Synthesis and Biological Activity of New 1,8-Diaza-2,9,10-anthracenetrione Derivatives

Gesto, C.; Cuesta, Elena de la; Avendaño, Carmen; Emling, F

doi:10.1002/jps.2600810819

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“…The preparation and study of a number of semisynthetic analogues of DAQA (compounds 3 and 4 ) led Ōmura to the conclusion that the bis-lactam structure of the natural product was an essential requisite for thimidylate synthase inhibition and antitumor activity [ 30 ]. However, when we investigated the antitumor activity of a small set of derivatives of the structure 5 , we found that they exhibited good antitumor activities, particularly towards solid tumors [ 31 ], while the introduction of a fluorine atom at C-3 led to compounds with antileukemic activity [ 32 ]. In order to assist the establishment of structure–activity relationships within this class of compounds, we describe here a systematic study of the in vitro antitumor properties of a large series of derivatives of structure 5 , their 5,8-dihydro derivatives 6 , where one of the electron-withdrawing pyridine nitrogen atoms has been replaced by an electron-releasing enamine-like moiety, 1-azaanthraquinones derived from structure 7 related to the marcanines and more simplified structures such as quinolinedione derivatives 8 where the lactam scaffold that appears to be essential for cytotoxic activity is maintained ( Figure 2 ).…”

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confidence: 99%

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives

Avendaño,

López-Alvarado,

Pérez

et al. 2024

Molecules

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The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels–Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure–activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.

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Section: Introductionmentioning

confidence: 99%

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives

Avendaño,

López-Alvarado,

Pérez

et al. 2024

Molecules

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Half‐Wave Potentials of 1‐AZA‐ and 1,8‐Diazaanthraquinones

Diaz‐Guerra

Ocaña

Pérez

et al. 1995

Bulletin des Soc Chimique

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The redox propexties of a series of l-azaanthracene-9,10-diones, l$-diazaanthracene-9,10-diones, 1 $-diazaanthracene-(lH)2,9,1O-triones and 1,8-diazaanthracene-(lH, 8H)2,7,9,lO-terraones have been studied. The results obtained show that the 2-pyridone moiety is a stronger electron acceptor than the pyridine ring, in agreement with reactivity data. 1-Hydroxy-lazaanthracene-2,9,10-triones, synthesized from l-azaanthracene-9,1O-dione-N-oxides, show redox properties close to 1,8-diazaanthracene-2,7,9,lO-tetraones, and therefore the cyclic hydroxamic acid unit behaves also as an strong electron acceptor. Voltammetric half-wave fist potentials correlate with the energies of the LUMO in model compounds. INTRODUCTIONThe redox properties of heterocyclic quinones have attracted considerable interest1 and their study is of relevance in the understanding of the biological roles of these compounds. Many well-known antitumour agents, including mitoxantrone, the anthracyclines, the naphthyridinomycinsaframycin family, and the mitomycins have a quinone

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Synthesis of 5,8‐dimethoxy‐2(1H)‐quinolinones by intramolecular Wittig reaction

1995

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The title compounds 12, which are key intermediates for antitumoral diazaquinomycin A analogues, are obtained by intramolecular Wittig reaction of 1-[3',6'-dimethoxy-2'-(1~-2(1H)-quinolinones 12 and 17 is examined. oxoacylamino)phenyl]alkyltriphenylphosphonium salts 11, which are prepared via lithiation of 2',5'-dimethoxy-N-pivaloylaniline 6. The applicability of this route to polysubstituted Diazaquinomycin A['], a novel Streptomyces sp. OM-704 metabolite, exhibits promising activity as an antitumor agent but failed to enter human trials because of its insolubility. Nevertheless, diazaquinomycin A is regarded as a novel "lead" compound to design diazaquinomycin congeners, which have currently been synthesized in our group by hetero Diels-Alder cyclizations12] of activated 1 -azadienes 1 with 2,5,8( 1H)-quinolinetriones 2. The dienophiles 2 are readily available by oxidative demethylatiod31 of 5,8-dimethoxy-2( 1H)-quinolinones, which are obtainable by means of several strategied41. The search of preparative routes for 3,4-disubstituted 5,8-dimethoxy-2( 1 H)-quinolinones 12 led us to the utilization of Capuano's 2( 1H)-quinolinone synthesis involving intramolecular Wittig reaction of 2-(a-oxoacylamino)benzyltriphenylphosphonium salts 3 as the key step, where three successful examples were already This reaction is chemoselective in spite of the possible competition between the keto and amide groups, affording 3-substituted 2-quinolinones 4 and 2-acylindoles 5 in a 1O:l ratio. The methods reported for the preparation of 2-amino-3,6-dimethoxybenzaldehyde as the potential starting material for the intramolecular Wittig reaction giving 5,8-dimethoxy-2-quinolinones are tedious and suffered from poor to modest overall yieldsc61. Therefore, we now describe a versatile and efficient method of preparing derivatives 7 and 8 by ortho functionalization of 2,5-dimethoxyaniline. Thus, lithiation of 2',5'-dimethoxy-N-pivaloylaniline 6 (nBuLi, THF, O'C), followed by addition of DMF or the corresponding aldehyde and subsequent reduction of 7, afforded 2'-(1-hydroxyalkyl)-3',6'-dimethoxy-N-pivaloylanilines 8 in good yields. The pivaloyl protecting group was hydrolytically removed by treatment with 10% hydrochloric acid and the free bases 9 were condensed with triphenylphosphonium bromide to afford the phosphonium salts 10, which were acylated with the adequate a-oxoacyl chloride to 11. Since the use of potassium tert-butoxide in the following cyclization step as described by Capuano et al.[5' gave poor results, triethylamine was employed instead. The outcome of the reaction depended on the nature of R1 in 11. The benzyltriphenylphosphonium salts lla-c (R' = H) mainly afforded, 2-quinolinones 12a-c in acceptable yields (25-39%), together with small amounts of 2-acylindoles 13a-c. When derivatives with R' C H were employed, only traces of 12d and 13d (R' = CH3) were detected. In the case of l l e (R' = Ph), 2-acetyl-5,8-dimethoxy-4-phenyl-4H-3,l-benzoxazine 14 was obtained as the only isolable product in 49% yield.Since the method to ...

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Synthesis and Biological Activity of New 1,8-Diaza-2,9,10-anthracenetrione Derivatives

Cited by 24 publications

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Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives

Half‐Wave Potentials of 1‐AZA‐ and 1,8‐Diazaanthraquinones

Synthesis of 5,8‐dimethoxy‐2(1H)‐quinolinones by intramolecular Wittig reaction

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