دورية أكاديمية
Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents.
| العنوان: | Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents. |
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| المؤلفون: | Cury NM; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, 13083-210, Brazil; Graduate Program in Genetics and Molecular Biology, State University of Campinas, Campinas, SP, 13083-210, Brazil., Capitão RM; Institute of Chemistry, State University of Campinas, Campinas, SP, 13083-970, Brazil., Almeida RDCB; Institute of Chemistry, State University of Campinas, Campinas, SP, 13083-970, Brazil., Artico LL; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, 13083-210, Brazil., Corrêa JR; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, 13083-210, Brazil., Simão Dos Santos EF; Institute of Chemistry, State University of Campinas, Campinas, SP, 13083-970, Brazil., Yunes JA; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, 13083-210, Brazil; Genetics Department, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, 13083-887, Brazil. Electronic address: andres@boldrini.org.br., Correia CRD; Institute of Chemistry, State University of Campinas, Campinas, SP, 13083-970, Brazil. Electronic address: roque@iqm.unicamp.br. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2019 Nov 01; Vol. 181, pp. 111570. Date of Electronic Publication: 2019 Jul 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Agents/*chemistry , Antineoplastic Agents/*therapeutic use , Indoles/*chemistry , Indoles/*therapeutic use , Leukemia, Promyelocytic, Acute/*drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy, Animals ; Antineoplastic Agents/chemical synthesis ; Apoptosis/drug effects ; Cinnamates/chemical synthesis ; Cinnamates/chemistry ; Cinnamates/therapeutic use ; G2 Phase Cell Cycle Checkpoints/drug effects ; HL-60 Cells ; HeLa Cells ; Humans ; Indoles/chemical synthesis ; Mice, Inbred NOD ; Mice, SCID |
| مستخلص: | 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 β,β-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 β-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. (Copyright © 2019 Elsevier Masson SAS. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Acute lymphoblastic leukemia; Apoptosis; Disubstituted acrylates; Heck arylations; Indoles; Tubulin inhibitor |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Cinnamates) 0 (Indoles) |
| تواريخ الأحداث: | Date Created: 20190814 Date Completed: 20191125 Latest Revision: 20191125 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.ejmech.2019.111570 |
| PMID: | 31408809 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2019.111570 |