title: New chiral derivatives of xanthones: synthesis and investigation of enantioselectivity as inhibitors of growth of human tumor cell lines.
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±2.03μM for A375-C5, 22.55±1.99μM for MCF-7, and 14.05±1.82μM 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.
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; 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; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Faculty of Science, Kasetsart University, 10900 Bangkok, Thailand.
authors.forename: Kamonporn
authors.initials: K
authors.lastname: Masawang
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal; 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.
authors.forename: Maria Elizabeth
authors.initials: ME
authors.lastname: Tiritan
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; 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; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.affiliation: Universidade Federal do Rio de Janeiro, Instituto de Química, LADETEC-LAB RES, Rio de Janeiro, RJ, Brazil.
authors.forename: Virgínia
authors.initials: V
authors.lastname: de Lima
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; 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; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Afonso
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal; 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.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bousbaa
authors.affiliation: Faculty of Science, Kasetsart University, 10900 Bangkok, Thailand.
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Sudprasert
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; 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. Electronic address: madalena.pedro@iscsn.cespu.pt.
authors.forename: Madalena
authors.initials: M
authors.lastname: Pedro
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; 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; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal. Electronic address: madalena@ff.up.pt.
authors.forename: Madalena M
authors.initials: MM
authors.lastname: Pinto
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D015394:Molecular Structure; D013237:Stereoisomerism; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones
keywords: Antitumor; Chiral derivatives of xanthones; Enantiomerically pure; Enantioselectivity; TBTU