Design, synthesis and high antitumor potential of new unsymmetrical bisacridine derivatives towards human solid tumors, specifically pancreatic cancers and their unique ability to stabilize DNA G-quadruplexes

• Published in: European journal of medicinal chemistry Vol. 204; p. 112599
• Main Authors: Paluszkiewicz, Ewa, Horowska, Barbara, Borowa-Mazgaj, Barbara, Peszyńska-Sularz, Grażyna, Paradziej-Łukowicz, Jolanta, Augustin, Ewa, Konopa, Jerzy, Mazerska, Zofia
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.10.2020
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor unsymmetrical bisacridines; Cell Line, Tumor; Chemistry Techniques, Synthetic; Cytotoxicity; DNA - chemistry; Drug Design; Drug Screening Assays, Antitumor; G-quadruplex stabilization; G-Quadruplexes - drug effects; Human tumor xenografts; Humans; Mice; Pancreatic Neoplasms - pathology; Structure-Activity Relationship; UAs; Human tumor xenografts; Cytotoxicity; Antitumor unsymmetrical bisacridines; UAs; G-quadruplex stabilization
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112599

New promising unsymmetrical bisacridine derivatives (UAs), have been developed. Three groups including 36 compounds were synthesized by the condensation of 4-nitro or 4-methylacridinone, imidazoacridinone and triazoloacridinone derivatives with 1-nitroacridine compounds linked with an aminoalkyl chain. Cytotoxicity screening revealed the high potency of these compounds against several tumor cell lines. Particularly, imidazoacridinone-1-nitroacridine dimers strongly inhibited pancreatic Panc-1, Mia-Pa-Ca-2, Capan-2 and prostate cancer DU-145 cell growth. The studied compounds showed very strong antitumor activity (T/C> 300%) against Walker 256 rat adenocarcinoma. The selected 26 UAs were tested against 12 human tumor xenografts in nude mice, including colon, breast, prostate and pancreatic cancers. The studies on the molecular mechanism of action demonstrated that these unsymmetrical dimers significantly responded to the presence of G-quadruplex not to dsDNA. Structure-activity relationships for UAs potency to G-quadruplex stabilization indicated that thermal stability of this drug-G-quadruplex complex depended not only on the structure of heterocyclic rings, but also on the properties of dialkylamino chains of the ring linkers. In conclusion, the presented studies identified the new group of effective antitumor agents against solid human tumors, particularly pancreatic Panc-1, BxPC-3 and Mia-Pa-Ca-2 and strongly indicated their distinctive interactions with DNA. In contrast to monomers, G-quadruplex not dsDNA is proposed to be the first molecular target for these compounds. [Display omitted] •The set of 36 new unsymmetrical bisacridine derivatives were synthesized.•They expressed high cytotoxicity, mainly against prostate and pancreatic cancers.•High antitumor action was shown against several human solid tumor xenografts in mice.•Molecular mechanism was proposed by G-quadruplexes not by DNA-duplex stabilization.