title: Multidimensional optimization of promising antitumor xanthone derivatives.
abstract: A promising antitumor xanthone derivative was optimized following a multidimensional approach that involved the synthesis of 17 analogues, the study of their lipophilicity and solubility, and the evaluation of their growth inhibitory activity on four human tumor cell lines. A new synthetic route for the hit xanthone derivative was also developed and applied for the synthesis of its analogues. Among the used cell lines, the HL-60 showed to be in general more sensitive to the compounds tested, with the most potent compound having a GI50 of 5.1 μM, lower than the hit compound. Lipophilicity was evaluated by the partition coefficient (K(p)) of a solute between buffer and two membrane models, namely liposomes and micelles. The compounds showed a logK(p) between 3 and 5 and the two membrane models showed a good correlation (r(2)=0.916) between each other. Studies concerning relationship between solubility and structure were developed for the hit compound and 5 of its analogues.
authors.affiliation: Centro de Química Medicinal da Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal.
authors.forename: Carlos M G
authors.initials: CM
authors.lastname: Azevedo
authors.forename: Carlos M M
authors.initials: CM
authors.lastname: Afonso
authors.forename: Diana
authors.initials: D
authors.lastname: Sousa
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
authors.forename: Madalena
authors.initials: M
authors.lastname: Pedro
authors.forename: João
authors.initials: J
authors.lastname: Barbosa
authors.forename: Arlene G
authors.initials: AG
authors.lastname: Corrêa
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
authors.forename: Madalena M M
authors.initials: MM
authors.lastname: Pinto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry; D008823:Micelles; D009928:Organ Specificity; D012995:Solubility; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D008823:Micelles; D044004:Xanthones