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Molecules 2018, 23(1), 145; https://doi.org/10.3390/molecules23010145

Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents

1
School of Chemical Sciences, University of Auckland, 23 Symonds Street, 1142 Auckland, New Zealand
2
Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, 1142 Auckland, New Zealand
3
Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK
*
Author to whom correspondence should be addressed.
Received: 18 December 2017 / Revised: 3 January 2018 / Accepted: 8 January 2018 / Published: 11 January 2018
(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)
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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. View Full-Text
Keywords: morpholine substitution; 1H-pyrrolo[2,3-b]pyridine; molecular modelling; nano aggregates; polymer formulation morpholine substitution; 1H-pyrrolo[2,3-b]pyridine; molecular modelling; nano aggregates; polymer formulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Zafar, A.; Pilkington, L.I.; Haverkate, N.A.; van Rensburg, M.; Leung, E.; Kumara, S.; Denny, W.A.; Barker, D.; Alsuraifi, A.; Hoskins, C.; Reynisson, J. Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents. Molecules 2018, 23, 145.

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