title: Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications.
abstract: The intercalation of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with DNA duplex was investigated, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Both DOX and FDOX were intercalated into DNA duplex with the free binding energy of -4.99 kcal for DOX-DNA and -4.92 kcal for FDOX-DNA adducts and the presence of H-bonding network between doxorubicin NH2 group and cytosine-19. Spectroscopic results showed FDOX forms more stable complexes than DOX with KDOX-DNA=2.5(± 0.5)× 10(4)M(-1) and KFDOX-DNA=3.4(± 0.7)× 10(4)M(-1). The number of drug molecules bound per DNA (n) was 1.2 for DOX and 0.6 for FDOX. Major alterations of DNA structure were observed by DOX intercalation with a partial B to A-DNA transition, while no DNA conformational changes occurred upon FDOX interaction. This study further confirms the importance of unmodified daunosamine amino group for optimal interactions with DNA. The results of in vitro MTT assay carried out on SKC01 colon carcinoma corroborate the observed DNA interactions. Such DNA structural changes can be related to doxorubicin antitumor activity, which prevents DNA duplication.
authors.affiliation: Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Agudelo
authors.affiliation: Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourassa
authors.affiliation: Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada.
authors.forename: Gervais
authors.initials: G
authors.lastname: Bérubé
authors.affiliation: Department of Chemistry, Biochemistry and Physics, University of Québec at Trois-Rivières, C.P. 500, Trois-Rivières G9A 5H7 Québec, Canada. Electronic address: tajmirri@uqtr.ca.
authors.forename: Heidar-Ali
authors.initials: HA
authors.lastname: Tajmir-Riahi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry*; D009690:Nucleic Acid Conformation
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D007364:Intercalating Agents; C031902:doxorubicin-DNA; D004317:Doxorubicin; D004247:DNA
keywords: Conformation; DNA; Doxorubicin; Intercalation; Molecular modeling