New chiral derivatives of xanthones: Synthesis and investigation of enantioselectivity as inhibitors of growth of human tumor cell lines |
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| Affiliation: | 1. Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 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 228, 4050-313 Porto, Portugal;3. Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal;4. Faculty of Science, Kasetsart University, 10900 Bangkok, Thailand;5. Cooperativa de Ensino Superior, Politécnico e Universitário (CESPU), Centro de Investigação em Ciências da Saúde, Instituto Superior de Ciências da Saúde-Norte (CICS-ISCS-N), Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal;6. Universidade Federal do Rio de Janeiro, Instituto de Química, LADETEC—LAB RES, Rio de Janeiro, RJ, Brazil;1. Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy;2. Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa Località Germaneto, I-88100 Catanzaro, Italy;3. Dipartimento di Biomedicina Clinica e Molecolare, Sezione di Farmacologia e Biochimica, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy;4. Dipartimento di Scienze Bio-Mediche, Sezione di Fisiologia, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy;5. Departamento de Química Orgánica I, Universidad de Alcalá, Campus Universitario, 28871 Alcalá de Henares, Madrid, Spain;1. Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal;2. Faculty of Science, Kasetsart University, 10900 Bangkok, Thailand;3. CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, IINFACTS, Rua Central de Gandra 1317, 4585-116 Gandra PRD, Portugal;4. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal;5. Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123, Porto, Portugal;6. Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luís, km 235–SP-310, CEP 13565-905 São Carlos, São Paulo, Brazil;1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;3. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;4. Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China;1. Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran;2. Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran;3. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA;4. School of Pharmacy, Chapman University, Orange, CA 92866, USA |
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| Abstract: | A highly efficient and practical methodology for synthesis of new chiral derivatives of xanthones (CDXs) in enantiomerically pure form has been developed. According to this approach, thirty CDXs (3–32) were synthesized by coupling a carboxyxanthone (1) and a carboxymethoxyxanthone (2) with both enantiomers of commercially available chiral building blocks, namely six amino alcohols, one amine and one amino ester. The activation of the carboxylic acid group of the xanthonic scaffold was carried out with the coupling reagent O-(benzotriazol-1-yl)-N-N-N′-N′-tetramethyluronium tetrafluoroborate (TBTU), in the presence of a catalytic amount of TEA in anhydrous THF. The coupling reactions with the chiral blocks were performed at room temperature with short reactions times, excellent yields (ranging from 94% to 99%), and very high enantiomeric excess. The synthesized CDXs were evaluated for their effect on the in vitro growth of three human tumor cell lines, namely A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer). The most active compound was CDX 15 being active in all human tumor cell lines with values of GI50 of 32.15 ± 2.03 μM for A375-C5, 22.55 ± 1.99 μM for MCF-7, and 14.05 ± 1.82 μM for NCI-H460. Nevertheless, some CDXs showed cell-type selectivity. Furthermore, the growth inhibitory effects, in some cases, demonstrated to be depending on the stereochemistry of the CDXs. An interesting example was observed with the enantiomers 3 and 4, which demonstrated high enantioselectivity for MCF-7 and NCI-H460 cell lines. It can be inferred that the effects on the growth of the human tumor cell lines can be ascribed not only to the nature and positions of substituents on the xanthonic scaffold but also to the stereochemistry of the CDXs. Some considerations regarding structure–activity relationship within this class of compounds will be highlighted. |
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| Keywords: | Chiral derivatives of xanthones Enantiomerically pure TBTU Antitumor Enantioselectivity |
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