Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid and related derivatives

Wentland, Mark P.; Lesher, George Y.; Reuman, Michael; Gruett, Monte D.; Singh, Baldev; Aldous, Suzanne C.; Dorff, Peter H.; Rake, James B.; Coughlin, Susan A.

doi:10.1021/jm00071a010

Cited by 74 publications

(41 citation statements)

References 19 publications

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“…The geometrical configuration of C-2Ј was proved to be E by a large coupling constant (J 2ЈH-3ЈH ϭ15.0 Hz). The correspondence of 13 C chemical shifts assigned to the chromophore moiety between 1 and quinolone compounds such as PSC-D, YM-30059 and CJ-13,136 strongly supported the structure of 1 [3ϳ5]. Thus, the structure of 1 was established to be (E)-3-methyl-2-(2-octenyl)-4-quinolone as shown in Fig.…”

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confidence: 80%

Burkholone, A New Cytotoxic Antibiotic against IGF-I Dependent Cells from Burkholderia sp.

Mori¹,

Yamashita

Furihata

et al. 2007

J Antibiot

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In the course of our screening program for new inhibitors of IGF-I signaling, we isolated a new cytotoxic antibiotic, burkholone, from the culture broth of Burkholderia sp. QN15488. The structure of burkholone was determined to be (E)-3-methyl-2-(2-octenyl)-4-quinolone by a series of NMR analyses. Burkholone induced cell death 32D/GR15 cells with an IC 50 value of 160 nM in IGF-I containing medium, while no cell death was observed in IL-3 containing medium even at the concentration of 37 mM.Keywords burkholone, insulin-like growth factor, quinolone, cytotoxic antibiotic Insulin-like growth factors (IGFs) play in part a key role in human cancer progression. IGF signals through IGF-I receptor are known to be significant for tumor cell growth and survival [1]. Thus, inhibitors of IGF signal transduction are expected to be promising drugs for cancer chemotherapy. To evaluate the anti-IGF activity, we employed IGF-I receptor harboring 32D/GR15 cells which were derived from hematopoietic cell line 32D cells by transformed with the IGF-I receptor [2]. Viability and proliferation of 32D/GR15 cells are strictly dependent on cytokines such as interleukin-3 (IL-3). The IL-3-dependent 32D/GR15 cells undergo rapid apoptosis in the absence of IL-3. However, 32D/GR15 cells completely survive in an IL-3-free medium containing IGF-I [2]. Using 32D/GR15 cells enables to distinguish the survival signaling between IL-3 and IGF-I [2]. In the course of our screening program for new inhibitors of IGF-I signaling, a new quinolone compound, (E)-3-methyl-2-(2-octenyl)-4-quinolone designated as burkholone (1, Fig. 1) was isolated from the culture broth of Burkholderia sp. QN15488.In this paper, we report the production, isolation, physico-chemical properties, structure elucidation and brief biological properties of 1.Strain QN15488 was isolated from a soil sample

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confidence: 80%

Burkholone, A New Cytotoxic Antibiotic against IGF-I Dependent Cells from Burkholderia sp.

Mori¹,

Yamashita

Furihata

et al. 2007

J Antibiot

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“…Since that initial report, a number of novel quinolones with activity against topoisomerase II, eukaryotic cells, or mammalian tumors have been described (8,9,18,19,31,32,37,(39)(40)(41). In contrast to clinically relevant quinolone antimicrobial agents, many of these latter compounds contain an aromatic substituent at the C-7 position (3,9,18,31,32,39,40).…”

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confidence: 99%

“…Substitution of the aromatic C-7 4'-hydroxyphenyl ring by either an aliphatic 4'-hydroxypiperidine group 472) (35,42) and is supported by the fact that most quinolones with activity against the eukaryotic type II enzyme contain a C-7 ring with a hydrogen-bonding group either at the 4'-position (3,19,(39)(40)(41) or as a substituent off the 4'-position (18,31,32,41). A second and intriguing possibility is that the C-7 4'-hydroxyphenyl ring mimics the active-site tyrosine of topoisomerase II (26,29) …”

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confidence: 99%

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

Elsea

McGuirk

Gootz

et al. 1993

Antimicrob Agents Chemother

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). However, the features of the drug that contribute to its activity towards mammalian systems have not been characterized. Therefore, CP-115,953 and a series of related quinolones were examined for their activity against calf thymus topoisomerase H and cultured mammalian cells. CP-115,953 stimulated DNA cleavage mediated by the type H enzyme with a potency that was -600-fold greater than that of the antimicrobial quinolone ciprofloxacin and -50-fold greater than that of the antineoplastic drug etoposide. As determined by the ability to enhance enzyme-mediated DNA cleavage, quinolone activity towards calf thymus topoisomerase H was enhanced by the presence of a cyclopropyl group at the N-1 ring position and by the presence of a fluorine at C-8. Furthermore, the 4'-hydroxyphenyl substituent at the C-7 position was critical for the potency of CP-115,953 towards the mammalian type H enzyme. In this regard, the aromatic nature of the C-7 ring as well as the presence and the position of the 4'-hydroxyl group contributed greatly to drug activity. Finally, the cytotoxicity of quinolones in the CP-115,953 series towards mammalian cells paralleled the in vitro stimulation of DNA cleavage by topoisomerase H rather than the inhibition of enzyme-catalyzed DNA relaxation. This correlation strongly suggests that these quinolones promote cell death by converting topoisomerase IT to a cellular poison.

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“…1). Conversely, quinolones that display activity toward the eukaryotic type II enzyme often contain aromatic substituents at C-7 including hydroxyphenyl (5,6,37,38), quinoline (7), pyridine (2), and 2,6-dimethylpyridine (20,48,49).…”

Section: Resultsmentioning

confidence: 99%

A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential

Corbett

Guerry

Pflieger

et al. 1993

Antimicrob Agents Chemother

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Recently, a number of novel quinolones with potent activity against topoisomerase H and eukaryotic cells have been described. Many of these compounds contain aromatic substituents in their C-7 ring positions. To determine whether pyrimido[1,6-albenzimidazoles, a class of drugs modeled on quinolones, also display activity toward eukaryotic systems, the effects of Ro 46-7864 and Ro 47-3359 on Drosophila melanogaster topoisomerase II and Kc cells were characterized. While the former drug contains an aliphatic group (4-N-methylpiperazine) at the ring position equivalent to C-7 in quinolones, the latter compound contains an aromatic substituent (2,6-dimethylpyridine). Both pyrimido [1,6-

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Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid and related derivatives

Cited by 74 publications

References 19 publications

Burkholone, A New Cytotoxic Antibiotic against IGF-I Dependent Cells from Burkholderia sp.

Burkholone, A New Cytotoxic Antibiotic against IGF-I Dependent Cells from Burkholderia sp.

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential

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