title: A new bisintercalating anthracycline with picomolar DNA binding affinity.
abstract: A new bisintercalating anthracycline (WP762) has been designed, in which monomeric units of daunorubicin have been linked through their amino groups on the daunosamine moieties using an m-xylenyl linker. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP762 to DNA. The binding constant for the interaction of WP762 with herring sperm DNA was determined to be 7.3 (+/-0.2) x 10(12) M(-1) at 20 degrees C. The large favorable binding free energy of -17.3 kcal mol(-1) was found to result from a large negative enthalpic contribution of -33.8 kcal mol(-1) and an opposing entropic term (-TDeltaS = +16.5 kcal mol(-1)). A comparative molecular modeling study rationalized the increased binding by the m-xylenyl linker of WP762 positioning in the DNA minor groove compared to the p-xylenyl linker found in WP631, the first bis-anthracycline of this type. The cytotoxicity of WP762 was compared to that of other anthracyclines in Jurkat T lymphocytes. These studies, together with an analysis of the cell-cycle traverse in the presence of WP762, suggest that in these cells the new drug is more cytotoxic than the structurally related WP631.
authors.affiliation: Instituto de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Josep Samitier, 1-5, E-08028, Barcelona, Spain. jpmbmc@ibmb.csic.es
authors.forename: José
authors.initials: J
authors.lastname: Portugal
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Cashman
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Neus
authors.initials: N
authors.lastname: Ferrer-Miralles
authors.forename: Teresa
authors.initials: T
authors.lastname: Przewloka
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Chaires
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D004247:DNA / Q000737:chemistry* / Q000528:radiation effects; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005399:Fishes; D005434:Flow Cytometry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D013094:Spermatozoa / Q000737:chemistry; D013816:Thermodynamics; D014466:Ultraviolet Rays
chemical_list: D007364:Intercalating Agents; C104426:WP 631; C507405:WP 762; D004247:DNA; D003630:Daunorubicin