Multidimensional optimization of promising antitumor xanthone derivatives |
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| Authors: | Carlos M.G. Azevedo Carlos M.M. Afonso Diana Sousa Raquel T. Lima M. Helena Vasconcelos Madalena Pedro João Barbosa Arlene G. Corrêa Salette Reis Madalena M.M. Pinto |
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| Affiliation: | 1. Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal;2. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal;3. Cancer Drug Resistance Group, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal;4. Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal;5. Grupo de Biologia Molecular e Celular (GBMC), Centro de Investigação em ciências da Saúde (CICS), Instituto Superior de Ciências da Saúde do norte, CESPU, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal;6. Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luís, km 235, CEP 13565-905, São Carlos, SP, Brazil;7. REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal |
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| 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 (Kp) of a solute between buffer and two membrane models, namely liposomes and micelles. The compounds showed a log Kp between 3 and 5 and the two membrane models showed a good correlation (r2 = 0.916) between each other. Studies concerning relationship between solubility and structure were developed for the hit compound and 5 of its analogues. |
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| Keywords: | Xanthones Xanthen-9-ones Antitumor Benzopyran Chromans Chromene Lipophilicity Solubility |
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