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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
Abstract
New promising unsymmetrical bisacridine derivatives (UAs), have been developed. Three groupsincluding 36 compounds were synthesized by the condensation of 4-nitro or 4-methylacridinone, imi-dazoacridinone and triazoloacridinone derivatives with 1-nitroacridine compounds linked with anaminoalkyl chain. Cytotoxicity screening revealed the high potency of these compounds against severaltumor cell lines. Particularly, imidazoacridinone-1-nitroacridine dimers strongly inhibited pancreaticPanc-1, Mia-Pa-Ca-2, Capan-2 and prostate cancer DU-145 cell growth. The studied compounds showedvery strong antitumor activity (T/C>300%) against Walker 256 rat adenocarcinoma. The selected 26 UAswere tested against 12 human tumor xenografts in nude mice, including colon, breast, prostate andpancreatic cancers. The studies on the molecular mechanism of action demonstrated that these un-symmetrical 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 ofthis drug-G-quadruplex complex depended not only on the structure of heterocyclic rings, but also onthe properties of dialkylamino chains of the ring linkers. In conclusion, the presented studies identifiedthe 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 tomonomers, G-quadruplex not dsDNA is proposed to be thefirst molecular target for these compounds.
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Authors (8)
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Barbara Borowa-Mazgaj
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Grażyna Peszyńska-Sularz
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Jolanta Paradziej-Łukowicz
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
-
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
no. 204,
ISSN: 0223-5234 - Language:
- English
- Publication year:
- 2020
- Bibliographic description:
- Paluszkiewicz E., Horowska B., Borowa-Mazgaj B., Peszyńska-Sularz G., Paradziej-Łukowicz J., Augustin E., Konopa J., Mazerska Z.: 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// EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY -Vol. 204, (2020), s.112599-
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2020.112599
- Sources of funding:
- Verified by:
- Gdańsk University of Technology
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