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

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 2; p. 489
• Main Authors: Avendaño, Carmen, López-Alvarado, Pilar, Pérez, José María, Alonso, Miguel Ángel, Pascual-Alfonso, Eva, Ruiz-Serrano, Miriam, Menéndez, J Carlos
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2024; MDPI
• Subjects: Anthracenes; antitumor activity; azaanthracene-2,9,10-triones; Biological Products; Cancer; Cell Line; Cytotoxicity; diazaanthracene-2,9,10-triones; diazaquinomycins; Drug resistance; hetero Diels–Alder reactions; Humans; Libraries; marcanines; Natural products; Nitrogen; Oxidation; Structure-Activity Relationship; Spain; azaanthracene-2,9,10-triones; hetero Diels–Alder reactions; marcanines; diazaanthracene-2,9,10-triones; antitumor activity; diazaquinomycins
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29020489

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.