“…Having a tetracyclic planar aromatic molecule with two heterocyclic nitrogen atoms and two methyl groups, DIMIQ is structurally similar to ellipticine. It has been found that cytotoxic DIMIQ is able to induce the formation of DNA-deavable complexes mediated by topoisomerase II at a concentration of 5 IxM (Pognan, et a!.,1992). Its cytotoxic activity (IDs0 against KB cells being equal to 0.004 tamolhriL) corresponds with antitumor properties: DIM1Q markedly prolonged the life span of murine leukemia and melanoma B 16 bearing animals (Kac~maarek, et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Microbial transformation of azacarbazoles X: Regioselective hydroxylation of 5,11-dimethyl-5H-indolo [2,3-b]quinoline, a novel DNA topoisomerase II inhibitor, by Rhizopus arrhizus

et al. 1996

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Microbial transformation of cytotoxic 5,1 l-dimethyl-5H-indolo[2,3-b]quinoline (a compound displaying antitumor activity and affecting the activity of calf thymus DNA topoisomerase 1I) was performed by the Rhizopus arrhizus strain and yielded a 9-hydroxy derivative. The metabolite obtained displayed a stronger cytotoxity against KB cells than the parenat compound (IDs0=0.001 !Ltmol/mL), and stimulated also the formafon of calf thymus topoisomerase II mediated pSP65 DNA cleavage in vitro at the concentration of 3 [aM. Being analogous to 9-hydroxyellipticine (wluch is an antitumor alkaloid), this novel indolo[2,3-b] quinoline derivative can be regarded as a novel potential antitumor agent.

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“…5,6 The active compounds increase the DNA denaturation temperature and stimulate the formation of calf thymus topoisomerase II-mediated DNA cleavage. 5,7 The aim of our work is to construct an effective anticancer drug by modification of the parent 5H-and 6H-indoloquinoline system. The modification should lead to derivatives, which combine DNA intercalating and topoisomerase II-inhibiting activity with a more pronounced affinity to specific sites in the polynucleotide chain (DNA sequence-reading drug).…”

Section: Introductionmentioning

confidence: 99%