Cargando…

An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells

A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorh...

Descripción completa

Detalles Bibliográficos
Autores principales: Orfanoudaki, Maria, Smith, Emily A., Hill, Natasha T., Garman, Khalid A., Brownell, Isaac, Copp, Brent R., Grkovic, Tanja, Henrich, Curtis J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532587/
https://www.ncbi.nlm.nih.gov/pubmed/37755087
http://dx.doi.org/10.3390/md21090474
_version_ 1785111995786199040
author Orfanoudaki, Maria
Smith, Emily A.
Hill, Natasha T.
Garman, Khalid A.
Brownell, Isaac
Copp, Brent R.
Grkovic, Tanja
Henrich, Curtis J.
author_facet Orfanoudaki, Maria
Smith, Emily A.
Hill, Natasha T.
Garman, Khalid A.
Brownell, Isaac
Copp, Brent R.
Grkovic, Tanja
Henrich, Curtis J.
author_sort Orfanoudaki, Maria
collection PubMed
description A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death.
format Online
Article
Text
id pubmed-10532587
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-105325872023-09-28 An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells Orfanoudaki, Maria Smith, Emily A. Hill, Natasha T. Garman, Khalid A. Brownell, Isaac Copp, Brent R. Grkovic, Tanja Henrich, Curtis J. Mar Drugs Article A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death. MDPI 2023-08-29 /pmc/articles/PMC10532587/ /pubmed/37755087 http://dx.doi.org/10.3390/md21090474 Text en © 2023 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
Orfanoudaki, Maria
Smith, Emily A.
Hill, Natasha T.
Garman, Khalid A.
Brownell, Isaac
Copp, Brent R.
Grkovic, Tanja
Henrich, Curtis J.
An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title_full An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title_fullStr An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title_full_unstemmed An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title_short An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
title_sort investigation of structure–activity relationships and cell death mechanisms of the marine alkaloids discorhabdins in merkel cell carcinoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532587/
https://www.ncbi.nlm.nih.gov/pubmed/37755087
http://dx.doi.org/10.3390/md21090474
work_keys_str_mv AT orfanoudakimaria aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT smithemilya aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT hillnatashat aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT garmankhalida aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT brownellisaac aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT coppbrentr aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT grkovictanja aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT henrichcurtisj aninvestigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT orfanoudakimaria investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT smithemilya investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT hillnatashat investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT garmankhalida investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT brownellisaac investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT coppbrentr investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT grkovictanja investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells
AT henrichcurtisj investigationofstructureactivityrelationshipsandcelldeathmechanismsofthemarinealkaloidsdiscorhabdinsinmerkelcellcarcinomacells