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Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring
A series of 3,5-bis(benzylidene)-4-piperidones 2a–u were prepared as candidate cytotoxic agents. In general, the compounds are highly toxic to human gingival carcinoma (Ca9-22), human squamous carcinoma-2 (HSC-2) and human squamous carcinoma-4 (HSC-4) neoplasms, but less so towards non-malignant hum...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707244/ https://www.ncbi.nlm.nih.gov/pubmed/34940290 http://dx.doi.org/10.3390/medicines8120078 |
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author | Roayapalley, Praveen K. Sakagami, Hiroshi Satoh, Keitaro Amano, Shigeru Bandow, Kenjiro Aguilera, Renato J. Hernandez, Karla G. Cano Schiaffino Bustamante, Austre Y. Dimmock, Stephen G. Sharma, Rajendra K. Das, Umashankar Dimmock, Jonathan R. |
author_facet | Roayapalley, Praveen K. Sakagami, Hiroshi Satoh, Keitaro Amano, Shigeru Bandow, Kenjiro Aguilera, Renato J. Hernandez, Karla G. Cano Schiaffino Bustamante, Austre Y. Dimmock, Stephen G. Sharma, Rajendra K. Das, Umashankar Dimmock, Jonathan R. |
author_sort | Roayapalley, Praveen K. |
collection | PubMed |
description | A series of 3,5-bis(benzylidene)-4-piperidones 2a–u were prepared as candidate cytotoxic agents. In general, the compounds are highly toxic to human gingival carcinoma (Ca9-22), human squamous carcinoma-2 (HSC-2) and human squamous carcinoma-4 (HSC-4) neoplasms, but less so towards non-malignant human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF) and human pulp cells (HPC), thereby demonstrating tumour-selective toxicity. A further study revealed that most of the compounds in series 2 were more toxic to the human Colo-205 adenocarcinoma cell line (Colo-205), human HT29 colorectal adenocarcinoma cells (HT-29) and human CEM lymphoid cells (CEM) neoplasms than towards non-malignant human foreskin Hs27 fibroblast line (Hs27) cells. The potency of the cytotoxins towards the six malignant cell lines increased as the sigma and sigma star values of the aryl substituents rose. Attempts to condense various aryl aldehydes with 2,2,6,6-tetramethyl-4-piperidone led to the isolation of some 1,5-diaryl-1,4-pentadien-3-ones. The highest specificity for oral cancer cells was displayed by 2e and 2r. In the case of 2r, its selective toxicity exceeded that of doxorubicin and melphalan. The enones 2k, m, o have the highest SI values towards colon cancer and leukemic cells. Both 2e,r inhibited mitosis and increased the subG1 population (with a transient increase in G2/M phase cells). Slight activation of caspase-3, based on the cleavage of poly(ADP-ribose)polymerase (PARP) and procaspase 3, was detected. |
format | Online Article Text |
id | pubmed-8707244 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87072442021-12-25 Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring Roayapalley, Praveen K. Sakagami, Hiroshi Satoh, Keitaro Amano, Shigeru Bandow, Kenjiro Aguilera, Renato J. Hernandez, Karla G. Cano Schiaffino Bustamante, Austre Y. Dimmock, Stephen G. Sharma, Rajendra K. Das, Umashankar Dimmock, Jonathan R. Medicines (Basel) Article A series of 3,5-bis(benzylidene)-4-piperidones 2a–u were prepared as candidate cytotoxic agents. In general, the compounds are highly toxic to human gingival carcinoma (Ca9-22), human squamous carcinoma-2 (HSC-2) and human squamous carcinoma-4 (HSC-4) neoplasms, but less so towards non-malignant human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF) and human pulp cells (HPC), thereby demonstrating tumour-selective toxicity. A further study revealed that most of the compounds in series 2 were more toxic to the human Colo-205 adenocarcinoma cell line (Colo-205), human HT29 colorectal adenocarcinoma cells (HT-29) and human CEM lymphoid cells (CEM) neoplasms than towards non-malignant human foreskin Hs27 fibroblast line (Hs27) cells. The potency of the cytotoxins towards the six malignant cell lines increased as the sigma and sigma star values of the aryl substituents rose. Attempts to condense various aryl aldehydes with 2,2,6,6-tetramethyl-4-piperidone led to the isolation of some 1,5-diaryl-1,4-pentadien-3-ones. The highest specificity for oral cancer cells was displayed by 2e and 2r. In the case of 2r, its selective toxicity exceeded that of doxorubicin and melphalan. The enones 2k, m, o have the highest SI values towards colon cancer and leukemic cells. Both 2e,r inhibited mitosis and increased the subG1 population (with a transient increase in G2/M phase cells). Slight activation of caspase-3, based on the cleavage of poly(ADP-ribose)polymerase (PARP) and procaspase 3, was detected. MDPI 2021-12-16 /pmc/articles/PMC8707244/ /pubmed/34940290 http://dx.doi.org/10.3390/medicines8120078 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Roayapalley, Praveen K. Sakagami, Hiroshi Satoh, Keitaro Amano, Shigeru Bandow, Kenjiro Aguilera, Renato J. Hernandez, Karla G. Cano Schiaffino Bustamante, Austre Y. Dimmock, Stephen G. Sharma, Rajendra K. Das, Umashankar Dimmock, Jonathan R. Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title | Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title_full | Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title_fullStr | Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title_full_unstemmed | Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title_short | Cytotoxic Tumour-Selective 1,5-Diaryl-3-Oxo-1,4-Pentadienes Mounted on a Piperidine Ring |
title_sort | cytotoxic tumour-selective 1,5-diaryl-3-oxo-1,4-pentadienes mounted on a piperidine ring |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707244/ https://www.ncbi.nlm.nih.gov/pubmed/34940290 http://dx.doi.org/10.3390/medicines8120078 |
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