Cargando…

Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid

The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display...

Descripción completa

Detalles Bibliográficos
Autores principales: Lisboa, Thaís, Silva, Daiana, Duarte, Sâmia, Ferreira, Rafael, Andrade, Camyla, Lopes, Ana Luiza, Ribeiro, Juliana, Farias, Davi, Moura, Ricardo, Reis, Malu, Medeiros, Karina, Magalhães, Hemerson, Sobral, Marianna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983054/
https://www.ncbi.nlm.nih.gov/pubmed/31878135
http://dx.doi.org/10.3390/molecules25010064
_version_ 1783491431408599040
author Lisboa, Thaís
Silva, Daiana
Duarte, Sâmia
Ferreira, Rafael
Andrade, Camyla
Lopes, Ana Luiza
Ribeiro, Juliana
Farias, Davi
Moura, Ricardo
Reis, Malu
Medeiros, Karina
Magalhães, Hemerson
Sobral, Marianna
author_facet Lisboa, Thaís
Silva, Daiana
Duarte, Sâmia
Ferreira, Rafael
Andrade, Camyla
Lopes, Ana Luiza
Ribeiro, Juliana
Farias, Davi
Moura, Ricardo
Reis, Malu
Medeiros, Karina
Magalhães, Hemerson
Sobral, Marianna
author_sort Lisboa, Thaís
collection PubMed
description The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene–acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound.
format Online
Article
Text
id pubmed-6983054
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-69830542020-02-06 Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid Lisboa, Thaís Silva, Daiana Duarte, Sâmia Ferreira, Rafael Andrade, Camyla Lopes, Ana Luiza Ribeiro, Juliana Farias, Davi Moura, Ricardo Reis, Malu Medeiros, Karina Magalhães, Hemerson Sobral, Marianna Molecules Communication The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene–acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound. MDPI 2019-12-24 /pmc/articles/PMC6983054/ /pubmed/31878135 http://dx.doi.org/10.3390/molecules25010064 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Lisboa, Thaís
Silva, Daiana
Duarte, Sâmia
Ferreira, Rafael
Andrade, Camyla
Lopes, Ana Luiza
Ribeiro, Juliana
Farias, Davi
Moura, Ricardo
Reis, Malu
Medeiros, Karina
Magalhães, Hemerson
Sobral, Marianna
Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title_full Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title_fullStr Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title_full_unstemmed Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title_short Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid
title_sort toxicity and antitumor activity of a thiophene–acridine hybrid
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983054/
https://www.ncbi.nlm.nih.gov/pubmed/31878135
http://dx.doi.org/10.3390/molecules25010064
work_keys_str_mv AT lisboathais toxicityandantitumoractivityofathiopheneacridinehybrid
AT silvadaiana toxicityandantitumoractivityofathiopheneacridinehybrid
AT duartesamia toxicityandantitumoractivityofathiopheneacridinehybrid
AT ferreirarafael toxicityandantitumoractivityofathiopheneacridinehybrid
AT andradecamyla toxicityandantitumoractivityofathiopheneacridinehybrid
AT lopesanaluiza toxicityandantitumoractivityofathiopheneacridinehybrid
AT ribeirojuliana toxicityandantitumoractivityofathiopheneacridinehybrid
AT fariasdavi toxicityandantitumoractivityofathiopheneacridinehybrid
AT mouraricardo toxicityandantitumoractivityofathiopheneacridinehybrid
AT reismalu toxicityandantitumoractivityofathiopheneacridinehybrid
AT medeiroskarina toxicityandantitumoractivityofathiopheneacridinehybrid
AT magalhaeshemerson toxicityandantitumoractivityofathiopheneacridinehybrid
AT sobralmarianna toxicityandantitumoractivityofathiopheneacridinehybrid