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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-01-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1420-3049/23/1/145 |
| _version_ | 1819157053508157440 |
|---|---|
| author | Ayesha Zafar Lisa I. Pilkington Natalie A. Haverkate Michelle van Rensburg Euphemia Leung Sisira Kumara William A. Denny David Barker Ali Alsuraifi Clare Hoskins Jóhannes Reynisson |
| author_facet | Ayesha Zafar Lisa I. Pilkington Natalie A. Haverkate Michelle van Rensburg Euphemia Leung Sisira Kumara William A. Denny David Barker Ali Alsuraifi Clare Hoskins Jóhannes Reynisson |
| author_sort | Ayesha Zafar |
| collection | DOAJ |
| 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 IC50 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. |
| first_indexed | 2024-12-22T16:02:39Z |
| format | Article |
| id | doaj.art-880d214164b0497080900bd06403ec99 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-22T16:02:39Z |
| publishDate | 2018-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-880d214164b0497080900bd06403ec992022-12-21T18:20:40ZengMDPI AGMolecules1420-30492018-01-0123114510.3390/molecules23010145molecules23010145Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative AgentsAyesha Zafar0Lisa I. Pilkington1Natalie A. Haverkate2Michelle van Rensburg3Euphemia Leung4Sisira Kumara5William A. Denny6David Barker7Ali Alsuraifi8Clare Hoskins9Jóhannes Reynisson10School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandSchool of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandSchool of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandSchool of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandAuckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New ZealandAuckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New ZealandAuckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New ZealandSchool of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandInstitute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UKInstitute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UKSchool of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New ZealandIt 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 IC50 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.http://www.mdpi.com/1420-3049/23/1/145morpholine substitution1H-pyrrolo[2,3-b]pyridinemolecular modellingnano aggregatespolymer formulation |
| spellingShingle | Ayesha Zafar Lisa I. Pilkington Natalie A. Haverkate Michelle van Rensburg Euphemia Leung Sisira Kumara William A. Denny David Barker Ali Alsuraifi Clare Hoskins Jóhannes Reynisson Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents Molecules morpholine substitution 1H-pyrrolo[2,3-b]pyridine molecular modelling nano aggregates polymer formulation |
| 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 | morpholine substitution 1H-pyrrolo[2,3-b]pyridine molecular modelling nano aggregates polymer formulation |
| url | http://www.mdpi.com/1420-3049/23/1/145 |
| work_keys_str_mv | AT ayeshazafar investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT lisaipilkington investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT natalieahaverkate investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT michellevanrensburg investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT euphemialeung investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT sisirakumara investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT williamadenny investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT davidbarker investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT alialsuraifi investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT clarehoskins investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents AT johannesreynisson investigationintoimprovingtheaqueoussolubilityofthethieno23bpyridineantiproliferativeagents |