Cargando…

Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides

The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1–3 and a dimethylsulfoxide...

Descripción completa

Detalles Bibliográficos
Autores principales: Delfosse, Pierre, Seaton, Colin C., Male, Louise, Lord, Rianne M., Pike, Sarah J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277928/
https://www.ncbi.nlm.nih.gov/pubmed/34277574
http://dx.doi.org/10.3389/fchem.2021.709161
_version_ 1783722157332758528
author Delfosse, Pierre
Seaton, Colin C.
Male, Louise
Lord, Rianne M.
Pike, Sarah J.
author_facet Delfosse, Pierre
Seaton, Colin C.
Male, Louise
Lord, Rianne M.
Pike, Sarah J.
author_sort Delfosse, Pierre
collection PubMed
description The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1–3 and a dimethylsulfoxide (DMSO) solvate of 2 (2-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH(3))(2) hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in 1–3. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity. The chemosensitivity results highlight that modification of the terminal group from Ac to Boc in 1 and 2 leads to a 3-fold increase in antiproliferative activity against the cisplatin-sensitive ovarian carcinoma cell line, A2780. The presence of the amine termini in 3 gave the only member of the series to display activity against the cisplatin-resistance ovarian carcinoma cell line, A2780cisR. Compound 2 is the lead candidate of this series, displaying high selectivity towards A2780 cancer cells when compared to non-malignant PNT-2 cells, with a selectivity index value >4.2. Importantly, this compound is more selective towards A2780 (cf. PNT-2) than the clinical platinum drugs oxaliplatin by > 2.6-fold and carboplatin by > 1.6-fold.
format Online
Article
Text
id pubmed-8277928
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-82779282021-07-15 Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides Delfosse, Pierre Seaton, Colin C. Male, Louise Lord, Rianne M. Pike, Sarah J. Front Chem Chemistry The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1–3 and a dimethylsulfoxide (DMSO) solvate of 2 (2-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH(3))(2) hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in 1–3. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity. The chemosensitivity results highlight that modification of the terminal group from Ac to Boc in 1 and 2 leads to a 3-fold increase in antiproliferative activity against the cisplatin-sensitive ovarian carcinoma cell line, A2780. The presence of the amine termini in 3 gave the only member of the series to display activity against the cisplatin-resistance ovarian carcinoma cell line, A2780cisR. Compound 2 is the lead candidate of this series, displaying high selectivity towards A2780 cancer cells when compared to non-malignant PNT-2 cells, with a selectivity index value >4.2. Importantly, this compound is more selective towards A2780 (cf. PNT-2) than the clinical platinum drugs oxaliplatin by > 2.6-fold and carboplatin by > 1.6-fold. Frontiers Media S.A. 2021-06-30 /pmc/articles/PMC8277928/ /pubmed/34277574 http://dx.doi.org/10.3389/fchem.2021.709161 Text en Copyright © 2021 Delfosse, Seaton, Male, Lord and Pike. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Delfosse, Pierre
Seaton, Colin C.
Male, Louise
Lord, Rianne M.
Pike, Sarah J.
Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title_full Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title_fullStr Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title_full_unstemmed Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title_short Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides
title_sort influence of terminal functionality on the crystal packing behaviour and cytotoxicity of aromatic oligoamides
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277928/
https://www.ncbi.nlm.nih.gov/pubmed/34277574
http://dx.doi.org/10.3389/fchem.2021.709161
work_keys_str_mv AT delfossepierre influenceofterminalfunctionalityonthecrystalpackingbehaviourandcytotoxicityofaromaticoligoamides
AT seatoncolinc influenceofterminalfunctionalityonthecrystalpackingbehaviourandcytotoxicityofaromaticoligoamides
AT malelouise influenceofterminalfunctionalityonthecrystalpackingbehaviourandcytotoxicityofaromaticoligoamides
AT lordriannem influenceofterminalfunctionalityonthecrystalpackingbehaviourandcytotoxicityofaromaticoligoamides
AT pikesarahj influenceofterminalfunctionalityonthecrystalpackingbehaviourandcytotoxicityofaromaticoligoamides