Investigation into improving the aqueous solubility of the thieno[2,3-b]pyridine anti-proliferative agents

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

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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.
Original languageEnglish
Article number145
Number of pages14
JournalMolecules
Volume23
Issue number1
DOIs
Publication statusPublished - 11 Jan 2018

Keywords

  • 1H-pyrrolo[2,3-b]pyridine
  • polymer formulation
  • nano aggregates
  • morpholine substitution
  • molecular modelling

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