Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents

Autor(es)

Cury, Nathalia Moreno ^{[1, 2]} ; Capitao, Rebeca Monique ^[3] ; Borges de Almeida, Renan do Canto ^[3] ; Artico, Leonardo Luis ^[1] ; Correa, Juliana Ronchi ^[1] ; Simao dos Santos, Eric Francisco ^[3] ; Yunes, Jose Andres ^{[1, 4]} ; Duarte Correia, Carlos Roque ^[3]

Afiliação do(s) autor(es)

^[1] Ctr Infantil Boldrini, Lab Biol Mol, BR-13083210 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Grad Program Genet & Mol Biol, BR-13083210 Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Inst Chem, BR-13083970 Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Fac Med Sci, Genet Dept, BR-13083887 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 181, NOV 1 2019.
• Citações Web of Science: 0

Resumo

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate beta,beta-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates. The method developed led to the synthesis of twenty-one novel functionalized indoles. Of these, indole 20 showed selective cytotoxicity against leukemia cells at the nanomolar scale, and, therefore, it was selected for the investigation of its mechanism of action. Indole 20 was found to target tubulin leading to G2/M cell cycle arrest, DNA damage and apoptosis. Indole 20 decreased beta-tubulin protein in leukemia cells in a time-dependent manner and induced depolymerization of the microtubule network in Hela cells, thus fully characterizing its microtubule destabilizer activity. The connectivity map analysis of HL60 promyelocytic leukemia cells treated with indole 20 revealed a transcriptional profile similar to that of cells treated with prostaglandins, apparently due to the induction of cellular differentiation as addressed by the expression of CD11 and CD14 markers. Finally, indole 20 given intraperitoneally, at 10 mg/kg, 5x/week significantly prolonged the overall survival of NOD/SCID mice transplanted with RS4; 11 B-ALL cells. (C) 2019 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
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• Modalidade de apoio: Bolsas no Brasil - Doutorado
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• Modalidade de apoio: Auxílio à Pesquisa - Temático
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• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
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• Modalidade de apoio: Bolsas no Brasil - Doutorado