Zafar, A, Pilkington, LI, Haverkate, NA, van Rensburg, M, Leung, E, Kumara, S, Denny, WA, Barker, D, Alsuraifi, A, Hoskins, C ORCID: https://orcid.org/0000-0002-7200-0566 and Reynisson, J (2018) Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents. Molecules, 23 (145).

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: morpholine substitution; 1H-pyrrolo[2,3-b]pyridine; molecular modelling; nano aggregates; polymer formulation
Subjects: R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 12 Jan 2018 08:56
Last Modified: 18 Mar 2019 14:09
URI: http://eprints.keele.ac.uk/id/eprint/4348

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