5-[(Aminoalkyl)amino]imidazo[4,5,1-de]acridin-6-ones as a novel class of antineoplastic agents. Synthesis and biological activity

Cholody, Wieslaw M.; Martelli, Sante; Paradziej-Łukowicz, Jolanta; Konopa, Jerzy

doi:10.1021/jm00163a009

Cited by 88 publications

(55 citation statements)

References 3 publications

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“…Acta Pharmacologica Sinica npg droxyimidazoacridinone (C-1311) was synthesized in our department [4][5][6] . It is the leading compound in a novel class of imidazoacridinones that are inhibitors of both topoisomerases and certain receptor kinases, including the FMS-like tyrosine kinase FLT3 [7,8] .…”

Section: Wwwchinapharcom Pawłowska M Et Almentioning

confidence: 99%

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CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

2013

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Aim: To examine whether CYP3A4 overexpression influences the metabolism of anticancer agent imidazoacridinone C-1311 in CHO cells and the responses of the cells to C-1311. Methods: Wild type CHO cells (CHO-WT), CHO cells overexpressing cytochrome P450 reductase (CPR) [CHO-HR] and CHO cells coexpressing CPR and CYP3A4 (CHO-HR-3A4) were used. Metabolic transformation of C-1311 and CYP3A4 activity were measured using RP-HPLC. Flow cytometry analyses were used to examine cell cycle, caspase-3 activity and cell apoptosis. The expression of pH 6.0-dependent β-galactosidase (SA-β-gal) was studied to evaluate accelerated senescence. ROS generation was analyzed with CM-H 2 DCFDA staining. Results: CYP3A4 overexpression did not change the metabolism of C-1311 in CHO cells: the levels of all metabolites of C-1311 increased with the exposure time to a similar extent, and the differences in the peak level of the main metabolite M3 were statistically insignificant among the three CHO cell lines. In CHO-HR-3A4 cells, C-1311 effectively inhibited CYP3A4 activity without affecting CYP3A4 protein level. In the presence of C-1311, CHO-WT cells underwent rather stable G 2 /M arrest, while the two types of transfected cells only transiently accumulated at this phase. C-1311-induced apoptosis and necrosis in the two types of transfected cells occurred with a significantly faster speed and to a greater extent than in CHO-WT cells. Additionally, C-1311 induced ROS generation in the two types of transfected cells, but not in CHO-WT cells. Moreover, CHO-HR-3A4 cells that did not die underwent accelerated senescence. Conclusion: CYP3A4 overexpression in CHO cells enhances apoptosis induced by C-1311, whereas the metabolism of C-1311 is minimal and does not depend on CYP3A4 expression.

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Section: Wwwchinapharcom Pawłowska M Et Almentioning

confidence: 99%

“…Imidazoacridinone C-1311 (NSC 645809) [4,5] was synthesized by Barbara HOROWSKA, PhD in our department. C-1311 was prepared as a 10 mmol/L stock solution in 50% ethanol and kept at -20 ºC until use.…”

Section: Chemicalsmentioning

confidence: 99%

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

2013

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“…In this respect, we have recently shown that Symadex is efficiently extruded by ABCG2-overexpressing A549/K1.5 lung cancer cells (Cholody et al, 1990b;Bram et al, 2007). Here we explored the possibility of establishing a practical approach for the discovery of drug determinants facilitating ABCG2-dependent MDR in human cancers, using this novel group of IAs.…”

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confidence: 99%

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

Bram

Adar²,

Mesika³

et al. 2009

Molecular Pharmacology

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Symadex is the lead acridine compound of a novel class of imidazoacridinones (IAs) currently undergoing phase II clinical trials for the treatment of various cancers. Recently, we have shown that Symadex is extruded by ABCG2-overexpressing lung cancer A549/K1.5 cells, thereby resulting in a marked resistance to certain IAs. To identify the IA residues essential for substrate recognition by ABCG2, we here explored the ability of ABCG2 to extrude and confer resistance to a series of 23 IAs differing at defined residue(s) surrounding their common 10-azaanthracene structure. Taking advantage of the inherent fluorescent properties of IAs, ABCG2-dependent efflux and drug resistance were determined in A549/K1.5 cells using flow cytometry in the presence or absence of fumitremorgin C, a specific ABCG2 transport inhibitor. We find that a hydroxyl group at one of the R1, R2, or R3 positions in the proximal IA ring was essential for ABCG2-mediated efflux and consequent IA resistance. Moreover, elongation of the common distal aliphatic side chain attenuated ABCG2-dependent efflux, thereby resulting in the retention of parental cell sensitivity. Hence, the current study offers novel molecular insight into the structural determinants that facilitate ABCG2-mediated drug efflux and consequent drug resistance using a unique platform of fluorescent IAs. Moreover, these results establish that the IA determinants mediating cytotoxicity are precisely those that facilitate ABCG2-dependent drug efflux and IA resistance. The possible clinical implications for the future design of novel acridines that overcome ABCG2-dependent multidrug resistance are discussed.

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“…Therefore, a series of imidazoacridinones has recently been developed in an effort to generate antineoplastic agents, which combine common characteristics of acridines and anthracyclines essential for anti-cancer activity, such as planar structure and polycyclic nucleus, with higher affinity to target DNA and resistance to production of radicals by enzymatic reduction (Cholody et al, 1990a). Diethylamino groups thought to be capable of binding electrostatically to phosphate moieties of DNA were introduced (Cholody et al, 1990b), and a pyrazole ring was added to increase the electron density of the 7t ring system preventing free radical generation (Cholody et al, 1990a). Preliminary screening results for several of these compounds showed cytotoxic activity towards HeLaS3 cells and anti-tumour activity against P388 leukaemia (Cholody et al, 1990a,b), B16 melanoma and colon adenocarcinoma C26 and C38 (Kusnierczyk et al, 1994) in mice.…”

mentioning

confidence: 99%

Preclinical evaluation of novel imidazoacridinone derivatives with potent activity against experimental colorectal cancer

Burger

Double²,

Konopa³

et al. 1996

Br J Cancer

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5-[(Aminoalkyl)amino]imidazo[4,5,1-de]acridin-6-ones as a novel class of antineoplastic agents. Synthesis and biological activity

Cited by 88 publications

References 3 publications

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

Preclinical evaluation of novel imidazoacridinone derivatives with potent activity against experimental colorectal cancer

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