Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound.

Aims: In search of new promising anti-cancer agents. Background: Six N-acyl derivatives of aminocombretastatin A-4 have been synthesized and evaluated as regards their interaction with tubulin and as c-Myc downregulators. Objective: This study is focused on the synthesis and the biological evaluation of N-acyl derivatives of aminocombretastatin A-4 (CA-4). Docking studies were carried out in order to find out whether the synthetic derivatives could bind to tubulin at the colchicine site in a conformation similar to that of CA-4. The effect of the synthetic derivatives on the proliferation of several cancer cells and on non-cancer cells has been measured. In addition, their effect on tubulin polymerization, on cell cycle distribution, on the microtubule network and on c-Myc expression have also been evaluated. Method: A set of six N-acyl derivatives were achieved by means of a peptide-type coupling of aminocombretastatin A-4 and the corresponding carboxylic acid. The ability of the synthetic compounds to inhibit cell proliferation was measured by MTT assay against three human carcinoma cell lines (colorectal HT-29, lung A549 and breast adenocarcinoma MCF-7) and one non-tumor cell line (HEK-293). Inhibition of tubulin polymerization was evaluated by turbidimetry time-course measurements. The action of the synthetic derivatives on cell cycle distribution was measured by flow cytometry and their effects on the microtubule network was determined by immunofluorescence microscopy. Finally, the downregulation of the synthetic derivatives on c-Myc protein was quantified by ELISA assay while the effect on cMyc gene was measured by RT-qPCR analysis. Results: Derivatives bearing pentanoyl (compound 2), hexanoyl (compound 3), and heptanoyl (compound 4) side chains show antiproliferative activities on the HT-29 line in the low nanomolar range, with values similar to that exhibited by AmCA-4 but far exceeding those of CA-4. Compounds 1 (butanoyl side chain) and 2-3 inhibit tubulin polymerization in vitro in a manner similar to that of CA-4 and AmCA-4 whereas compounds 4, 5 (octanoyl side chain) and 6 (dodecanoyl side chain) may be considered as partial inhibitors of tubulin polymerization. While all derivatives are able to accumulate cells in G2/M phase, compounds with the longest acyl chains (5 and 6) are the least active ones in this particular action. Moreover, compounds 2-3 were the most active ones as c-Myc downregulators. Conclusion: Our studies show that the most active compounds in the disruption of the microtubule network are also the most potent ones in the downregulation of c-Myc expression. Other: Compounds 2 and 3 are good candidates for in vivo studies as they combine the best anti-mitotic and c-Myc downregulation activities at low doses.

Objetivo: elaborar e testar uma Escala de Triagem Odontológica para Pacientes com Necessidades Especiais (PNEs). Métodos: a escala foi elaborada a partir da experiência clínica de um centro de referência para atendimento odontológico a PNEs e de evidências científicas. Foi construída utilizando cinco critérios principais: comportamento, necessidade e possibilidade de estabilização protetora, urgência odontológica (dor), número e complexidade de procedimentos odontológicos e local do atendimento (acessibilidade). O instrumento foi testado em 14 PNEs, que participaram de uma triagem no Centro de Especialidades Odontológicas (CEO) Jequitibá, na Faculdade de Odontologia da Universidade Federal de Pelotas (UFPel). Estudantes de graduação a partir do oitavo semestre fizeram a aplicação, e o resultado da escala foi comparado ao parecer clínico realizado pelos pesquisadores experientes no atendimento a esses pacientes. Resultados: foi observada uma concordância em 85% dos casos. Conclusão: o instrumento apresentou desempenho comparável à avaliação de profissionais com expertise, e a escala pode ser um instrumento útil para ser empregado em serviços odontológicos que oferecem atendimento aos PNEs. A sua utilização em meio acadêmico também pode proporcionar o empoderamento dos critérios de avaliação pelos estudantes, proporcionando maior segurança em acolher, atender ou encaminhar esse público no seu futuro profissional. Palavras-chave: acessibilidade aos serviços de saúde; assistência odontológica; pessoas com deficiência.