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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 181, NOV 1 2019.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/02400-7 - Development of an animal model of precursor B-cell acute lymphoblastic leukemia with the oncogenic IL7R mutation
• Grantee: Juliana Ronchi Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/25770-6 - New frontiers in cross-coupling reactions promoted by palladium: combining enantioselective catalysis, C-H activations, new materials and in flux reactions aiming at high efficiency and sustainability in synthetic processes
• Grantee: Carlos Roque Duarte Correia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/03239-5 - IGFBP7 and dexamethasone resistance in acute lymphoblastic leukemia
• Grantee: Leonardo Luís Artico
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/14737-6 - Preclinical study of a colchicine binding site tubulin inhibitor with potent anti-leukemia activity and low toxicity
• Grantee: Nathalia Moreno Cury
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/08247-8 - Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia
• Grantee: Nathalia Moreno Cury
• Support Opportunities: Scholarships in Brazil - Doctorate