Aza and diaza bioisosteric anthracene-9,10-diones as antitumor agents.

Krapcho, A. Paul; Maresch, Martin J.; Hacker, Miles P.; Menta, Ernesto; Oliva, Ambrogio; Giuliani, F; Spinelli, Silvano

doi:10.18388/abp.1995_4896

Cited by 13 publications

(6 citation statements)

References 5 publications

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“…Pixantrone is a novel aza-anthracenedione developed to reduce the risk of cardiotoxicity while maintaining efficacy in the treatment of aggressive lymphomas (5)(6)(7)(8). It targets DNA topoisomerase IIα and produces semiquinone free radicals in an enzymatic reducing system.…”

Section: Introductionmentioning

confidence: 99%

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

2020

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Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with poor outcomes in patients ineligible for autologous stem cell transplantation. In this setting, novel treatment approaches are urgently required and the innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival (OS). The present study retrospectively analyzed 12 patients routinely

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Section: Introductionmentioning

confidence: 99%

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

2020

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“…18 Starting from alternatively substituted 1,4-naphtoquinones, a wide range of 2,3-diazaanthracenediones, also called diaza-anthraquinones (DAAQs), can be synthesizedaffording a great opportunity for the investigation of the structure−property relationships of diazabased quinone compounds for RFBs. Previously utilized solely for pharmacological applications (e.g., cancer treatment 19,20 ), this class of compounds may be a promising supplement to homocyclic quinone derivatives for energy storage applications.…”

Section: ■ Introductionmentioning

confidence: 99%

Quest for Organic Active Materials for Redox Flow Batteries: 2,3-Diaza-anthraquinones and Their Electrochemical Properties

Hofmann

Pfanschilling

Krawczyk³

et al. 2018

Chem. Mater.

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To be competitive with other electrically rechargeable large scale energy storage, the range of active materials for redox flow batteries is currently expanded by organic compoundsthis holds especially for the redox active material class of quinones that can be derived from naturally abundant resources at low cost. Here we propose the modified quinone 2,3-diaza-anthracenedione, and two of its derivatives, as a promising active material for aqueous redox flow batteries. We systematically study the electrochemical performance (redox potentials, rate constants, diffusion coefficients) for these three compounds at different pH values experimentally and complement the results with density functional calculations: A positive redox potential shift of about 300 mV is achieved by the incorporation of a diaza moiety into the anthraquinone base structure. Our experiments at low pH show that the addition of a methoxy group to the base structure of the 2,3-diaza-anthracenedione strongly increases the electrochemical stability in aqueous acidic mediaalthough the impact of the conjugate base is not clear yet. Furthermore, a functionalization with two hydroxyl groups evokes a negative redox potential shift of 54 mV in acidic and 264 mV in alkaline solution. This demonstrates that this novel class of compounds is very versatile and can be tailor-made for use as active material in redox flow batterieseither in alkaline or acidic media. The 2,3-diaza-anthracenediones presented in this study were used as anolyte active materials in a full redox flow cell as a proof of concept; best cycling stability was achieved with 2,3-diaza-anthracenediones functionalized with a methoxy group as active material. Transferring our findings to other quinone base structures, such as naphthoquinones, could lead to even better performing catholyte and anolyte active materials for future redox flow batteries with organic active material.

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“…Over the past few years, the introduction of heteroatoms into different positions of the anthracene-9,10-dione chromophore has been investigated by our group as a means of identification of effective second-generation anthracene-9,10-dione chemotypes lacking the 5,8-dihydroxy substitution pattern. − These bioisosteres would clearly differ from their carbocyclic counterparts in their interactions with DNA and enzymes, as well as in their reduction potentials. A number of aza-bioisosteric chemotypes related to mitoxantrone have been synthesized, and the position of the nitrogen atom was found to exert a profound effect on the antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of 2,5-Disubstituted- Indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-Aza-anthrapyrazoles)

et al. 1998

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The synthesis and antitumor evaluation of 2, 5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates.

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Aza and diaza bioisosteric anthracene-9,10-diones as antitumor agents.

Cited by 13 publications

References 5 publications

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma

Quest for Organic Active Materials for Redox Flow Batteries: 2,3-Diaza-anthraquinones and Their Electrochemical Properties

Synthesis and Antitumor Evaluation of 2,5-Disubstituted- Indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-Aza-anthrapyrazoles)

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