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Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents
It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molec...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017400/ https://www.ncbi.nlm.nih.gov/pubmed/29324695 http://dx.doi.org/10.3390/molecules23010145 |
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author | Zafar, Ayesha Pilkington, Lisa I. Haverkate, Natalie A. van Rensburg, Michelle Leung, Euphemia Kumara, Sisira Denny, William A. Barker, David Alsuraifi, Ali Hoskins, Clare Reynisson, Jóhannes |
author_facet | Zafar, Ayesha Pilkington, Lisa I. Haverkate, Natalie A. van Rensburg, Michelle Leung, Euphemia Kumara, Sisira Denny, William A. Barker, David Alsuraifi, Ali Hoskins, Clare Reynisson, Jóhannes |
author_sort | Zafar, Ayesha |
collection | PubMed |
description | It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC(50) value of 0.5 μg/mL (1.30 μM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach. |
format | Online Article Text |
id | pubmed-6017400 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-60174002018-11-13 Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents Zafar, Ayesha Pilkington, Lisa I. Haverkate, Natalie A. van Rensburg, Michelle Leung, Euphemia Kumara, Sisira Denny, William A. Barker, David Alsuraifi, Ali Hoskins, Clare Reynisson, Jóhannes Molecules Article It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC(50) value of 0.5 μg/mL (1.30 μM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach. MDPI 2018-01-11 /pmc/articles/PMC6017400/ /pubmed/29324695 http://dx.doi.org/10.3390/molecules23010145 Text en © 2018 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 | Article Zafar, Ayesha Pilkington, Lisa I. Haverkate, Natalie A. van Rensburg, Michelle Leung, Euphemia Kumara, Sisira Denny, William A. Barker, David Alsuraifi, Ali Hoskins, Clare Reynisson, Jóhannes Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title | Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title_full | Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title_fullStr | Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title_full_unstemmed | Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title_short | Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents |
title_sort | investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017400/ https://www.ncbi.nlm.nih.gov/pubmed/29324695 http://dx.doi.org/10.3390/molecules23010145 |
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