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Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents

Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of var...

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Autores principales: Sil, Diptesh, Panja, Sudipta, Jogdeo, Chinmay M., Kumar, Raj, Yu, Ao, Holbert, Cassandra E., Ding, Ling, Foley, Jackson R., Stewart, Tracy Murray, Casero, Robert A., Oupický, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032695/
https://www.ncbi.nlm.nih.gov/pubmed/35458639
http://dx.doi.org/10.3390/molecules27082441
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author Sil, Diptesh
Panja, Sudipta
Jogdeo, Chinmay M.
Kumar, Raj
Yu, Ao
Holbert, Cassandra E.
Ding, Ling
Foley, Jackson R.
Stewart, Tracy Murray
Casero, Robert A.
Oupický, David
author_facet Sil, Diptesh
Panja, Sudipta
Jogdeo, Chinmay M.
Kumar, Raj
Yu, Ao
Holbert, Cassandra E.
Ding, Ling
Foley, Jackson R.
Stewart, Tracy Murray
Casero, Robert A.
Oupický, David
author_sort Sil, Diptesh
collection PubMed
description Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group’s increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog.
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spelling pubmed-90326952022-04-23 Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents Sil, Diptesh Panja, Sudipta Jogdeo, Chinmay M. Kumar, Raj Yu, Ao Holbert, Cassandra E. Ding, Ling Foley, Jackson R. Stewart, Tracy Murray Casero, Robert A. Oupický, David Molecules Article Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure–activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group’s increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog. MDPI 2022-04-10 /pmc/articles/PMC9032695/ /pubmed/35458639 http://dx.doi.org/10.3390/molecules27082441 Text en © 2022 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
Sil, Diptesh
Panja, Sudipta
Jogdeo, Chinmay M.
Kumar, Raj
Yu, Ao
Holbert, Cassandra E.
Ding, Ling
Foley, Jackson R.
Stewart, Tracy Murray
Casero, Robert A.
Oupický, David
Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title_full Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title_fullStr Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title_full_unstemmed Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title_short Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents
title_sort self-assembled alkylated polyamine analogs as supramolecular anticancer agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032695/
https://www.ncbi.nlm.nih.gov/pubmed/35458639
http://dx.doi.org/10.3390/molecules27082441
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